Conditions: HIV Infections
Keywords: Current antiretroviral regimen (CAR) HIV-1 Long-term antiviral activity Dolutegravir/lamivudine Fixed dose combination
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 493
Healthy volunteers: no

Brief summary:
The aim of this study is to determine if virologically suppressed Human Immunodeficiency Virus (HIV) Type 1 infected adults on a current antiretroviral regimen (CAR) (including 2 nucleoside reverse transcriptase inhibitors \[NRTIs\] plus a third agent) remain suppressed upon switching to dolutegravir/lamivudine (DTG/3TC) fixed dose combination (FDC). The main objective of the study is to demonstrate the non-inferior antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 48 weeks in virologically suppressed adults living with HIV-1. The study will also evaluate information regarding the safety and health related quality of life. The study will include Screening Phase (up to 28 days), a Randomization Phase (up to Week 52) and a Continuation Phase (post Week 52). The Continuation Phase is not applicable for participants in Sweden and Denmark. Approximately 490 participants will be randomized in 1:1 ratio to receive DTG/3TC FDC once daily for up to 52 weeks or continue their CAR for 52 weeks. Participants in the DTG/3TC FDC arm who successfully complete up to 52 weeks of treatment will have the opportunity to continue receiving DTG/3TC FDC once daily in Continuation Phase.

Detailed description:

Arms:
arm 1: Eligible participants will be randomized to receive 50 milligrams (mg)/300 mg DTG/3TC FDC therapy from Day 1 up to 52 weeks. Participants who complete 52 weeks of treatment will have the opportunity to continue receiving DTG/3TC FDC once daily in the continuation phase. arm 2: Eligible participants will continue to receive CAR from Day 1 up to 52 weeks.

Interventions: intervention 1: DTG/3TC FDC intervention 2: CAR
Intervention descriptions: intervention 1: DTG/3TC FDC will be available as white, oval, film-coated tablets at a unit dose strength of 50 mg/300 mg. Participants will take DTG/3TC once daily via oral route. intervention 2: Participants who are randomized to the CAR arm will continue to take the current treatment until Week 52. CAR will include 2 NTRIs plus either an INI, NNRTI, or boosted PI or atazanavir unboosted.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan
Study ID:  208090
Official Title of Study: Reporting and Analysis Plan Amendment 1 for A Phase III, 
randomized, multicenter, open-label, non-inferiority study evaluating the efficacy, safety 
and tolerability of switching to dolutegravir/lamivudine fixed dose combination in HIV-1 
infected adults who are virologically suppressed
Date of Document: 29-Sep-2022


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
208090 
1 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan Amendment 1 for A Phase III, 
randomized, multicenter, open-label, non-inferiority study 
evaluating the efficacy, safety and tolerability of switching 
to dolutegravir/lamivudine fixed dose combination in HIV-
1 infected adults who are virologically suppressed  
Compound Number  : GSK1349572+GR109714 (GSK3515864) 
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 208090 (SALSA). 
• 
This RAP will be provided to the study team members to convey the content of 
the 208090 Statistical Analysis Complete (SAC) deliverables for the reporting 
effort up to Week 52.  
• 
This version of the RAP amendment 1 (to the originally approved RAP dated 03-
Nov-2020) is to provide details on the Final End of Study (EOS) analysis. 
 
 
RAP Author(s): 
Author  
Date 
Lead 
 
14-Sep-2022 
Associate Statistician, Biostatistics 
 
 
 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


 
CONFIDENTIAL 
 
 
208090 
2 
RAP Team Review Confirmations  
(Method: E-mail) 
Reviewer  
Date 
  
19-Sep-2022 
Medicine Development Leader, ViiV 
  
21-Sep-2022 
, ViiV 
 
16-Sep-2022 
Manager, Data Management, GSK 
  
20-Sep-2022 
Clinical Development Manager, GSK 
 
21-Sep-2022 
, GSK 
 
, GSK 
16-Sep-2022 
  
20-Sep-2022 
, Clinical Development, ViiV 
  
20-Sep-2022 
Clinical Development Investigator, ViiV 
  
19-Sep-2022 
, Global Health Outcomes Teams, ViiV 
 
21-Sep-2022 
Principal Programmer, Clinical Programming, GSK 
  
20-Sep-2022 
Clinical Development Leader, ViiV 
Clinical Statistics & Clinical Programming Line Approvals  
(Method: Pharma eTMF eSignature) 
Approver 
Date 
 
29-Sep-2022 
Principal Statistician, Biostatistics 
  
29-Sep-2022 
, Clinical Programming 
 
The main changes included in RAP Amendment 1 are listed in Section 15.16 Appendix 
16 – Final (End of Study) Analysis 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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CONFIDENTIAL 
 
 
208090 
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 ................................................. 9 
3. 
PLANNED ANALYSES .......................................................................................... 10 
3.1. 
Interim Analyses ......................................................................................... 10 
3.2. 
Final Analyses ............................................................................................ 10 
4. 
ANALYSIS POPULATIONS ................................................................................... 11 
4.1. 
Protocol Deviations ..................................................................................... 12 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 14 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 14 
5.2. 
Baseline Definitions .................................................................................... 14 
5.3. 
Multicentre Studies ..................................................................................... 14 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 14 
5.4.1. 
Covariates and Other Strata ........................................................ 14 
5.4.2. 
Examination of Subgroups ........................................................... 16 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 18 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 18 
6. 
STUDY POPULATION ANALYSES ....................................................................... 19 
6.1. 
Overview of Planned Study Population Analyses ........................................ 19 
7. 
EFFICACY ANALYSES .......................................................................................... 21 
7.1. 
Primary Efficacy Analyses .......................................................................... 21 
7.1.1. 
Endpoint / Variables ..................................................................... 21 
7.1.2. 
Summary Measure ...................................................................... 21 
7.1.3. 
Population of Interest ................................................................... 21 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 21 
7.1.5. 
Statistical Analyses / Methods ..................................................... 22 
7.2. 
Secondary Efficacy Analyses ...................................................................... 25 
7.2.1. 
Endpoint / Variables ..................................................................... 25 
7.2.2. 
Summary Measure ...................................................................... 25 
7.2.3. 
Population of Interest ................................................................... 25 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 25 
7.2.5. 
Statistical Analyses / Methods ..................................................... 26 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 30 
8. 
SAFETY ANALYSES ............................................................................................. 30 
8.1. 
Adverse Events Analyses ........................................................................... 30 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 32 
8.3. 
Clinical Laboratory and Biomarker Analyses ............................................... 33 


 
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208090 
4 
8.3.1. 
Lipid Parameters Analyses .......................................................... 35 
8.3.2. 
HOMA-IR and HbA1c Analyses ................................................... 37 
8.3.3. 
Bone Biomarkers Analyses .......................................................... 39 
8.3.4. 
Renal Biomarkers Analyses ......................................................... 40 
8.3.5. 
Inflammatory Biomarkers Analyses .............................................. 41 
8.4. 
Other Safety Analyses ................................................................................ 43 
8.4.1. 
Weight and BMI Analyses ............................................................ 45 
9. 
OTHER STATISTICAL ANALYSES ....................................................................... 46 
9.1. 
Health Outcomes ........................................................................................ 46 
9.1.1. 
Overview of Planned Analyses .................................................... 46 
9.1.2. 
Planned Health Outcomes Statistical Analyses ............................ 46 
9.2. 
Virology ...................................................................................................... 48 
9.2.1. 
Overview of Planned Analyses .................................................... 48 
9.2.2. 
Planned Virology Statistical Analysis ........................................... 48 
10. PHARMACOKINETIC ANALYSES ......................................................................... 50 
11. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 50 
12. PHARMACODYNAMIC ANALYSES....................................................................... 50 
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 50 
14. REFERENCES ....................................................................................................... 51 
15. APPENDICES ........................................................................................................ 53 
15.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 54 
15.1.1. 
Exclusions from Per Protocol Population ..................................... 54 
15.2. 
Appendix 2: Schedule of Activities .............................................................. 56 
15.2.1. 
Protocol Defined Schedule of Events ........................................... 56 
15.3. 
Appendix 3: Assessment Windows ............................................................. 61 
15.3.1. 
Definitions of Assessment Windows for Analyses ........................ 61 
15.4. 
Appendix 4: Study Phases and Emergent Adverse Events ......................... 63 
15.4.1. 
Study Phases .............................................................................. 63 
15.4.2. 
Combining Treatment Phases and States .................................... 67 
15.4.3. 
Emergent Flag for Adverse Events .............................................. 68 
15.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 69 
15.5.1. 
Reporting Process ....................................................................... 69 
15.5.2. 
Reporting Standards .................................................................... 69 
15.6. 
Appendix 6: Derived and Transformed Data ............................................... 71 
15.6.1. 
General ........................................................................................ 71 
15.6.2. 
Study Population .......................................................................... 72 
15.6.3. 
Efficacy ........................................................................................ 74 
15.6.4. 
Safety .......................................................................................... 76 
15.6.5. 
Viral Genotyping and Phenotyping ............................................... 82 
15.6.6. 
Health Outcomes ......................................................................... 90 
15.6.7. 
Cut-off date for protocol deviations .............................................. 93 
15.6.8. 
eCRF Baseline Third Agent Class Determination ......................... 94 
15.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 95 
15.7.1. 
Premature Withdrawals ................................................................ 95 
15.7.2. 
Handling of Missing Data ............................................................. 96 


 
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208090 
5 
15.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 98 
15.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 99 
15.10. Appendix 10: Time to Event Details .......................................................... 100 
15.10.1. TRDF Detailed Steps ................................................................. 100 
15.10.2. TRDF Detailed Steps for the Kaplan-Meier plot ......................... 105 
15.10.3. ERDF Detailed Steps ....................................................................... 108 
15.11. Appendix 11: Snapshot Algorithm Details ................................................. 109 
15.12. Appendix 12: Modified Snapshot Algorithm Details ................................... 114 
15.13. Appendix 13: Abbreviations & Trade Marks .............................................. 118 
15.13.1. Abbreviations ............................................................................. 118 
15.13.2. Trademarks ............................................................................... 119 
15.14. Appendix 14: Model Checking and Diagnostics for Statistical 
Analyses ................................................................................................... 120 
15.14.1. Statistical Analysis Assumptions ................................................ 120 
15.15. Appendix 15: Test of Homogeneity: Fleiss, Liu & Kelly Method ................. 121 
15.15.1. Statistical Analysis Method for Test of Homogeneity by 
Fleiss, Liu & Kelly ...................................................................... 121 
15.16. Appendix 16: Final (End of Study) Analysis .............................................. 122 
15.16.1. Study Phases ............................................................................ 122 
15.16.2. Analysis Populations for the Continuation Phase ....................... 123 
15.16.3. Study Population ........................................................................ 123 
15.16.4. Efficacy Analysis ........................................................................ 123 
15.16.5. Safety Analysis .......................................................................... 124 
15.16.6. Virology Analysis ....................................................................... 124 
15.16.7. COVID - 19 analysis .................................................................. 125 
15.16.8. Other Analyses (Health Outcomes) ............................................ 125 
15.16.9. List of Data Displays for End of Study (EOS) Final Report ......... 125 
15.17. Appendix 17: List of Data Displays............................................................ 132 
15.17.1. Data Display Numbering ............................................................ 132 
15.17.2. Mock Example Shell Referencing .............................................. 132 
15.17.3. Deliverables ............................................................................... 132 
15.17.4. Study Population Tables ............................................................ 133 
15.17.5. Study Population Figures ........................................................... 137 
15.17.6. Efficacy Tables .......................................................................... 137 
15.17.7. Efficacy Figures ......................................................................... 141 
15.17.8. Safety Tables ............................................................................. 142 
15.17.9. Safety Figures ........................................................................... 150 
15.17.10. Virology Tables .......................................................................... 152 
15.17.11. Pharmacokinetic Tables ............................................................. 153 
15.17.12. Pharmacokinetic Figures ........................................................... 153 
15.17.13. Health Outcomes Tables ........................................................... 153 
15.17.14. Health Outcomes Figures .......................................................... 155 
15.17.15. ICH Listings ............................................................................... 156 
15.17.16. Non-ICH Listings ........................................................................ 159 
15.18. Appendix 18: Example Mock Shells for Data Displays .............................. 166 
 


 
CONFIDENTIAL 
 
 
 
208090 
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 208090. The RAP is based on the 
following 208090 protocol versions Amendment 04 (05May2020), Amendment 04/CHI-
1(20May2020) 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The following changes were made to the agreed upon sections in the protocol [(Dated: 14 
NOV 2018)]. 
Section # and Name 
Description of Change and Rationale 
Exploratory 
Objective/Endpoints: 
• 
Protocol Section 
3.0 
 
• 
Addition of an exploratory objective/endpoints that were not specified in 
the protocol Section 3.0. 
o Objective:   
o To evaluate the effect of subject characteristics (e.g., 
demographic factors, Baseline CD4) on antiviral and 
immunological responses to DTG/3TC compared to CAR 
 
o Endpoints:  
o Proportion of subjects by subgroups with plasma HIV-1 RNA 
<50 c/mL using the Snapshot algorithm at Weeks 24 and 48 
o Change from Baseline in CD4+ cell counts at Weeks 24 and 
48 by patient subgroups 
 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) 
Objectives 
Estimands / Endpoints 
Primary  
Primary  
To demonstrate the non-inferior antiviral 
activity of switching to DTG/3TC FDC once 
daily compared to continuation of CAR 
over 48 weeks in virologically suppressed 
adults living with HIV-1 
Proportion of subjects with plasma HIV-1 RNA ≥50 c/mL) 
endpoint as per FDA snapshot category at Week 48 using the 
Snapshot algorithm for the ITT-E population  
Secondary  
Secondary  
To demonstrate the antiviral activity of 
switching to DTG/3TC FDC once daily 
compared to continuation of CAR over 48 
weeks 
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at 
Week 48 using the Snapshot algorithm for the ITT-E 
population 
To evaluate the antiviral activity of 
switching to DTG/3TC FDC once daily 
compared to continuation of CAR over 24 
weeks 
• 
Proportion of subjects with plasma HIV-1 RNA ≥50 c/mL) 
endpoint as per FDA snapshot category at Week 24 
• 
Proportion of subjects with plasma HIV-1 RNA <50 c/mL 
at Week 24 using the Snapshot algorithm for the ITT-E 
population 


 
CONFIDENTIAL 
 
 
 
208090 
7 
Objectives 
Estimands / Endpoints 
To evaluate the immune effects of 
DTG/3TC FDC once daily compared to 
continuation of CAR 
• 
Change from Baseline in CD4+ cell count and in 
CD4+/CD8+ cell counts ratio at Weeks 24 and 48 
• 
Incidence of disease progression (HIV-associated 
conditions, AIDS, and death) through Weeks 24 and 48 
To evaluate the safety and tolerability of 
DTG/3TC FDC once daily compared to 
CAR over time 
• 
Incidence and severity of adverse events (AEs) and 
laboratory abnormalities  
• 
Proportion of subjects who discontinue treatment due to 
AEs 
To evaluate the safety and tolerability of 
DTG/3TC FDC once daily in those with 
creatinine clearance of between 30-
49 mL/min/1.73m2 compared to those with 
a creatinine clearance of 50 
mL/min/1.73m2 
 
• 
Incidence and severity of AEs and laboratory 
abnormalities  
• 
Proportion of subjects who discontinue treatment due to 
AEs 
To evaluate the effects of DTG/3TC FDC 
once daily on fasting lipids over time 
compared to CAR 
Change from Baseline in fasting lipids at Weeks 24 and 48 
To assess viral resistance in participants 
meeting Confirmed Virologic Withdrawal 
(CVW) Criteria 
Incidence of observed genotypic and phenotypic resistance to 
ARVs for participants meeting CVW Criteria 
To assess health related quality of life for 
participants treated with DTG/3TC FDC 
compared to CAR 
Change from Baseline in health status using HIV TSQ at 
Weeks 24 and 48 (or Withdrawal from the study) and SDM at 
Weeks 24, 48 and every 24 weeks during the continuation 
phase (or Withdrawal from the study) 
Tertiary/Exploratory  
Tertiary/Exploratory  
To assess willingness to switch for 
participants treated with DTG/3TC FDC 
compared to CAR 
Reasons for Willingness to Switch at Day 1 
To evaluate renal (in urine and blood), 
bone (in blood), inflammatory (in blood) 
biomarkers and insulin resistance in 
participants treated with DTG/3TC FDC 
compared to CAR 
Change from Baseline in renal, bone and inflammatory 
biomarkers and homeostasis model of assessment-insulin 
resistance (HOMA-IR) at Weeks 24 and 48 
To evaluate biomarkers of telomerasea 
function in participants treated with 
DTG/3TC FDC compared to CAR. 
Change from baseline in biomarkers of telomerase function at 
Week 48 
a Separate RAP and report will be produced for biomarkers of telomerase 
 


 
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208090 
8 
2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
This is a 52-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group non-inferiority study.  The study will include a Screening Phase (up to 
28 days), a Randomized Phase (Day 1 up to Week 52), and a Continuation Phase 
(post Week 52).   
Dosing 
• 
Patients receiving DTG/TC will receive DTG (50mg)/3TC (300mg) FDC once daily.  
Patients receiving CAR will receive the dose as determined by their prescribing 
physician.    
Time & 
Events 
• 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• 
Approximately 490 subjects who are stable on CAR will be randomized 1:1 to 
switch to DTG/3TC FDC once daily (DTG/3TC arm) for up to 52 weeks, or to 
continue their CAR for 52 weeks (if HIV1 RNA <50 c/mL at Week 48 (or at Week 52 
if re-tested)) 
Interim 
Analysis 
• 
An analysis will be conducted to evaluate the primary objective of the protocol when 
all subjects have completed their Week 48 visit and any HIV-1 RNA re-tests as 
appropriate.  An interim analysis will be conducted when all subjects have 
completed their Week 24 visit and any HIV-1 RNA re-tests as appropriate (see 
Blinding Agreement for more details).  To minimise bias, the Week 24 results will 
not be shared with subjects and investigators, or presented externally until after the 
last subject completes their Week 48 visit 
Sub-study 
• 
A sub-study is planned in this study that will evaluate and determine the virologic 
response to subsequent regimens of subjects in DTG/3TC FDC arm with HIV-1 
RNA ≥ 50 c/mL. The evaluation period will start from the time the subjects is 
discontinued from the 208090 study for confirmed virologic withdrawal (CVW) or 
precautionary virologic withdrawal (PVW) criteria while on DTG/3TC FDC and will 
last for up to 12 months. A sub-study RAP will be developed in a separate 
document. 
See study protocol for further details 
 


 
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208090 
9 
2.4. 
Statistical Hypotheses / Statistical Analyses 
This study is designed to show that the antiviral effect of switching to a simplified two-
drug regimen of DTG/3TC FDC once-daily is non-inferior to continuation on CAR. 
Non-inferiority in the proportion of subjects with plasma HIV-1 RNA ≥ 50 c/mL at Week 
48 as measured by using the FDA (Food and Drug Administration) Snapshot algorithm 
(see Appendix 11), can be concluded if the upper bound of a two-sided 95% confidence 
interval for the difference in the proportion of subjects with plasma HIV-1 RNA ≥ 50 
c/mL between the two treatment arms (DTG/3TC - CAR) is less than 5%. If rd is the 
response rate on DTG/3TC and rc is the response rate on CAR, then the hypotheses can 
be written as follows: 
H0:  rd – rc ≥ 5%                   H1: rd – rc < 5% 


 
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208090 
10 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
An interim analysis will be performed at Week 24. To minimise bias, the results of the 
Week 24 results will not be shared with subjects and investigators or presented externally 
until after the last subject completes their Week 48 visit. Please refer to the Blinding 
Agreement for more details. 
The planned analysis at Week 24 will be performed after the completion of the following 
sequential steps: 
• Last subject has completed their visit at Week 24 as defined in the protocol, 
including any re-test as appropriate.  
• All required database cleaning activities have been completed and, final database 
release and database freeze have been declared by Data Management. 
• All criteria for unblinding1 the randomization codes at Week 24 have been met.  
No adjustment for multiplicity will be made as the Week 24 analyses will be secondary, 
however non-inferiority at Week 24 will be declared if the upper bound of a two-sided 
95% confidence interval for the difference in HIV-1 RNA ≥ 50 c/mL rates between the 
two treatment arms is less than 5%2. 
An IDMC is instituted to ensure external objective medical and/or statistical review of 
efficacy and safety to protect the ethical interests and well-being of subjects and to 
protect the scientific validity of the study. An ad-hoc review of data by the IDMC will be 
triggered whenever the number of confirmed virologic withdrawals (CVWs) exceeds 
thresholds pre-specified in the IDMC charter. Full details of the methods, timing, 
decision criteria and operating characteristics are pre-specified in the IDMC Charter. 
Details of the analyses and outputs provided to the IDMC are detailed in an IDMC RAP.  
1. Note that analyses for time points will be performed when subjects complete visits relevant to that time point i.e. 
Week 24 analysis takes place when the last patient has completed their Week 24 visit.. 
2. Please refer to Section 7.1.5.1 for details and conditions for presentation of test for superiority 
 
3.2. 
Final Analyses 
The primary analysis is at Week 48. An additional analysis will be performed at the end 
of the continuation phase .  
The planned analyses at Weeks 48 and end of continuation phase3 will be performed after 
the completion of the following sequential steps: 
• Last subject has completed their relevant visit at week 48 (or end of continuation) 
as defined in the protocol, including any re-test as appropriate.  
• All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 


 
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208090 
11 
• All criteria for unblinding the randomization codes at Week 48 have been met.  
Further data cuts and analyses may be conducted as necessary in support of regulatory 
submissions and publications.  
The Sub-study analyses will be covered by separate RAPs. 
3.  Note that analyses for time points will be performed when subjects complete visits relevant to that time point i.e. 
Week 48 analysis takes place when the last patient has completed their Week 48 visit, and not when they have 
completed their Week 48 and end of continuation phase. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• 
Comprises Screened for inclusion in the study, 
including screen-failures. 
• 
This population will be based on the treatment to 
which the subject was randomized. Screen-failures 
will be categorised as “Non-randomized”. 
• 
Study Population 
Randomized 
• 
The Randomized population will consist of all 
subjects who are randomized in the study 
• 
Any subject who receives a treatment 
randomization number will be considered to have 
been randomized. 
• 
Study Population 
 
Intent-to-Treat 
(ITT) 
• 
Comprises all randomized subjects 
• 
Subjects will be assessed according to the 
treatment to which the subject was randomized 
regardless of treatment they actually received. 
• 
Any subject receiving a treatment randomization 
number will be considered to be randomized. 
• 
Efficacy (sensitivity 
analyses) 
 
Intent-To-Treat 
Exposed (ITT-E) 
• 
Comprises all randomized subjects who receive at 
least one dose of study treatment either DTG/3TC 
or CAR. 
• 
This population will be based on the treatment to 
which the subject was randomized. 
• 
 Study Population, 
Efficacy and Health 
Outcomes 
 
Per-Protocol (PP) 
• 
This population will consist of subjects in the ITT-E 
Population with the exception of significant protocol 
violators. 
• 
Protocol deviations that would exclude subjects 
from the PP population are defined in Section 4.1 
(Protocol Deviations) and Appendix 1 (Protocol 
Deviation Management and Definition for Per-
Protocol Population). 
 
• 
Efficacy (Sensitivity 
Analysis) 
CVW 
• 
Comprises all subjects in the ITT-E population who 
have met the derived CVW criteria (see  Section 
15.6.3) 
• 
Genotypic 
• 
Phenotypic 


 
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208090 
12 
Population 
Definition / Criteria 
Analyses Evaluated 
• 
Efficacy  
 
potential 
Precautionary 
Virologic 
Withdrawal 
(pPVW) 
• 
Comprises subjects in the ITT-E population having 
2 consecutive measurements between 50 and 200 
c/mL. The current HIV-1 RNA values must be 
below 200 c/mL, but the previous HIV-1 RNA can 
also have been >=200 c/mL 
• 
Genotypic 
• 
Phenotypic 
Safety 
• 
Comprises all subjects who receive at least one 
dose of study treatment either DTG/3TC or CAR. 
• 
This population will be based on the treatment the 
subject actually received4. 
• 
Safety 
 
1. NOTES:  
• 
Please refer to Appendix 17: List of Data Displays which details the population to be used for each display 
being generated. 
4. As recorded on IVRS. If the randomized treatment is incorrect, the actual treatment will only be recorded in IVRS 
through sponsor intervention 
 
4.1. 
Protocol Deviations 
Term 
Definition 
Study Deviation Rules 
Document 
The document describing study deviations (and associated coding/naming 
conventions) that may be identified during a study and the frequency of study 
deviation reviews. 
Protocol Deviation 
(PD) 
Any departure from study-specific requirements specified in a protocol. 
Subsets of protocol deviations are categorized as important or significant. 
 
Important Protocol 
Deviations 
A subset of protocol deviations that may significantly impact the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a 
subject's rights, safety, or well-being.  All important deviations have a Violation 
Flag in CTMS and are associated with a Rule Number. 
Significant Protocol 
Deviations 
Considered a subset of important protocol deviations, typically impacting 
efficacy assessments, which lead to the exclusion from the per-protocol 
population. All significant deviations are captured in CTMS and are associated 
with a Rule Number. 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management , patient assessment) will be 
summarised and listed. 


 
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208090 
13 
Separately, important deviations which result in exclusion from analysis populations and 
events that results in exclusion from the analysis population will be summarised and 
listed (see Appendix 1).  
The COVID-19 Pandemic has the potential to impact subject visit completion. This may 
result in PDs being reported which are related to COVID-19 rather than study non-
compliance by subjects or sites. As a result, all COVID-19 specific PDs identified using 
“COVID-19” prefix as defined in the protocol deviations specification document will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Deviation Rule Document.  
o Data will be reviewed prior to unblinding and freezing of the database with the 
aim of capturing and categorising all important deviations. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
 
 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Description 
Order [1] 
DTG/3TC  
1 
CAR 
2 
NOTES: 
1. Order represents treatments being presented in TFL, as appropriate. 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. DTG/3TC vs CAR 
5.2. 
Baseline Definitions 
For all endpoints (unless otherwise stated) the baseline value will be the latest pre-dose 
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.  
Unless otherwise stated, if baseline data are missing no derivation will be performed and 
baseline will be set to missing. 
Unless otherwise specified, the baseline definitions specified in the table below will be 
used for derivations for endpoints/parameters and indicated on summaries and listings. 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
% Change from Baseline 
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline] 
 
5.3. 
Multicentre Studies 
Data will be summarised for all centres combined. Country will be included as an 
exploratory subgroup for analyses of specific endpoints.   
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
• 
 Table 1 presents the covariates that may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. 
• 
Additional covariates of clinical interest may also be considered.  
 
 


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 Table 1 
List of Covariates for Descriptive Summaries and Statistical Analyses 
Details 
Endpoints 
 
Renal 
Biomarkers 
Bone 
Biomarkers 
Inflammatory 
Biomarkers 
HOMA-IR , 
HbA1c 
Weight, 
BMI/Lipids 
HO (SDM and 
HIVTSQ) 
Randomization is stratified by baseline third agent class: 
 
• 
Baseline third agent class (PI, INI,  NNRTI). 
for analysis purposes, randomization strata will be derived using 
eCRF data, even if this differs from the strata captured in IVRS 
(details of how this is derived can be found in Section 15.6.8) 
 
All statistical analyses will adjust for the above randomization strata, 
unless stated otherwise.  Treatment-by-Strata interactions will be 
assessed as specified in the analysis sections. 
Y 
Y 
Y 
Y 
Y 
Y 
Age (years): (Continuous) 
Y 
Y 
Y 
Y 
Y 
Y 
Gender: Male & Female 
Y 
Y 
Y 
Y 
Y 
Y 
Baseline CD4+ cell count (continuous) 
Y 
Y 
Y 
Y 
Y 
 
Race (White, Black or African American, Asian, Other) 
Y 
Y 
Y 
Y 
Y 
Y 
BMI (continuous) 
Y 
Y 
Y 
Y 
 
 
Smoking status (Never vs. Former vs. Current Smoker) 
 
Y 
Y 
 
 
 
Diabetes mellitus (Yes vs. No) 
Y 
 
 
Y (for 
HbA1c) 
 
 
Hypertension (Yes vs. No) 
Y 
 
 
Y 
 
 
HCV-coinfection (Yes vs. No) 
 
 
Y 
 
 
 
Baseline value of the endpoint*  
Y 
Y 
Y 
Y 
Y 
Y 
* Baseline value will be continuous, and if the outcome is log-transformed the baseline value will be log-transformed as well 
 
 
 


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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 subjects is small within a subgroup, then the subgroup categories 
may be refined prior to unblinding the trial. 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.  
Subgroup 
Subgroups 
Randomization Strata  
Randomization is stratified by baseline third agent class: 
 
• Baseline third agent class (PI, INI, NNRTI). 
 
For analysis purposes, randomization strata will be derived 
using eCRF data, even if this differs from the strata captured in 
IVRS 
 
All statistical analyses will adjust for the above randomization 
strata, unless stated otherwise.  Treatment-by-Strata 
interactions will be assessed as specified in the analysis 
sections. 
Demographic and Baseline 
Characteristics 
• Age (years):   
o <35, 35 - 49, ≥50, and <50 vs. ≥50 
o <60 and ≥60 may also be performed if specifically 
required for regulatory purposes 
• Gender: Male & Female 
• Race:  
o White, Black or African American, Asian, Other  
o White, Non-White  
• Country 
• Baseline CD4+ cell count: 
o <500, ≥500 cells/mm3 
• CDC HIV-1 classification 
o HIV infection stage 0  
o HIV infection stage 1 
o HIV infection stage 2 
o HIV infection stage 3 (AIDS) 
o HIV infection stage unknown 
• Baseline Creatinine Clearance 
o 30-49 mL/min/1.73m2 
o 50 mL/min/1.73m2 


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208090 
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Subgroup 
Subgroups 
• Baseline concerns with long-term side effects of their 
current ART (PCLTT): (Yes/No) * 
* Subgroup is for Health outcome analysis. This is derived from Willingness to switch questionnaire with baseline 
response given as "Concerned about long-term side effects" as the reason for willingness to participate in a 
clinical study where their current HIV medication may be switched. 
 
Subgroup analyses for endpoints will be presented as shown in the Table 2. 
Table 2 
List of Subgroup Variables for Descriptive Summaries and 
Statistical Analyses 
 
Endpoint 
Subgroup 
Proportion 
of patients 
with 
plasma 
HIV-1 RNA 
<501 c/mL2 
Summary 
of Study 
Snapshot 
outcomes 
(Plasma 
HIV-1 
RNA ≥/< 
50 c/mL) 
CD4+ Cell 
Count and 
CD4+/CD8+ 
Ratio 
Change 
from 
Baseline 
AEs3 Clinical 
Chemistry, 
Hematology 
and Liver 
Chemistries 
HO 
(SDM 
and 
HIVTSQ) 
Baseline third agent class (PI, INI, 
NNRTI,) 
Y 
Y 
Y 
Y 
 
Y 
Age (years): <35, 35 - 49, ≥50  
Y 
Y 
Y 
Y 
 
 
Age (years): <50, ≥50 
Y 
Y 
 
 
 
 
Gender: Male & Female 
Y 
Y 
Y 
Y 
 
 
Country  
Y 
Y 
 
 
 
 
Race: White, Black or African 
American, Asian, Other 
Y 
Y 
Y 
Y 
 
 
Race: White, non-white 
Y 
Y 
Y 
 
 
 
Baseline CD4+ cell count:  <500, ≥500 
cells/mm3 
Y 
Y 
Y 
Y 
 
 
CDC HIV-1 classification:: HIV 
infection stage 0, 1, 2, 3 (AIDS), 
Unknown 
Y 
Y 
Y 
Y 
 
 
Baseline Creatinine Clearance: 30-
49 mL/min/1.73m2,  50 
mL/min/1.73m2 
 
 
 
Y 
Y 
 
Baseline concerns about long-term 
side effects of their current HIV 
regimen (PCLTT): (Yes/No) 
 
 
 
 
 
Y 
1. 
A sensitivity analysis will also be performed for the following endpoint: HIV-1 RNA <40 c/mL and Target Not 
Detected Status. See Section 7.2.5 for more details. 
2. 
Includes forest plot for unadjusted difference of patients with plasma HIV 1 RNA <50 c/mL between treatment 
arms. 


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208090 
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3. 
Subgroup analyses will be presented for the following analyses: Adverse Events by System Organ Class (see 
Appendix 17 Full Data Displays for more information) 
 
5.5. 
Multiple Comparisons and Multiplicity 
The primary comparison of interest is the comparison between DTG/3TC and CAR for 
the primary endpoint in the ITT-E population. This analysis will be adjusted for by the 
actual stratification factor as determined from the eCRF data (not as recorded in IVRS) 
randomisation. 
No adjustment for multiplicity is required as there is only one primary comparison of 
interest.  
5.6. 
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 
Section 15.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
Section 15.2 
Appendix 2: Schedule of Activities 
Section 15.3 
Appendix 3: Assessment Windows 
Section 15.4 
Appendix 4: Study Phases and Emergent Adverse Events 
Section 15.5 
Appendix 5: Data Display Standards & Handling Conventions 
Section 15.6 
Appendix 6: Derived and Transformed Data 
Section 15.7 
Appendix 7: Reporting Standards for Missing Data 
Section 15.8 
Appendix 8: Values of Potential Clinical Importance 
Section 15.9 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Section 15.10 
Appendix 10: Time to Event Details 
Section 15.11 
Appendix 11: Snapshot 
Section 15.12 
Appendix 12: Modified Snapshot 
Section 15.13 
Appendix 13: Abbreviations & Trade Marks 
Section 15.14 
Appendix 14: Model Checking and Diagnostics for Statistical Analyses 
Section 15.15 
Appendix 15: Test of Homogeneity: Fleiss, Liu & Kelly Method 
Section 15.16 
Appendix 16: Final (End of Study) analysis 
Section 15.17 
Appendix 17: List of Data Displays 
Section 15.18 
Appendix 18: Example Mock Shells for Data Displays 
 
 


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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Intent-To-Treat Exposed (ITT-E) 
population, unless otherwise specified. 
Table 3 provides an overview of the planned study population analyses, with full details of 
data displays being presented in Appendix 17: List of Data Displays. 
Table 3 
Overview of Planned Study Population Analyses 
Display Type 
Data Displays Generated 
Table 
Listing 
Randomization 
Randomization 
 
Y [1] 
Misrandomized Strata or Treatment 
Y 
 
Subject Disposition 
Subjects Enrolled by Country and Site ID [2] 
Y 
Y 
Subjects Enrolled by Country and Site ID relative to 
COVID-19 Pandemic measures 
Y 
 
Country Level Listing of Start Dates of COVID-19 
Pandemic Measures 
 
Y 
History of Rescreened Subjects [2] 
 
Y 
Reasons for Screen Failure [2]  
Y 
Y 
Subject Disposition 
Y [3,4] 
 
Subject Status and Subject Disposition by 
Relationship to COVID-19 Pandemic 
Y 
 
Treatment Status and Reasons for Discontinuation of 
Study Treatment by relationship to COVID-19 
Pandemic 
Y 
 
Reasons for Withdrawal by Visit 
Y 
Y 
Study Visit Dates   
 
Y 
Visits Impacted by COVID-19 Pandemic[11] 
Y 
Y 
Populations Analysed 
Study Populations [2] 
Y 
Y 
Protocol deviations 
Important Protocol Deviations by Relationship to 
COVID-19 
Y 
Y 
Deviations leading to exclusion from PP 
Y 
Y 
Inclusion and Exclusion Criteria Deviations 
 
Y 


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208090 
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Display Type 
Data Displays Generated 
Table 
Listing 
Non-Important Protocol Deviation Related to COVID-
19 
 
Y 
Demography and baseline characteristics 
Demographic Characteristics [5] 
Y 
Y 
Summary of Age Ranges 
Y 
 
Race & Racial Combinations [6] 
Y  
Y 
Hepatitis C Status 
Y 
Y 
CDC Classification of HIV infection at Baseline 
Y 
Y 
HIV Risk Factor 
Y 
Y 
Cardiovascular Risk Assessments at Baseline 
Y 
Y 
Distribution of CD4+ Cell Counts 
Y 
 
Distribution of HIV-1 RNA (c/mL) 
Y 
 
Distribution of CD4+/CD8+ cell count ratio 
Y 
Y 
Medical Conditions, Concomitant Medications & Antiretroviral Therapy 
Medical Conditions (Current and Past)  
Y  
Y 
Medical Conditions: Sub-conditions (Current/Past)  
Y  
 
Concomitant Medications (non-ART) 
Y [7] 
Y [8] 
Prior and Concomitant ART Medications 
Y 
Y [9]  
Baseline third agent class (Strata) [10] 
Y 
Y 
Lipid Modifying agents (Baseline and Post-Baseline) 
Y 
 
Other  
History of Depression and Anxiety at Baseline 
Y 
 
1. NOTES: 
• 
Y = Display Generated, T = Tables, L = Listings, IP = Investigational Product 
1. 
ITT-E. One listing of subjects randomized but not treated, and one listing of planned and actual treatment strata. 
2. 
Screened population. 
3. 
Subject Accountability by Phase (Overall, Randomized Phase, Continuation Phase) 
4. 
Subjects who have not been recorded as withdrawing from the study in the respective phase will be categorized 
as “Ongoing at time of the analysis” for summary purposes. 
5. 
Age, sex, ethnicity, weight, height, BMI (kg/m^2) and child-bearing potential collected at screening. 
6. 
The five high level FDA race categories and designated Asian subcategories will be summarised along with all 
combinations of high level categories which exist in the data. The nine race categories collected will be 
summarised along with categories for mixed race. A by-subject listing of race will also be produced. 
7. 
Summarised by Ingredient ATC Level 1 
8. 
One listing for concomitant non-ART medications and one listing showing the relationship between verbatim text, 
ingredient and ATC Level 1. 
9. 
One listing for Prior ART, one listing for concomitant ART and one listing showing the relationship between 
verbatim text, ingredient, combination and ATC Level 4. 
10. Based on the actual third agent class that subjects were classified into according to data captured on the eCRF. 
11. Visits impacted by COVID-19 Pandemic will also be presented by stacked bar chart 
 


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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
The primary treatment effect to be estimated will be the effect on the composite virologic 
outcome at Week 48,  using the FDA (Food and Drug Administration) Snapshot 
algorithm.  The variable is the binary response indicating the virologic outcome category 
of plasma HIV-1 RNA ≥50 copies/mL (c/mL) at Week 48 and the summary measure is 
the difference in the percent of subjects with plasma HIV-1 RNA ≥50 c/mL at Week 48 
between each treatment group. The population is all subjects in the Intent-to-Treat 
Exposed (ITT-E) population. The individual components of the estimand are detailed as 
follows. 
7.1.1. 
Endpoint / Variables 
The primary endpoint is the percent of subjects with plasma HIV-1 RNA ≥50 c/mL at 
Week 48 using the FDA Snapshot algorithm (see Section 15.11). 
The primary endpoint is the binary response indicating the virologic outcome category of 
plasma HIV-1 RNA ≥50 c/mL at Week 48 using the FDA Snapshot algorithm (See 
Appendix 11). The other Snapshot outcomes (HIV-1 RNA <50 c/mL and no virologic 
data at Week 48 Window) will be collapsed into the non-response category. 
7.1.2. 
Summary Measure 
Difference in the percent of subjects with plasma HIV-1 RNA ≥50 c/mL at Week 48, 
defined by the FDA snapshot algorithm (see Appendix 11), between each treatment 
groups (DTG/3TC – CAR). 
 
7.1.3. 
Population of Interest  
The primary efficacy analyses will be based on the Intent-To-Treat Exposed (ITT-E) 
population (defined in Section 4) unless otherwise specified. 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
A treatment policy strategy will be used for intercurrent events such as discontinuations, 
missing plasma HIV-1 RNA samples and change in background regimen are handled 
using the Snapshot algorithm (see Section 15.11), which details how to assign each 
subject’s virologic outcome. 
 
 


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208090 
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7.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 17: List of Data Displays and 
will be based on GSK data standards and statistical principles commonly applied in GSK 
HIV-1 trials. 
Table 4 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 17: List of Data Displays. 
Table 4 
Overview of Planned Primary Efficacy Analyses 
Endpoint 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Percent of Subjects with plasma HIV 1 RNA ≥50 c/mL at week 48 – Snapshot  
Primary Analysis 
Y [1] 
 
Y  
 
 
 
 
Sparse Data 
Analysis 
Y [2] 
 
 
 
 
 
 
1. NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
2 
[1] Generated using the ‘Intent-to-Treat Exposed’ (primary), ‘Per-Protocol’ and ‘Intent-to-Treat’ (sensitivity) 
populations. 
3 
[2] See methodology section for more information. 
 
7.1.5.1. 
Statistical Methodology Specification 
Endpoint  
The binary response indicating the virologic outcome category of plasma HIV 1 RNA ≥50 c/mL 
at Week 48 using the FDA Snapshot algorithm (see Appendix 11).  
Model Specification 
The primary efficacy endpoint will be analysed using a stratified analysis for proportions with 
Cochran-Mantel-Haenszel (CMH) weights, adjusting for baseline third agent class (PI, INI, 
NNRTI). The CMH estimate of the adjusted treatment difference will be calculated as a weighted 
average of strata-specific estimates of the treatment difference calculated within each of the 
following three Baseline analysis strata: 
o Baseline third agent: PI 
o Baseline third agent: INI 
o Baseline third agent: NNRTI 
If nk is the number of DTG/3TC treated subjects, mk is the number of PI-, INI-, or NNRTI-based 
ART treated subjects, and Nk = nk + mk is the total number of subjects in the kth stratum, then 
the CMH estimate is given by: 
 


CONFIDENTIAL 
 
 
208090 
23 
 
       where, 
  
are CMH weights and dk are estimates of the differences in proportions of subjects with plasma 
HIV-1 RNA ≥50 c/mL between the two treatment arms, rDTG/3TC -rCAR, for the kth strata. 
 
The corresponding two-sided 95% CI will be calculated as 
 
Where the variance estimator (Sato ,1989) is consistent in both sparse data and large strata 
and is given below.   
 
(
)
(
)
(
)
(
)
(
)2
2
ˆ
ˆ
ˆ
raˆ
v






+
=
+
=
k
k
k
cmh
k
k
k
k
k
cmh
cmh
W
Q
P
d
N
m
n
Q
P
d
d
, 
where 
 
2
2
2
2
/)
(
k
k
k
k
k
k
k
k
k
k
N
n
m
m
n
x
m
y
n
P
−
+
−
=
 
 
2
/)
(
/)
(
k
k
k
k
k
k
k
k
k
N
x
n
y
N
y
m
x
Q
−
+
−
=
. 
With xk and yk corresponding to the number of subjects with HIV-1 RNA ≥50 c/mL at Week 
48 as determined by the FDA Snapshot algorithm (See Appendix 11) for treatment and 
comparator, respectively, for the kth stratum. 
Model Checking & Diagnostics 
Not applicable 
Model Results Presentation 
Adjusted CMH estimate of the difference in the proportion of subjects with plasma HIV-1 RNA ≥ 
50 c/mL between each treatment group (DTG/3TC – CAR) and corresponding 95% confidence 
interval will be presented. 
Non-inferiority will be concluded if the upper bound of the two-sided 95% confidence interval (CI) 
for the CMH adjusted difference in the proportion of patients with plasma HIV-1 RNA ≥ 50 c/mL 


=
k
k
k
cmh
W
d
W
d
ˆ
ˆ
 
k
k
k
k
N
m
n
W
=
 
)
ˆ
r(
aˆ
v
96
.1
ˆ
cmh
cmh
d
d




CONFIDENTIAL 
 
 
208090 
24 
between each treatment group (DTG/3TC – CAR) is less than 5%.  The p-value for non-
inferiority based on a non-inferiority margin of 5% will also be presented. 95% confidence 
intervals for the percent of subjects with virologic failure by treatment group. 
If the analysis shows non-inferiority, then a superiority hypothesis will be tested at the two-sided 
5% level of significance. Superiority favoring DTG/3TC will be declared if the upper bound of 
two-sided confidence interval is below 0%. If superiority is declared, the p-value for superiority 
will also be presented. 
 
Subgroup Analyses 
•  Subgroup analyses will not be performed for this endpoint 
Sensitivity and Supportive Analyses 
1. Per-Protocol population analysis: 
• To assess the impact of significant protocol deviations, statistical analysis will be 
repeated using the Per-protocol population and compared for consistency with the 
results from the primary ITT-E population analysis.  If both analyses show non-inferiority 
then the hypothesis that the antiviral effect of treatment with DTG/3TC is superior to 
treatment with CAR will be tested at the two-sided 5% level of significance.   
2. Intent-to-Treat population analysis: 
• Statistical analysis will be repeated using the Intent-to-Treat population and compared for 
consistency with the results from the ITT-E and PP populations. 
• In this analysis, subjects randomized but not exposed to study treatment will be classified 
as “having no virologic data”. 
 
3. Separate supportive analyses will be performed to enable the assessment of the 
homogeneity of the treatment difference across strata. 
The weighted least squares chi-squared statistic of [D’Agostino, 2008,Fleiss, 1981] will be 
used to test for one-way homogeneity of the treatment difference across the levels of each 
strata for baseline third agent class (PI, INI, NNRTI), with each categorical variable 
considered separately. Following Lui and Kelly [Lui, 2000], ½ will be added to each cell in 
any strata for which the stratum-specific rate estimates of either rDTG/3TC or rCAR are zero or 
one, and tests will be one-sided.  Tests of homogeneity will be assessed at the one-sided 
10% level of significance. For details see Appendix 15. 
 
For each stratum in addition to the proportion of subjects with plasm HIV-1 RNA≥50 c/mL by 
treatment group and subgroup (with 95% Cl type CI) as described in Appendix 15 , the p-
value from the test of homogeneity will also be reported for each categorical stratification 
variable. 
These results will be used to assess the statistical assumption underlying the CMH stratified 
analysis procedure - namely the assumption on a common difference in unadjusted 
proportions across strata. 
4. As the expected rate of HIV-1 RNA≥50 c/mL at week 48 is close to 0 (as a result of 
suppressed entry criteria), the 95% adjusted CI may be sensitive to the statistical method 


CONFIDENTIAL 
 
 
208090 
25 
used in its construction. Therefore, a sensitivity analysis using the Summary Score method 
(computed from the Miettinen-Nurminen CI limits of the stratum risk difference) will be 
performed to calculate the 95% CI of the adjusted treatment difference. This will be 
compared to the primary analysis method of CMH detailed above. 
 
 
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
The secondary endpoints will include the following: 
• The binary responses indicating the virologic outcome category of plasma HIV 1 
RNA ≥50 c/mL at week 24 using the FDA Snapshot algorithm (see Appendix 11).  
• The binary responses indicating the virologic outcome category of plasma HIV 1 
RNA <50 c/mL at week 24 and Week 48 using the FDA Snapshot algorithm (see 
Appendix 11).  
• CD4+ cell count at weeks 24 and 48. 
• CD4+/CD8+ cell count ratio at weeks 24 and 48. 
• Incidence of disease progression (HIV-associated conditions, AIDS, and death) 
through weeks 24 and 48 
7.2.2. 
Summary Measure 
• The number and percent of subjects with plasma HIV 1 RNA ≥50 c/mL at weeks 24 
using the FDA snapshot algorithm (see Appendix 11). 
• The number and percent of subjects with plasma HIV 1 RNA <50 c/mL at weeks 24 
and 48 using the FDA snapshot algorithm (see Appendix 11). 
• Change from baseline in CD4+ cell count at weeks 24 and 48. 
• Change from baseline in CD4+/CD8+ cell count ratio at weeks 24 and 48. 
• Incidence of disease progression (HIV-associated conditions, AIDS, and death) 
through weeks 24 and 48. 
 
7.2.3. 
Population of Interest  
The secondary efficacy analyses will be based on the ITT-E population. 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Intercurrent events such as discontinuations, missing plasma HIV-1 RNA samples and 
change in background regimen are handled using the FDA snapshot algorithm (see 
Appendix 11) which details how to assign each subject’s virologic outcome. Intercurrent 
events will not be controlled for in disease progression and CD4+ cell count analyses. 
 


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7.2.5. 
Statistical Analyses / Methods 
Table 5 provides an overview of the planned secondary efficacy analyses, with full 
details of data displays being presented in Appendix 17: List of Data Displays. 
Table 5 
 Overview of Planned Secondary Efficacy Analyses 
 
Endpoints  
Absolute  
Change from Baseline  
Stats 
Analysis 
Summary 
Individual 
Stats 
Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Percent of Subjects with Plasma HIV-1 RNA / <50 c/mL–  Snapshot 
Plasma HIV-1 
RNA 50 c/mL 
analysis at Week 
24 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 
RNA <50 c/mL 
analysis at Week X 
[6] 
Y[11] 
 
 
Y[10] 
 
 
 
 
 
 
 
 
 
 
Study Outcomes 
(Plasma HIV-1 
RNA / < 50 c/mL) 
based on the 
Snapshot at Week 
X [6] 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Plasma HIV-1 
RNA <50 c/mL 
analysis By Visit 
through Week X [6]   
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 
RNA 50 c/mL 
analysis By Visit 
through Week X [6]   
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 
RNA <50 c/mL 
analysis by 
subgroup at Week 
X [6]   
 
 
 
Y 
Y 
[1] 
 
 
 
 
 
 
 
 
 
Study Outcomes 
(Plasma HIV-1 
RNA / < 50 c/mL) 
based on the 
Snapshot by 
subgroup at Week 
X [6]   
 
 
 
Y   
 
 
 
 
 
 
 
 
 
 


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208090 
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Endpoints  
Absolute  
Change from Baseline  
Stats 
Analysis 
Summary 
Individual 
Stats 
Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Percent of Subjects with Plasma HIV-1 RNA / <50 c/mL–  Modified Snapshot 
Study Outcomes 
(Plasma HIV-1 
RNA / < 50 c/mL) 
at Week x [6] 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Confirmed Virologic Withdrawal (CVW) 
HIV-1 RNA 
distribution at time 
of suspected and 
confirmed Virologic 
withdrawal 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Potential Precautionary Virologic Withdrawal (pPVW) 
pPVW by Visit 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Plasma HIV-1 RNA over time –  Observed  
By Visit through 
Week X[6] 
 
 
 
 
 
 
Y 
[2,9] 
 
 
 
Y [5] 
 
 
 
CD4+ Cell Counts [ 3]   
By Visit through 
Week X [6] 
 
 
 
 
 
Y 
[2] 
Y 
 
 
 
Y 
 
 
Y 
By Subgroup at 
Week X[ 6] 
 
 
 
 
 
 
 
 
 
 
Y 
 
 
 
CD4+/CD8+ Cell Count Ratio [3]     
By Visit through 
Week X [6] 
 
 
 
 
 
Y 
[2] 
Y 
 
 
 
Y 
 
 
Y 
By Subgroup at 
Week X[ 6] 
 
 
 
 
 
 
 
 
 
 
Y 
 
 
 
Post-baseline HIV-1 Disease Progression [4] 
HIV Conditions 
including 
Recurrences at 
Week X [6,7] 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
HIV Conditions 
excluding 
Recurrences at 
Week X [6,7]  
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
HIV Disease 
Progressions at 
Week X [6,8] 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
1. NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 


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• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
1. 
Plot of 95% confidence intervals for unadjusted treatment difference in the proportion of subjects below 50 
c/mL with overall and by subgroup. 
2. 
Individual plasma HIV-1 RNA and CD4+ profiles only for subjects with at least one HIV-1 RNA levels ≥ 50 
c/mL observed including at Day 1 and through withdrawal visit. 
3. 
Using observed case (OC) data which contains the data that is available at a particular time point, with no 
imputation for missing values. 
4. 
HIV disease progressions categories: CDC Category Stage 1 at enrolment to Stage 3 event; CDC Category 
Stage 2 at enrolment to Stage 3 event; CDC Category Stage 3 at enrolment to New Stage 3 Event; CDC 
Category Stage 0, 1, 2 or 3 at enrolment to Death. 
5. 
Descriptive summary of the log10 change from baseline HIV-1 RNA by visit presented. 
6. 
Week X refers to Week 24 and Week 48. 
7. 
Stage 3 only. 
8. 
Progression to Stage 3 or death. 
9. 
Includes target detected/not detected flag see Section 15.6.3 for more information.  
10. Repeated on the following endpoint: <40 c/mL and Target Not Detected Status. 
11. Repeated on the following endpoints: 1) <40 c/mL only, 2) <40 c/mL and Target Not Detected Status. 
 
 


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7.2.5.1. 
Statistical Methodology Specification 
Endpoint  
• The binary responses indicating the virologic outcome category of plasma HIV 1 RNA ≥50 
c/mL at week 24 using the FDA Snapshot algorithm (see Appendix 11).  
• The binary responses indicating the virologic outcome category of plasma HIV 1 RNA <50 
c/mL at week 24 and Week 48 using the FDA Snapshot algorithm (see Appendix 11).  
• The analysis approach will follow the methods as described for the primary endpoint.    
Model Specification 
• Specification will be same as described for the primary endpoint   
Model Checking & Diagnostics 
• Same as described for the primary endpoint 
Model Results Presentation 
• Model presentation will be the same as described for the primary endpoint.  
• Percent of subjects with plasma HIV 1 RNA ≥50 c/mL will be analysed at Weeks 24. Percent 
subjects with plasma HIV 1 RNA <50 c/mL will be analysed at Week 24 and Week 48.  
• For Percent of subjects with plasma HIV-1 RNA <50 c/mL endpoint, non-inferiority of 
switching to DTG/3TC compared to continuation of CAR (as per FDA snapshot algorithm) 
will be assessed using a -12% non-inferiority margin. Non-inferiority will be concluded if the 
lower bound of a 2-sided 95% confidence interval for the difference in success rates 
between the two treatment arms is greater than -12%.  
Subgroup Analyses 
• Subgroup analyses will be performed for the percent of patients with plasma HIV 1 RNA <50 
c/mL, study outcomes and unadjusted difference in proportion of patients with plasma HIV 1 
RNA <50 c/mL between treatment arms at Week 24 and Week 48 endpoints (see Section 
5.4.2).   
Supportive Analyses 
 
1. Supportive analysis based on the <50 HIV-1 RNA endpoint will be performed based on the 
same analysis for the following endpoints: 
• Percent of Subjects with Plasma HIV-1 RNA <40 c/mL at Week 24 and Week 48 
• Percent of Subjects with Plasma HIV-1 RNA <40 c/mL and Target Not Detected 
Status at Week 24 and Week 48 
• Percent of Subjects with Plasma HIV-1 RNA <40 c/mL and Target Not Detected 
Status at Week 24 and Week 48 by Baseline Third Agent Class 
2. Proportion of subjects without virologic (ERDF) or virologic/tolerability (TRDF) failure: 
• Estimated using the Kaplan-Meier nonparametric method based on the time to 
Confirmed Virologic Withdrawal (CVW) criteria met or treatment-related (i.e. drug-


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related AE, protocol defined safety stopping criteria, or lack of efficacy)/efficacy 
related discontinuation (i.e. lack of efficacy).  
• The detailed algorithm for TRDF (and ERDF) is listed in Appendix 10. The estimate of 
the standard error used to derive confidence intervals for the difference in proportions 
between treatment groups will be based on Greenwood’s formula [Kalbfleisch,1980] 
• The estimated proportion of subjects without Confirmed Virologic Withdrawal and not 
discontinued due to treatment-related/efficacy-related reasons at Week 24 and at 
Week 48 will be presented by treatment group, along with estimated difference in 
proportions between treatment groups and its associated two-sided 95% CI. 
 
3. Modified snapshot algorithm for study outcomes at Week 24 and Week48: 
• Snapshot study outcomes will be repeated using the modified snapshot algorithm. The 
modified snapshot includes additional sub-reasons under “HIV-1 RNA≥50 c/mL” and “No 
Virologic Data” snapshot categories that are further divided by relationship to COVID-19. 
For details see Section 15.12 . 
7.3. 
Exploratory Efficacy Analyses 
• Subjects with plasma HIV-1 RNA <50 c/mL using the Snapshot algorithm at 
Week 24 and 48 by subgroup, based on the ITT-E population. 
• Change from baseline CD4+ and CD4+/CD8+ ratio cell counts at Week 24 and 48 
by subgroup. 
 
These analyses have been specified in previous sections.  
8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified.   
8.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 17: List of Data Displays. 
Emergent AEs will be tabulated by treatment group and a total column. For AEs captured 
more than once, the most severe intensity will be included in summaries, and all events 
will be included in listings. For the purposes of summarising AE data, unless stated 
otherwise, the summaries will include post-baseline data.  
For Week 24 and 48 analyses, outputs will be presented for the Randomized Phase unless 
otherwise specified. Safety data presented through weeks 24 and 48, will comprise all 
available safety data collected at that time point. For example, if some earlier recruiting 
subjects have reached Week 36 and have available safety data, this will be presented for 
the Week 24 analysis.  
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 17: List of Data Displays. 


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Table 6 
 Overview of Planned Safety Analyses 
 
Endpoint 
 
Absolute 
 
Summary 
Individual 
T 
F 
F 
L 
Exposure 
Extent of Exposure 
Y 
 
 
Y [1] 
Adverse Events [2] 
All AEs by SOC and PT[2, 7] 
Y 
 
 
Y 
All AEs by Maximum Grade [2] 
Y 
 
 
Y [3] 
Common AEs by Frequency [4] 
Y 
Y [5] 
 
 
Common Grade 2-5 AEs [4] by Frequency 
Y 
 
 
 
Drug-Related AEs by SOC and PT 
Y 
 
 
Y 
All Drug-Related AEs by SOC and Maximum Grade 
[2] 
Y 
 
 
 
Common non-Serious AEs by SOC and PT (subjects 
and number of occurrences) 
Y 
 
 
 
Common Drug-related Grade 2-5 AEs [4] 
Y 
 
 
 
Drug-Related AEs leading to withdrawal from study 
Y 
 
 
 
AEs Leading to Withdrawal from Study / Permanent 
Discontinuation of Study Treatment[8] 
Y 
 
 
Y 
Serious and Other Significant AEs 
All SAEs by SOC 
Y 
 
 
 
All Drug-Related SAEs by SOC 
Y 
 
 
 
Serious AEs by SOC and PT 
Y 
 
 
 
Reason for Considering as a Serious Adverse Event  
 
 
 
Y  
Possible Suicidality-Related Adverse Event (PSRAE) 
 
 
 
Y [6] 
Cardiovascular events 
 
 
 
Y 
Incidence of COVID-19 as reported as an AE and 
SAE[9] 
Y 
 
 
Y 
Incidence of treatment discontinuation due to AE of 
COVID-19 infection[9] 
Y 
 
 
Y 
Impact of Covid-19 on Assessment of Safety Based on COVID-19 eCRF 
All AEs of Suspected, Probable, Confirmed for 
COVID-19 Infection 
T 
 
 
L 
COVID-19 Diagnosis 
T 
 
 
L 
NOTES : 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed data.  


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1. 
Includes reason for any dose change/interruption in both arms. 
2. 
For AEs reported more than once by a subject, the most severe intensity will be included. 
3. 
One listing of all AEs including verbatim text and preferred term, one showing the relationship between verbatim 
text, preferred term and SOC and another giving subject numbers for individual all treatment emergent AEs. 
4. 
Common AEs are those with >=2% (or 0.5% for drug-related grade 2-5 AEs if there are no such AEs >=2%) 
incidence in either treatment group summarised by frequency. 
5. 
Plots of incidence rates and relative risk with 95% CI for DTG/3TC vs. CAR. 
6. 
Four PSRAE listings: Event and Description (Section 1- Section 2), Possible Cause (Section 3), Section 4 and 
Section 5-Section 8. 
7. 
Repeated by subgroup (see Section 5.4.2). 
8. 
Repeated by maximum grade as well. 
9. 
Incidence of COVID-19 reported as an AE, SAE, treatment discontinuation due to AE of COVID-19 infection 
will be available in the adverse events summary tables/listings.  
 
8.2. 
Adverse Events of Special Interest Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event (see Section 15.6.4) . 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. An 
overview of the planned adverse events of special interest analyses are presented in Table 
7 and full details of the planned displays are provided in Appendix 17: List of Data 
Displays. 
 


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Table 7 
Overview of Planned Adverse Events of Special Interest Analyses 
Endpoint 
 
Absolute 
 
Summary 
Individual 
T 
F 
F 
L 
Adverse Events of Special Interest[1] 
Characteristics of Post 
Baseline AESI 
Y 
 
 
 
1. 1 See Section 15.6.4. for detail list of AESI 
 
8.3. 
Clinical Laboratory and Biomarker Analyses 
Laboratory evaluations will be based on GSK Core Data Standards. Table 8 provides an 
overview of the planned laboratory analyses, with full details of data displays being 
presented in Appendix 17: List of Data Displays. 


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Table 8 
Overview of Planned Laboratory Analyses 
Endpoint 
 
Absolute 
 
Change from Baseline 
Max Post BL 
Summary Individual Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
F 
L 
T 
F 
F 
L 
T 
F 
T 
F 
F 
L 
Laboratory Values Over Time 
Clinical Chemistry[7]  
Y 
 
 
Y[1] 
Y 
 
 
 
 
 
 
 
 
 
Fasted Lipid 
(Triglycerides, LDL, 
HDL and TC and 
TC/HDL)[2]  
Y[4] 
 
Y[3,4] 
Y[1] 
Y[4] 
 
 
 
Y 
Y 
 
 
 
 
NCEP shifts in lipids 
 
 
 
 
Y[4] Y[3,4] 
 
 
 
 
 
 
 
 
Hematology [7]   
Y 
 
 
Y[1] 
Y 
 
 
 
 
 
 
 
 
 
Urine Dipstick 
 
 
 
Y[1] 
 
 
 
 
 
 
 
 
 
 
Urine Concentration 
 
 
 
Y[1] 
 
 
 
 
 
 
 
 
 
 
Liver Chemistries 
 
 
 
 
 
 
 
 
 
 
 
Y 
 
  
Clinical Laboratory and Biomarkers[8] 
Bone Biomarkers 
 
 
 
Y 
Y 
 
 
Y 
Y 
Y 
 
 
 
 
Renal Biomarkers 
 
 
 
Y 
Y 
 
 
Y 
Y 
Y 
 
 
 
 
Inflammation 
Biomarkers 
 
 
 
Y 
Y  
 
 
Y 
Y 
 Y 
 
 
 
 
Change from 
Baseline in HOMA-
IR, HbA1c at Week 
24 and 48 
 
 
 
Y 
Y 
 
 
Y 
Y 
 Y 
 
 
 
 
HOMA-IR, HbA1c by 
visit 
Y 
 
 
 
Y 
 
 
 
Y 
Y 
 
 
 
 
HOMA-IR vs Weight 
Scatter Plot 
 
 
 
 
 
 
Y[5] 
 
 
 
 
 
 
 
HOMA-IR cut-off 
(>=2, >=3 and 
>=4) at Week 24 
and 48 
 
 
 
 
Y 
 
 
 
Y 
  
 
 
 
 
Emergent Laboratory Toxicities 
Clinical Chemistry 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST, ALT and Total 
Bilirubin Maximum 
Post-Baseline 
Emergent Toxicity 
by Baseline 
Hepatitis C Status 
 
 
 
 
 
 
 
 
 
 
Y 
 
 
 
NOTES : 


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• 
T = Table, F = Figures, L = Listings, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
1. 
Listings for subjects with abnormalities for potential clinical concern/importance, defined as any Grade1-5 toxicity 
for Chemistry (Including Lipids), Hematology and Urinalysis. 
2. 
Present both mmol/L and mg/DL .  
3. 
Heatmap plot of NCEP categories in lipids over time. 
4. 
Subjects on lipid-lowering agents at baseline are not included in summaries. see Lipids. Section 15.6.4 for more 
details. 
5. 
A scatter plot of change in HOMA-IR (y-axis) vs change in weight (x-axis) at Weeks 24 and 48. 
6. 
See Section 15.6.4 for more details. 
7. 
Repeated by subgroup  
8. 
Subjects from China will not be evaluated on Inflammatory Biomarkers, telomere length, Bone biomarkers  and 
some Renal biomarkers (Retinol Binding Protein,Beta-2-Microglobulin, Urine RBP/creatinine and Urine 
B2M/creatinine) 
8.3.1. 
Lipid Parameters Analyses 
Statistical Analyses 
Endpoints 
• Change from Baseline in Fasting Lipids (Triglycerides, LDL cholesterol, HDL 
cholesterol, Total Cholesterol and TC/HDL ratio) at Weeks 24 and 48 
Covariates & Factors 
• Baseline 3rd Line Agent 
• CD4+ cell count (continuous)  
• Age (continuous) 
• Sex (Female vs. Male) 
• Race (White, Black or African American, Asian, Other)  
Data Handling 
• Before model fitting, missing values are assigned in the Observed Case Dataset:  
o Non-fasting values will be set to missing.    
o Subjects initiated serum lipid-lowering therapy at baseline (see Section 15.6.4) 
will be excluded from the analysis. 
o All values after initiation of lipid-lowering agents will be set to missing 
o Missing scheduled visits do not need to be created (given all scheduled visits 
appear in the dataset) 
o Non-missing values will need to be natural logarithm (ln) transformed(including 
baseline value when included in models) 
o Depending on data structure, transpose non-missing values by subject if 
necessary 
Model Specification 
• Multiple imputation technique will be used as described below; 
o Multiple imputations will be drawn from a multivariate normal imputation model 
(taking into account scheduled measurements prior to analysis timepoints) with 
a Markov Chain Monte Carlo (MCMC) approach to estimate posterior 
distributions. The MCMC method in the MI procedure in SAS calling SAS PROC 
MI will be used with multiple chains, 500 burn-in iterations, and a noninformative 


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Statistical Analyses 
prior. A random seed number of 208090 will be used in the SAS program. 
Where a subject has a monotone or non-monotone pattern of missingness, all 
of their missing observations can be imputed under this approach. The absolute 
value will be imputed before the change value is calculated. Imputations will be 
drawn separately for subsets of subjects according to their treatment group, i.e., 
based on means and variance-covariances from the same treatment group 
(Missing At Random (MAR) approach) conditioning on covariates (as defined 
above). 
o The imputations will be carried out 1,000 times. An ANCOVA (Week 24)/ 
MMRM (Week 48), using the observed margins (OM) option, will be performed 
on each dataset produced adjusting for the covariates (listed above), treatment, 
and baseline value, regardless of their significance. PROC MI ANALYZE in SAS 
will be used to combine the 1,000 estimated least squares means and 
difference to produce one estimated mean with 95% CI and associated p-value 
for the adjusted mean difference between each treatment group at Week 24 
and Week 48. 
o Interactions between treatment and covariates will not be assessed. 
 
Model Checking & Diagnostics 
Refer to Appendix 14: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Given that data is log transformed, estimated adjusted ratio (Week 24/Baseline or Week 
48/Baseline) for each treatment and geometric mean ratio ((DTG/3TC/ CAR)) together 
with corresponding 95% CI will be presented. Results of the ratio are also expressed as 
percent change in adjusted mean and percent treatment difference respectively where 
percent change is derived as 100* [Exp(model parameter estimate) -1]. 
 
Sensitivity Analyses - ANCOVA (Week 24) 
• Sensitivity Analysis with Analysis of Covariance (ANCOVA) will be performed on the 
original data without multiple imputation techniques to deal with the missing data.    
• ANCOVA will use the observed margins (OM) option, adjusting for treatment, covariates 
(listed above) and baseline value. 
• Type III tests for the least-squares (LS) means will be used for the statistical 
comparison; the 95% CI will also be reported. Treatment group comparisons at Week 24 
will be reported.  
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted 
least squares means will be presented for each treatment, together with estimated 
treatment difference (DTG/3TC – CAR) and corresponding 95% confidence interval and 
p-value. 
• Note: if any lipid parameter is not normally distributed then the geometric mean and a 
95% CI of geometric mean will be presented for each treatment, as well as geometric 
mean ratios and corresponding 95% CI and a p-value. 


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Statistical Analyses 
Sensitivity Analyses – MMRM( Week 48) 
• Sensitivity Analysis with Mixed Model Repeated Measures (MMRM) will be performed  
on the original data without multiple imputation techniques to deal with the missing data.   
• MMRM will use the observed margins (OM) option, adjusting for treatment, covariates 
(listed above) and baseline value, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations within-subject scores 
(the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary 
between visits (i.e.. a treatment*visit interaction will be included in the model). The 
model will also assume that the effect of baseline score for the endpoint can vary 
between visits (i.e.. baseline score*visit interaction will be included in the model). 
• The Kenward-Roger method will be used to estimate the denominator degrees of 
freedom. Type III tests for the least-squares (LS) means will be used for the statistical 
comparison; the 95% CI will also be reported. Treatment group comparisons at Week 24 
and Week 48 will be reported.  
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted 
least squares means will be presented for each treatment, together with estimated 
treatment difference (DTG/3TC – CAR) and corresponding 95% confidence interval and 
p-value. 
• Note: if any lipid parameter is not normally distributed then the geometric mean and a 
95% CI of geometric mean will be presented for each treatment, as well as geometric 
mean ratios and corresponding 95% CI and a p-value. 
 
 
8.3.2. 
HOMA-IR and HbA1c Analyses 
Statistical Analyses 
Endpoints 
• Change from baseline in HOMA-IR, HbA1c  at Weeks 24 and 48 (refer to  15.6.4 for details 
of derivation) 
Covariates & Factors 
• Baseline 3rd Line Agent 
• CD4+ cell count (continuous)  
• Age (continuous) 
• Sex (Female vs. Male) 
• Race (White, Black or African American, Asian, Other) 
• BMI (continuous) 
• Presence of diabetes mellitus (DM) (Yes vs no) : Applicable for HbA1c only  
• Hypertension (Yes vs no) 
• Baseline value(continuous ) 


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Statistical Analyses 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• If change in HOMA-IR or HbA1c is not normally distributed the data will be log transformed 
and geometric means will replace arithmetic means, a 95% CI will replace the standard 
deviations and mean changes from baseline will be presented as geometric mean ratios. 
• Change from baseline will be analysed for the comparison between DTG/3TC and CAR. 
• Using OC dataset, the Mixed Model Repeated Measures (MMRM), using the observed 
margins (OM) option, will adjust for treatment, covariates (listed above) and baseline value 
as a covariate, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations between a subject’s value 
(the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (i.e. a treatment*visit interaction will be included in the model), and separate estimates 
and 95% confidence intervals will be produced at each visit. The model will also assume that 
the effect of baseline value for the endpoint can vary between visits (i.e. baseline value*visit 
interaction will be included in the model). 
• Interactions between treatment and each of the covariates will not be assessed.   
Model Checking & Diagnostics 
• Refer to Appendix 14: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted least 
squares means will be presented for each treatment, together with estimated treatment 
difference (DTG/3TC – CAR) and corresponding 95% confidence interval and p-value. 
• Note: If change from baseline in HOMA-IR or HbA1c data are not normally distributed, the 
geometric mean and a 95% CI of geometric mean will be presented for each treatment, as 
well as geometric mean ratios and corresponding 95% CI and a p-value. 
Sensitivity Analyses 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change from 
Baseline will be generated for each treatment group by visit 
• A logistic regression model will be performed on the proportion of subjects with HOMA-IR 
cut-off (>=2, >=3 and >=4) at Week 24 and Week 48 adjusting for the same covariates as 
specified in the MMRM analysis (without visit or interaction terms). Odds ratios, standard 
errors, confidence intervals and p-values will be presented for all covariates specified in the 
model. This analysis will be repeated on the proportion of subjects with HOMA-IR cut-off 
(>=2, >=3 and >=4) at Week 24 and Week 48. Upon delivery of data, an assessment 
regarding the amount of missing data will be made. If it’s considered the amount of missing 
HOMA-IR outcome data at Week 24 and Week 48 as a result of COVID-19 is substantial, the 
logistic regression analysis may not be performed. 
Subgroup Analyses 
• Not applicable 
 
 


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8.3.3. 
Bone Biomarkers Analyses 
 
Statistical Analyses 
Endpoints 
• Change from baseline in bone biomarkers (bone specific alkaline phosphatase, procollagen 
type I N-terminal propeptide, type I collagen cross-linked C-telopeptide, osteocalcin) at 
Weeks 24 and 48 
Covariates & Factors 
• Baseline 3rd Line Agent  
• CD4+ cell count (continuous) 
• Age (continuous) 
• Sex (Female vs. Male) 
• Race (White, Black or African American, Asian, Other) 
• BMI (continuous) 
• Smoking status (Never vs. Former vs. Current Smoker) 
• Baseline value(continuous ) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification - ANCOVA (Week 24) 
• It is anticipated that at least some biomarkers will not be normally distributed and for those, 
the data will be log transformed and geometric means will replace arithmetic means, a 95% 
CI will replace the standard deviations and mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for each bone biomarker for the comparison between 
DTG/3TC and CAR. 
• An Analysis of Covariance  (ANCOVA), using the observed margins (OM) option, will adjust 
for treatment, covariates (listed above) and biomarker value at baseline as a covariate. The 
OC dataset will be used for ANCOVA model. 
Model Specification – MMRM (Week 48) 
• It is anticipated that at least some biomarkers will not be normally distributed and for those, 
the data will be log transformed and geometric means will replace arithmetic means, a 95% 
CI will replace the standard deviations and mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for each bone biomarker for the comparison between 
DTG/3TC and CAR. 
• Mixed Model Repeated Measures (MMRM), using the observed margins (OM) option, will 
adjust for treatment, covariates (listed above) and biomarker value at baseline as a 
covariate, with visit as the repeated factor. The OC dataset will be used for MMRM model. 
• The model will make no further assumptions about the correlations between a subject’s value 
(the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (i.e. a treatment*visit interaction will be included in the model) and separates estimates 
and 95% confidence intervals will be produced at each visit. The model will also assume that 
the effect of baseline value for the endpoint can vary between visits (i.e. baseline value*visit 
interaction will be included in the model). 


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Statistical Analyses 
• Interactions between treatment and each of the covariates will not be assessed. 
Model Checking & Diagnostics 
• Refer to Appendix 14: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted least 
squares means will be presented for each treatment, together with estimated treatment 
difference (DTG/3TC – CAR) and corresponding 95% confidence interval and p-value. 
• Note: For biomarkers that are not normally distributed, the geometric mean and a 95% CI of 
geometric mean will be presented for each treatment, as well as geometric mean ratios and 
corresponding 95% CI and a p-value. 
Sensitivity Analyses 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change from 
Baseline will be generated for each treatment group by visit 
Subgroup Analyses 
• Not applicable 
8.3.4. 
Renal Biomarkers Analyses 
 
Statistical Analyses 
Endpoints 
• Change from baseline in renal biomarkers (serum Cystatin C, Urine Beta-2 Microglobulin 
/Urine Creatinine ratio (mg/mmol), urine albumin/creatinine ratio, urine protein/creatinine 
ratio, urine phosphate, eGFR (based on CKD-EPI-creatinine and CKD-EPI-cystatin C), 
serum creatinine and Urine Retinol Binding Protein 4/Urine Creatinine ratio (ug/mmol)) at 
Weeks 24 and 48 
Covariates & Factors 
• Baseline 3rd Line Agent  
• CD4+ cell count (continuous) 
• Age (continuous)  
• 
Sex (Female vs. Male) 
• 
Race (White, Black or African American, Asian, Other) 
• 
BMI (continuous)  
• 
Presence of diabetes mellitus (DM) (Yes vs no) 
• 
Presence of Hypertension (Yes v no) 
• 
Baseline value(continuous ) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification - ANCOVA (Week 24) 
• It is anticipated that at least some biomarkers will not be normally distributed and for those, 
the data will be log transformed and geometric means will replace arithmetic means, a 95% 
CI will replace the standard deviations and mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for each bone biomarker for the comparison between 
DTG/3TC and CAR. 


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Statistical Analyses 
• An Analysis of Covariance  (ANCOVA), using the observed margins (OM) option, will adjust 
for treatment, covariates (listed above) and biomarker value at baseline as a covariate. The 
OC dataset will be used for ANCOVA model. 
Model Specification – MMRM (Week 48) 
• It is anticipated that at least some biomarkers will not be normally distributed and for those, 
the data will be log transformed and geometric means will replace arithmetic means, a 95% 
CI will replace the standard deviations and mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for each renal biomarker for the comparison between 
DTG/3TC and CAR. 
• Using OC dataset, the Mixed Model Repeated Measures (MMRM), using the observed 
margins (OM) option, will adjust for treatment, covariates (listed above) and baseline renal 
biomarker value at baseline as a covariate, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations between a subject’s value 
(the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (i.e. a treatment*visit interaction will be included in the model), and separate estimates 
and 95% confidence intervals will be produced at each visit. The model will also assume that 
the effect of baseline value for the endpoint can vary between visits (i.e. baseline value*visit 
interaction will be included in the model). 
• Interactions between treatment and each of the covariates will not be assessed.  
Model Checking & Diagnostics 
• Refer to Appendix 14: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted least 
squares means will be presented for each treatment, together with estimated treatment 
difference (DTG/3TC – CAR) and corresponding 95% confidence interval and p-value. 
• Note: For biomarkers that are not normally distributed, the geometric mean and a 95% CI of 
geometric mean will be presented for each treatment, as well as geometric mean ratios and 
corresponding 95% CI and a p-value. 
Sensitivity Analyses 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change from 
Baseline will be generated for each treatment group by visit 
• A sensitivity analysis will be performed for urine albumin/creatinine ratio and urine 
protein/creatinine ratio by imputing albumin, protein and creatinine values  that are below the 
limit of quantitation. See Appendix 7. 
Subgroup Analyses 
• Not applicable 
8.3.5. 
Inflammatory Biomarkers Analyses 
Statistical Analyses 
Endpoints 
• Change from baseline in inflammatory biomarkers (Interleukin-6 (IL-6), High-sensitivity C 
reactive protein (hs-CRP), D-dimer, Soluble CD14 (sCD14), Soluble CD163 (sCD163)) at 
Weeks 24 and 48 


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Statistical Analyses 
Covariates & Factors 
• Baseline 3rd Line Agent  
• CD4+ cell count (continuous) 
• Age (continuous) 
• 
Sex (Female vs. Male) 
• 
Race (White, Black or African American, Asian, Other) 
• 
BMI (continuous)  
• Smoking status (Never vs. Former vs. Current Smoker) 
• HCV-coinfection (Yes vs. No) 
• Baseline value(continuous ) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification - ANCOVA (Week 24) 
• It is anticipated that at least some biomarkers will not be normally distributed and for those, 
the data will be log transformed and geometric means will replace arithmetic means, a 95% 
CI will replace the standard deviations and mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for each bone biomarker for the comparison between 
DTG/3TC and CAR. 
• An Analysis of Covariance  (ANCOVA), using the observed margins (OM) option, will adjust 
for treatment, covariates (listed above) and biomarker value at baseline as a covariate. The 
OC dataset will be used for ANCOVA model. 
Model Specification – MMRM (Week 48) 
• It is anticipated that at least some biomarkers will not be normally distributed and for those, 
the data will be log transformed and geometric means will replace arithmetic means, a 95% 
CI will replace the standard deviations and mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for each inflammatory biomarker for the comparison 
between DTG/3TC and CAR. 
• Using OC dataset, the Mixed Model Repeated Measures (MMRM), using the observed 
margins (OM) option, will adjust for treatment, covariates (listed above) and baseline 
inflammatory biomarker value at as a covariate, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations between a subject’s value 
(the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (i.e. a treatment*visit interaction will be included in the model), and separate estimates 
and 95% confidence intervals will be produced at each visit. The model will also assume that 
the effect of baseline value for the endpoint can vary between visits (i.e. baseline value*visit 
interaction will be included in the model). 
• Interactions between treatment and each of the covariates will not be assessed.   
Model Checking & Diagnostics 
• Refer to Appendix 14: Model Checking and Diagnostics for Statistical Analyses. 


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Statistical Analyses 
Model Results Presentation 
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted least 
squares means will be presented for each treatment, together with estimated treatment 
difference (DTG/3TC – CAR) and corresponding 95% confidence interval and p-value. 
• Note: For biomarkers that are not normally distributed, the geometric mean and a 95% CI of 
geometric mean will be presented for each treatment, as well as geometric mean ratios and 
corresponding 95% CI and a p-value. 
Sensitivity Analyses 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change from 
Baseline will be generated for each treatment group by visit 
Subgroup Analyses 
• Not applicable 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results will be based on GSK Core Data 
Standards, unless otherwise specified. An overview of other safety analyses is presented 
in Table 9 and full details of the planned displays are presented in Appendix 17: List of 
Data Displays.  Note that ECGs and vital signs are only collected at screening, so will 
only be listed. 
Table 9 
Overview of Other Safety Analyses 
Endpoint 
 
Absolute 
Change from Baseline 
Max Post BL 
Summary Individual Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
F 
L 
T 
F 
F 
L 
T 
F 
T 
F 
F 
L 
Other Safety Analyses 
ECG at screening 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Liver Assessment 
Y 
 
 
Y  
 
 
 
 
 
 
 
 
 
 
Hepatobiliary 
Abnormality criteria 
Y 
 
 
Y[3] 
 
 
 
 
 
 
 
 
 
 
eC-SSRS 
Y 
 
 
Y[1] 
 
 
 
 
 
 
 
 
 
 
Subjects who 
became Pregnant 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Patient Profiles 
 
 
 
Y[2] 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
Listings for Subjects 
with Liver Stopping 
Events     
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 


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Endpoint 
 
Absolute 
Change from Baseline 
Max Post BL 
Summary Individual Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
F 
L 
T 
F 
F 
L 
T 
F 
T 
F 
F 
L 
Weight and BMI 
Change from 
baseline in BMI at 
Weight at Week 24 
and 48 
 
 
 
Y 
Y 
 
 
Y 
Y 
 Y 
 
 
 
 
BMI[4] and Weight by 
Visit 
Y 
 
 
 
Y 
 
 
 
Y 
Y 
 
 
 
 
BMI shift Table 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Includes Baseline and lists all visits for a subject who reports any ideation or behaviour at any visit. 
2. 
Patient profiles for subjects meeting protocol defined liver stopping criteria and for patients with HIV-1 RNA ≥ 50 
c/mL. Patient profiles can also be provided for any other subjects. 
3. 
All post-baseline abnormalities meeting Hepatobiliary Abnormality Criteria. 
4. 
Heatmap plot of BMI categories over time.  


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8.4.1. 
Weight and BMI Analyses 
Statistical Analyses 
Endpoints 
• Change from baseline in weight (kg) and BMI (kg/m2) at Weeks 24 and 48 
Covariates & Factors 
• Baseline 3rd Line Agent  
• CD4+ cell count (continuous) 
• Age (continuous) 
• Sex (Female vs. Male) 
• Race (White, Black or African American, Asian, Other) 
• Baseline value(continuous ) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• If the change from baseline in weight (BMI for BMI analysis) is not normally distributed, the 
data will be log transformed and geometric means will replace arithmetic means, a 95% CI 
will replace the standard deviations and mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for the comparison between DTG/3TC and CAR. 
• Using OC dataset, the Mixed Model Repeated Measures (MMRM), using the observed 
margins (OM) option, will adjust for treatment, covariates (listed above) and baseline weight 
(BMI for BMI analysis) value as a covariate, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations between a subject’s 
weight (BMI for BMI analysis) (the correlation matrix for within-subject errors will be 
unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (i.e. a treatment*visit interaction will be included in the model), and separate estimates 
and 95% confidence intervals will be produced at each visit. The model will also assume that 
the effect of baseline weight (BMI for BMI analysis) can vary between visits (i.e. baseline 
value*visit interaction will be included in the model). 
• Interactions between treatment and each of the covariates will not be assessed.  
Model Checking & Diagnostics 
• Refer to Appendix 14: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted least 
squares means will be presented for each treatment, together with estimated treatment 
difference (DTG/3TC – CAR) and corresponding 95% confidence interval. 
• Note: If change in weight is not normally distributed, the geometric mean and a 95% CI of 
geometric mean will be presented for each treatment, as well as geometric mean ratios and 
corresponding 95% CI and p-values. 
Sensitivity Analyses 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change from 
Baseline will be generated for each treatment group by visit. 
Subgroup Analyses 
• Not applicable 


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9. 
OTHER STATISTICAL ANALYSES 
9.1. 
Health Outcomes 
9.1.1. 
Overview of Planned Analyses 
The Health Outcomes analyses will be based on the Intent-To-Treat (Exposed) 
population, unless otherwise specified. 
Table 10 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 17: List of Data Displays. 
Table 10 
Overview of Planned Health Outcome Analyses 
Endpoints 
Absolute  
Change from Baseline  
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Symptom Distress Module (SDM) 
Symptom Count 
(at Week 24 and 
48)  
 
 
 
Y  
 
 
Y 
 
 
 
Y  
 
 
 
 
Symptom Bother 
Score (at Week 24 
and 48) 
 
 
 
Y  
 
 
Y 
Y[3] 
Y[1] 
 
Y  
 
 
 
Willingness to switch 
Willingness to 
switch survey 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Treatment satisfaction  
HIVTSQ individual 
item scores by 
Visit  
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
HIVTSQ (at Week 
24 and 48)  
Y[2] 
 
 
Y[2] 
 
 
 
Y[2,3] Y[1,2]  
Y[2] 
 
 
 
1. 
Line Plot of Adjusted Mean (95% CI) and Line Plot of Difference (95% CI) in Adjusted Mean Change from 
Baseline over time. 
2. 
Separate summaries for Total score (questionnaire items 1-10), General Satisfaction/Clinical sub-score 
(questionnaire items 
 and 
) and Lifestyle/ease sub-score (questionnaire items 
 and ).  
3. 
Repeat by subgroups (see Section 5.4.2). 
 
9.1.2. 
Planned Health Outcomes Statistical Analyses 
Statistical Analyses 
Endpoints 
• Change from baseline in Overall Symptom Bother score at Week 24 and 48 
• Change from baseline in HIVTSQ total score at Week 24 and 48  
• Change from baseline in HIVTSQ general satisfaction/clinical sub-score at Week 24 and 48  
• Change from baseline in HIVTSQ lifestyle/ease sub-scores at Week 24 and 48 
CCI
CCI
CCI
CC


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Covariates & Factors 
• Baseline 3rd Line Agent  
• Age (continuous)  
• 
Sex (Female vs. Male) 
• Race (White, Black or African American, Asian, Other) 
• Baseline score 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• If the endpoint is not be normally distributed then, the data will be log transformed and 
geometric means will replace arithmetic means, a 95% CI will replace the standard 
deviations and mean changes from baseline will be presented as geometric mean ratios. 
• Change from baseline will be analysed for the comparison between DTG/3TC and CAR 
• Using OC dataset, Mixed Model Repeated Measures (MMRM), using the observed margins 
(OM) option, will adjust for treatment, covariates (listed above) and baseline score value as 
a covariate, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations between a subject’s 
score (the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (i.e. a treatment*visit interaction will be included in the model) and separates estimates 
and 95% confidence intervals will be produced at each visit. The model will also assume that 
the effect of baseline score for the endpoint can vary between visits (i.e. baseline score*visit 
interaction will be included in the model). 
• Interactions between treatment and each of the covariates will not be assessed. 
Model Checking & Diagnostics 
• Refer to Appendix 14: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Adjusted least squares means and corresponding standard errors (SEs) of adjusted least 
squares means will be presented for each treatment, together with estimated treatment 
difference (DTG/3TC – CAR) and corresponding 95% confidence interval and p-value. 
• Note: if SDM bother score is not normally distributed, the geometric mean and a 95% CI of 
geometric mean will be presented for each treatment, as well as geometric mean ratios and 
corresponding 95% CI and a p-value. 
Sensitivity Analyses 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change from 
Baseline will be generated for each treatment group by visit 
Subgroup Analyses 
• Subgroup analyses will be performed for change from baseline in Overall Symptom Bother 
score and HIVTSQ total score at Week 24 and 48. Analysis will be performed as described 
above and will adjust for the covariates listed above, treatment, baseline score, subgroup, 
baseline score*visit and treatment*subgroup interaction term regardless of their significance 
(Subgroups are defined in Section 5.4.2).   
 


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Statistical Analyses 
Endpoint(s) 
• Willingness to switch survey 
Model Specification/Analysis Methodology 
• Assess the reason(s) for their participation and facilitate an understanding of subject’s 
willingness to switch  
• A single item question prior to randomisation. 
• 7 reasons for willingness to participate in a clinical study where the current HIV medication 
may be switched check all that apply 
• Any missing values will remain missing 
Model Results Presentation 
• Summary statistics will be presented by treatment group 
 
9.2. 
Virology 
9.2.1. 
Overview of Planned Analyses 
9.2.2. 
Planned Virology Statistical Analysis 
The virology analyses of genotype and phenotype data will be based on the CVW and 
pPVW resistance populations. Please see Section 15.6.3 for details of the derivation of 
CVW. Please see Section 15.6.3 for details of the derivation of pPVW. 
The CVW population will be based on subjects who have experienced a CVW at any 
point. Summary tables will present CVWs up to and including the time point of interest. 
CVWs must be confirmed within the phase in which they are reported. Listings will 
present CVWs occurring at any point. Summary tables will present CVWs at the time 
point of SVW (or first elevation if this was >=50 c/mL and <200 c/mL).' 
Table 11 provides an overview of the planned virology analyses, with full details of data 
displays being presented in  Appendix 17: List of Data Displays. 
Table 11 
Overview of Planned Virology Analyses 
Endpoint  
Absolute 
Summary 
Individual 
T 
F 
F 
L 
HIV-1 Subject Genotypic/Phenotypic Data Accountability 
Genotypic Accountability 
Y[2] 
 
 
 
Phenotypic Accountability 
Y[2] 
 
 
 
Genotypic resistance 
Genotypic resistance at time of CVW[1] 
Y[2] 
 
 
Y[4] 
Genotypic resistance for subjects on 
treatment non-CVW time point[1] 
Y[2] 
 
 
Y 
Phenotypic resistance[5] 
Phenotypic resistance at time of CVW[1] 
Y[3] 
 
 
Y[4] 


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Endpoint  
Absolute 
Summary 
Individual 
T 
F 
F 
L 
Phenotypic resistance for subjects on 
treatment at non-CVW time point[1] 
Y[2] 
 
 
Y 
INI and RT/PR replication capacity at time of 
CVW[1] 
 
 
 
Y[4] 
INI and RT/PR replication capacity at time of 
non-CVW[1] 
 
 
 
Y[4] 
Fold Change at CVW 
Y 
 
 
 
Net Assessment for Overall Susceptibility Score 
Overall Susceptibility Score (OSS) 
 
 
 
Y 
1. NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.    
1. Sample used for resistance testing is taken at the time suspected virologic withdrawal criteria are 
met, and only tested once virologic withdrawal criteria are confirmed at a subsequent visit.   
2. Separate outputs for INI and NRTI/NNRTI/PI mutations 
3. Separate outputs by phenotypic cut-off and by number of drugs to which subjects are resistant. 
4. Produce for CVW and pPVW resistance populations. 
5. Phenotypic data are not available at Baseline because Genosure archive assay being used only 
provides genotype and not phenotype 
 
 


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10. 
PHARMACOKINETIC ANALYSES 
There are no pharmacokinetic analyses planned for this study.   
  
11. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
There are no population pharmacokinetic analyses planned in this study.   
 
12. 
PHARMACODYNAMIC ANALYSES 
There are no pharmacodynamic analyses planned for this study.   
 
13. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
There are no pharmacokinetic / pharmacodynamic (PK/PD) analyses planned in this 
study.   
 


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14. 
REFERENCES 
D’Agostino R.B., Vasan R.S., Pencina M.J., Wolf P.A., Cobain M., Massaro J.M. 
Kannel W.B. General Cardiovascular Risk Profile for Use in Primary Care: The 
Framingham Heart Study. Epidemiology. 2008; 117:743-753. 
Fleiss J.L. Statistical Methods for Rates and Proportions. 2nd ed. New York:John Wiley; 
1981.  
Grundy S.M., et al. Executive summary of the third report of the National Cholesterol 
Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of 
High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285  
Inker LA, Schmid CH, Tighiouart H, et al; Estimating Glomerular Filtration Rate from 
Serum Creatinine and Cystatin C. N Engl J Med. 2012;367:20-9. 
Johnson VA, Calvez V, Gunthard HF, et. al.  Special Contribution.  Update of the Drug 
Resistance Mutations in HIV-1: March 2013.  IAS-USA Topics in Antiviral Medicine.  
Available at:  https://www.iasusa.org/sites/default/files/tam/21-1-6.pdf.  Accessed 
Octover 24, 2016.   
Justice A, Holmes W, Gifford A, et al. Development and validation of a self completed 
HIV symptom index. Journal of Clinical Epidemiology. 2001; 54:S77-S90 
 
Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data.  New York: 
Wiley, 1980 
Klingenberg. A new and improved confidence interval for the Mantel-Haenszel risk 
difference. Statistics in Medicine. 2014; 2968-2983. 
Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular 
filtration rate.  Ann Int Med. 2009;150:604-12. 
Liu TF, Shafer RW. Web Resources for HIV type 1 Genotypic-Resistance Test 
Interpretation. Clin Infect Dis. 2006;42 (11):1608-1618. 
Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, 
Biometrics, 2000;56:309-315. 
Miettinen O, Nurminen M. Comparative Analysis of two rates. Statistics in Medicine. 
1985; 4:213-226. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035–43. 
Sato T. On the variance estimator for the Mantel-Haenszel risk difference. Biometrics. 
1989;42:311-323.  


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Woodcock A, Bradley C . Validation of the HIV treatment satisfaction questionnaire 
(HIVTSQ). Qual Life Res. 2001;10(6):517-531. 
 
Woodcock A, Bradley C. Validation of the revised 10-item HIV Treatment Satisfaction 
Questionnaire status version and new change version. Value Health. 2006;9(5):320-333. 
 


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15. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 15.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 15.2 
Appendix 2: Schedule of Activities 
Section 15.3 
Appendix 3: Assessment Windows 
Section 15.4 
Appendix 4: Study Phases and Emergent Adverse Events 
Section 15.5 
Appendix 5: Data Display Standards & Handling Conventions 
Section 15.6 
Appendix 6: Derived and Transformed Data 
Section 15.7 
Appendix 7: Reporting Standards for Missing Data 
Section 15.8 
Appendix 8: Values of Potential Clinical Importance 
Section 15.9 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Section 15.10 
Appendix 10: Time to Event Details 
Section 15.11 
Appendix 11: Snapshot Algorithm details 
 Section 15.12 
Appendix 12: Modified Snapshot Algorithm details 
Other RAP Appendices 
Section 15.13 
Appendix 13: Abbreviations & Trade Marks 
Section 15.14 
Appendix 14: Model Checking and Diagnostics for Statistical Analyses 
Section 15.15 
Appendix 15: Test of Homogeneity: Fleiss, Liu & Kelly Method 
Section 15.16 
Appendix 16: Final (EoS) Analysis  
Section 15.17 
Appendix 17: List of Data Displays 
Section 15.18 
Appendix 18: Example Mock Shells for Data Displays 
 


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15.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
15.1.1. Exclusions from Per Protocol Population 
A subject meeting any of the following criteria (Significant Protocol Deviations) will be 
excluded from the Per Protocol population: 
Number 
Exclusion criteria 
01 
Subject deviates from any inclusion or 
exclusion criteria, as recorded in the eCRF 
02* 
Subject took/received incorrect IP, i.e., 
other than the one to which they were 
randomized for greater than 10% of the 
total time On-treatment 
03* 
Interruption of IP for greater than 10% of 
the total time On-treatment, for reasons 
other than treatment-related adverse 
events/laboratory abnormalities, based on 
eCRF IP exposure forms or eCRF 
CONMEDS forms in case commercial 
supply is used before study completion. 
04 
HIV immunotherapeutic vaccines used 
05 
Concurrent use of drugs that may decrease 
DTG concentration for >7 days: 
(Carbamazepine, Oxycarbamazapine, 
Phenobarbital, Phenytoin, St. John's wort 
(Hypericum perforatum), rifampin 
06 
Concomitant use of rifapentin 
07 
Other experimental agents, antiretroviral 
drugs not otherwise specified in the 
protocol, cytotoxic chemotherapy, or 
radiation therapy used 
08 
Systemically administered 
immunomodulators used through Week 48 
visit 
09 
HCV therapy based on interferon or any 
other medications that have a potential for 
adverse drug-drug interactions with study 
treatment 
10 
Concomitant use of acetaminophen in 
subjects with acute viral hepatitis 
11 
Dofetilide or pilsicainide used concurrently 


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Number 
Exclusion criteria 
with DTG 
12 
Subject's change (i.e., substitution or dose 
modification) of DTG, 3TC or component of 
CAR (except protocol allowed switches, e.g. 
switch of booster) but was not withdrawn 
from the study 
13 
Subject became pregnant while on study 
14 
Permanent discontinuation of IP/withdrawal 
due to a reason of “Protocol Deviation” (as 
recorded in the eCRF) 
*Programmatically derived protocol deviations (PD), which are defined in a separate 
protocol deviations specification document. Please refer to Section 15.6.7 regarding cut-
off dates regarding protocol deviations leading to exclusion from the per protocol set. 


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15.2. 
Appendix 2: Schedule of Activities 
15.2.1. Protocol Defined Schedule of Events 
 
Procedures 
Screening Visita 
Randomized Phase 
 
Continuation 
Phasec 
Withdrawal 
Follow-upd 
Baseline/
Day 1 
4 
12 
24 
36 
48b 
52 
Every 12 
Weeks 
After  
Week 52 
Clinical and Other Assessments 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteriae 
X 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Prior ART history 
X 
 
 
 
 
 
 
 
 
 
 
Medical historyf 
X 
 
 
 
 
 
 
 
 
 
 
Menopause historyg 
X 
X 
 
 
 
 
 
X 
 
X 
 
Current medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
Cardiovascular risk assessment including 
vital signsh 
X 
 
 
 
 
 
 
 
 
 
 
Body Weight (BMI will be calculated within 
the eCRF)i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV risk factors and mode of transmission 
 
X 
 
 
 
 
 
 
 
 
 
CDC HIV-1 classification 
X 
X 
 
 
 
 
 
 
 
 
 
HIV associated conditionsj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Columbia Suicidality Severity Rating Scale 
 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Directed Physical Examl 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 


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Procedures 
Screening Visita 
Randomized Phase 
 
Continuation 
Phasec 
Withdrawal 
Follow-upd 
Baseline/
Day 1 
4 
12 
24 
36 
48b 
52 
Every 12 
Weeks 
After  
Week 52 
12-lead ECGm 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Willingness to Switcho 
 
Xo 
 
 
 
 
 
 
 
 
 
HIV TSQp 
 
X 
X 
 
X 
 
X 
 
 
X 
 
Symptom Distress Modulep 
 
X 
X 
 
X 
 
X 
 
X (every 24 weeks) 
X 
 
Laboratory Assessments 
Quantitative plasma HIV-1 RNAq 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Lymphocyte subsetr 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Plasma for storages 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Clinical chemistryt 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
PT/INR (for Child-Pugh) 
X 
 
 
 
 
 
 
 
 
 
 
Fasting lipids and glucoseu 
 
X 
 
 
X 
 
X 
 
 
Xv 
 
Urinalysis and spot urine for protein 
analysisw 
 
X 
 
 
X 
 
X 
 
 
X 
X 
Pregnancy testx, y 
S 
U/Sz 
S 
S 
S 
S 
S 
S 
S 
S 
 
HBsAg, anti-HBc, Anti-HBs, and HBV 
DNAaa 
X 
 
 
 
 
 
 
 
 
 
 
HCV antibody 
X 
 
 
 
 
 
 
 
 
 
 
RPR 
X 
 
 
 
 
 
 
 
 
 
 


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Procedures 
Screening Visita 
Randomized Phase 
 
Continuation 
Phasec 
Withdrawal 
Follow-upd 
Baseline/
Day 1 
4 
12 
24 
36 
48b 
52 
Every 12 
Weeks 
After  
Week 52 
Renal, bone and inflammatory marker 
analytes (blood/urine) and HbA1c, insulin 
and glucosebb 
 
X 
 
 
X 
 
X 
 
 
X 
 
Whole Blood (Virology)cc 
 
X 
 
 
 
 
X 
 
 
X 
 
Whole Blood (Telomere Length)dd 
 
X 
 
 
 
 
X 
 
 
Xee 
 
PBMCsff 
 
X 
 
 
X 
 
X 
 
 
Xgg 
 
Study Treatment 
IVRS/IWRShh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense IP  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IP accountability (pill counts) 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
ART - antiretroviral therapy, BMI - body mass index, CDC - centers for disease control and prevention, DNA - deoxyribonucleic acid, ECG – electrocardiogram, eCRF - electronic case 
report form, HBV – hepatitis B virus, HCV – hepatitis C virus, INR - international normalized ratio, IP - investigational product 
a. 
As soon as all Screening results are available, randomization may occur. 
b. 
Participants with plasma HIV-1 RNA 50 c/mL at Week 48 (primary endpoint) must have HIV-1 RNA level re-assessed by a second measurement performed 2-4 weeks later, 
occurring prior to Week 52.   
c. 
All participants on the DTG/3TC FDC arm who complete through Week 52 will have the opportunity to enter the Continuation Phase.  The Continuation Phase is not applicable for 
participants in Sweden and Denmark.  For participants who will not continue past Week 52, do not dispense study intervention. Participants completing the Continuation Phase 
must return to the clinic for an End of Continuation Phase visit when transitioning to commercial supplies or to an alternate ART regimen, if appropriate. At this visit, conduct study 
assessments as specified for all Continuation Phase visits except for dispensing study intervention.  
d. 
An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study intervention for participants with the following conditions at the last on-study visit:  ongoing AEs, 
serious adverse events (SAEs) regardless of attributability, and any laboratory abnormalities that are considered to be AEs or potentially harmful to the participant. However, the 
investigator, in consultation with the medical monitor, should follow-up with the participant until the event is resolved, stabilized, otherwise explained, or the participant is lost to 
follow-up 


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e. 
Inclusion/exclusion criteria will be assessed fully at the Screening visit. Changes between the Screening visit and the Day 1 visit should be considered to ensure eligibility, 
including review of additional assessments performed at Day 1. Genotypic resistance testing results if available MUST be provided to ViiV after screening and before 
randomization.    
f. 
Full medical history will be conducted prior to randomization and include assessments of cardiovascular, metabolic (e.g., Type I or II diabetes mellitus), psychiatric (e.g., 
depression), renal (e.g., nephrolithiasis, nephropathy, renal failure), and bone disorders.  
g. 
Menopause history will include date of last menstrual period (collected at Day 1, Week 52 or withdrawal) and menopausal status (collected at Screening, Week 52 or withdrawal) 
based on the criteria in the Protocol Section 11.4.1.  A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.    
h. 
Assessment for cardiovascular risk 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. BMI will be calculated within the eCRF. 
i. 
The same scale should be used to measure body weight at each visit.  
j. 
Based on the participant’s current CDC status in the past 6 months. 
k. 
On Day 1, the electronic Columbia Suicidality Severity Rating Scale (eC-SSRS), participant completed questionnaire is to be administered prior to the first dose.   
l. 
Limited physical examination to include blood pressure at Day 1 (recorded in eCRF) for Framingham score assessment.  Blood pressure to be measured after resting in a semi-
supine position for at least 5 minutes.  
m. A 12-lead ECG will be performed in a semi-supine position after resting for at least 5 minutes. 
n. 
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and administration of study 
intervention at Day 1.  
o. 
Willingness to Switch Survey must be done prior to randomization. 
p. 
Questionnaire/Surveys are recommended to be administered at the beginning of the visit before any other assessments are conducted.  Only conduct questionnaires/surveys at 
Withdrawal if occurring prior to Week 48, except the Symptom Distress Module which should also be collected if Withdrawal occurs during the Continuation Phase. 
q. 
See Virologic Withdrawal and Stopping Criteria Section of protocol (Section 7.1.1). 
r. 
Lymphocyte subset will include collection of CD4 and CD8 for calculation of Cd4:CD8 ratio.  CD8 will also be reported to sponsor. 
s. 
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  These 
samples will be used when needed such as when samples are lost, arrive at the laboratory unevaluable, or for genotypic and/or phenotypic analyses when participants meet 
Suspected and Confirmed Virologic Withdrawal criteria.  
t. 
See Protocol Appendix 7 for a list of clinical chemistry labs. 
u. 
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable. 
v. 
Collect fasting lipids and glucose if the Withdrawal visit occurs at Weeks 24 or 48. 
w. A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate. 
x. 
Women of childbearing potential only. S=serum, U=urine. Pregnancy events will be captured starting at Day 1 following exposure to study intervention. 
y. 
Remind females of reproductive potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements. 
z. 
Local Pregnancy result must be available prior to randomization on Day 1.  Local serum pregnancy test on Day 1 is allowed if it can be done, and results obtained, within 
24 hours prior to randomization. 
aa. HBV DNA testing will be performed for participants with positive anti-HBc and negative HBsAg and negative anti-HBs (past and/or current evidence).  Participants must return to 
the clinic to provide a sample for HBV DNA testing prior to randomisation. 
bb. Blood sample for HbA1c, insulin, glucose, renal, bone and inflammation biomarker assessments: Renal: Cystatin C, Beta-2-Microglobulin (urine), Retinol Binding Protein (RBP; 
urine), urine   B2M/creatinine ratio, urine RPB/creatinine ratio, urine albumin/creatinine ratio, urine protein/creatinine ratio, urine phosphate, serum creatinine; Bone: bone specific 


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alkaline phosphatase, procollagen type 1-N-propeptide, type 1 collagen cross-linked C-telopeptide, osteocalcin; Inflammation: Interleukin-6 (IL-6), High-sensitivity C reactive 
protein (hs-CRP), D-dimer, Soluble CD14 (sCD14), Soluble CD163 (sCD163); insulin and glucose for HOMA-IR calculation 
cc. Where local country or laboratory practices allow, whole blood (Virology) may be used for virologic analyses as described in the protocol.   
dd. Where local country or laboratory practices allow, whole blood will be used for telomere length evaluation. 
ee. Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 48. 
ff. 
Where local country or laboratory practices allow, PBMC collection samples may be used for virologic analyses as described in Protocol Section 8.10. 
gg. Collect sample only if Withdrawal visit occurs at Weeks 24 or 48. 
hh. At Screening, a subject number will be generated. 
 


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15.3. 
Appendix 3: Assessment Windows 
Laboratory data, health outcomes, vital signs, e-CSSRS and genotypic and 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. 
A window around a target Study Day will typically include all days from the midpoints between it 
and the target Study Days of the previous and the proceeding visits.  In general, the nominal target 
study day for week w is (7*w)+1. 
15.3.1. Definitions of Assessment Windows for Analyses 
 
Analysis Set 
/ Domain 
Parameter (if 
applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy, 
Labs and 
Health 
outcomes 
(not collected 
at Week 52) 
Laboratory Assessments 
(including HIV-1 RNA, 
lipids and biomarkers), 
HIVTSQ, SDM  
 
 
 
 
 
 
 
-28 
-4 
-4 
Screening 
 
 
1 
-3 
1 
Day 1 
 
 
29 
2 
56 
Week 4 
 
 
85 
57 
126 
Week 12 
 
 
169 
127 
210 
Week 24 
 
 
253 
211 
294 
Week 36 
 
 
337 
295 
378 
Week 48 
 
 
449 
379 
490 
Week 64 
 
 
7*w+1 
7*w-41 
7*w+42 
Week w, 
w=76, 88, ... 
 
 
Study Day 
of last dose 
+ 28 
>Study Day 
of last dose 
+1 
>Study Day of 
last dose +1 
Follow-up 
 
Efficacy and 
Safety Data 
collected at 
Week 48 and 
Week 52) 
Weight, BMI, eCSSRS 
 
 
 
 
 
 
-28 
-4 
-4 
Screening 
 
 
1 
-3 
1 
Day 1 
 
 
29 
2 
56 
Week 4 
 
 
85 
57 
126 
Week 12 
 
 
169 
127 
210 
Week 24 
 
 
253 
211 
294 
Week 36 


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Analysis Set 
/ Domain 
Parameter (if 
applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
 
 
337 
295 
350 
Week 48 
 
 
365 
351 
406 
Week 52 
 
 
449 
407 
490 
Week 64 
 
 
7*w+1 
7*w-41 
7*w+42 
Week w, w= 
76, 88, ... 
 
 
Study Day 
of last dose 
+ 28 
>Study Day 
of last dose 
+1 
>Study Day of 
last dose +1 
Follow-up 
 
1. NOTES: 
• 
For parameters which are not scheduled to be assessed at particular visits, the all-inclusive windows 
defined will still be used.  
• 
Assessments at unscheduled visits will be included for ‘any time On-treatment’ time points and in 
data listings, as well as algorithms that make use of additional data (e.g., Snapshot). 
• 
In the event a baseline value is missing, the latest pre-dose value prior to baseline will be used, 
notwithstanding this date occurring more than 3 days prior to baseline.  
 


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15.4. 
Appendix 4: Study Phases and Emergent Adverse Events 
15.4.1. Study Phases 
Data collected from both arms up to and including the date of the Week 52 visit will be 
considered to be during the Randomized Phase of the study.  
 
For subjects randomized to DTG/3TC, data collected after Week 52 will be considered to 
be during the Continuation Phase of the study. For subjects randomized to the CAR arm, 
Continuation Phase of the study is not applicable. 
 
Phase 
Randomized 
Arm 
Start 
End  
Randomized 
Phase 
DTG/3TC 
IP start date 
Week 52 DOV 
 or  
Withdrawal date before Week 52 DOV 
CAR 
Day 1 DOV 
Week 52 DOV  
or  
Withdrawal date before Week 52 DOV 
Continuation 
Phase 
DTG/3TC 
Week 52 
DOV+1 
IP end date or Withdrawal date 
CAR 
Not applicable 
Not applicable 
 
 
15.4.1.1. 
Study Phases for for Laboratory, HIV Associated Conditions, Vital 
Signs, Health Outcomes and Genotypic and Phenotypic Data  
Treatment State 
Definition 
Pre-Treatment 
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Study 
Treatment Stop Date + 1 
Post-Treatment 
Date > Study Treatment Stop Date +1 
1. NOTES:  
• 
If the study treatment stop date is missing then the assessment will be considered to be On-Treatment 
15.4.1.2. 
Study Phases for Adverse Events 
For adverse events, partial AE start date will use imputation as described in Section 
15.7.2.1. In the case of a completely missing start date, the event will be considered to 
have started On-treatment unless an end date for the AE is provided which is before start 
of study treatment; in such a case the AE is assigned as Pre-treatment. 


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Treatment State 
Definition 
Pre-Treatment 
AE Start Date < Study Treatment Start Date 
On-Treatment 
If AE onset date is on or after treatment start date & on or before 
treatment stop date. 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment 
Stop Date  
Post-Treatment 
If AE onset date is after the treatment stop date. 
AE Start Date > Study Treatment Stop Date  
Onset Time Since 1st Dose 
(Days) 
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - 
Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - 
Treatment Start Date +1 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
Drug-related 
If relationship is marked ‘YES’ on eCRF.  
NOTES:  
• 
Partial AE start date will use imputation as described in Section 15.7.2.1 
• 
In the case of a completely missing start date, the event will be considered to have started On-treatment 
unless an end date for the AE is provided which is before start of investigational product; in such a case the AE 
is assigned as Pre-treatment. 
• 
If the IP Stop Date is missing, then any event with a start date on or after IP Start Date will be considered to be 
On-treatment.  
• 
If the start date of the AE is after IP Stop Date but has been recorded as potentially related to IP, then it will be 
classified as On-treatment. 
 
15.4.1.3. 
Study Phases for Concomitant Medication 
• Prior medications: Those taken (i.e., started) before the start date of investigational 
product.  
• Concomitant medications: Those taken (i.e., started or continued) at any time between 
the start date and stop date of study treatment, inclusive. Prior medications that were 
continued during this period are also considered as concomitant medications.  
• Post treatment medications: Those started after the stop date of study treatment. 
Concomitant medications that were continued during this period are also considered 
as post-treatment medications. 
It will be assumed that medication has been taken on the date in which it is reported as 
started or stopped. For any medication starting on the same date as study treatment, it will 
be assumed that the medication was taken after the subject started taking study treatment. 
Duration of episodes of concomitant medication will be calculated as medication stop 
date – medication start date, so long as the medication is defined as concomitant 
according to the rules above (and presented below in the scenario matrix). Durations will 
be left blank if stop date is missing. 
ART medications will also be classified as prior to screening, concomitant to screening 
and/or post-treatment according with the following modifications: 


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• ART starting on study treatment stop date will be considered as only post-
treatment and not concomitant. It is expected that after discontinuation of study 
treatment, a subject may immediately begin taking another ART. 
• ART stopping on study treatment start date will only be considered as prior and 
not concomitant. 
• Any ART entered on the Prior ART eCRF with partial end date will be assumed 
to have finished before Screening. 
• ART stopped prior to screening includes all ART that has stopped prior to 
screening. All ingredients from any regimen that is switched to another regimen 
prior to the screening visit e.g. from TDF-based to TAF-based ART will be 
presented as having stopped.   
• ART Medications received at or after Screening includes all ART that is either 
being received at the screening visit or is introduced at a later date. Note, for CAR 
patients this could be pre- or post- randomization and for DTG/3TC patients this 
can be pre-randomization only; at randomization and beyond for DTG/3TC 
patients, ART is recorded as ‘study treatment’ and not recorded via ART-specific 
concomitant medication pages. 
• ART Medications Received at Screening includes all ART that is ongoing at the 
screening visit only.  


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Pre-treatment 
On-treatment 
Post-treatment 
Prior 
Concomitant 
Post 
(a) 
x⎯⎯⎯ 
IP Start Date 
 
IP Stop Date 
IP Stop Date+1 
 
Y 
N 
N 
(b) 
x⎯⎯⎯⎯  
⎯⎯⎯⎯x 
 
Y 
Y 
N 
(c) 
x⎯⎯⎯⎯  
⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
Y 
Y 
Y 
(d) 
 
x⎯⎯⎯ 
 
N 
Y 
N 
(e) 
 
x⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
N 
Y 
Y 
(f) 
 
 
x⎯⎯⎯ 
N 
N 
Y 
(g) 
?⎯⎯⎯x 
 
 
Y 
N 
N 
(h) 
?⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
 
Y* 
Y 
N 
(i) 
?⎯⎯⎯⎯ 
⎯⎯⎯⎯ 
⎯⎯⎯⎯x 
Y* 
Y* 
Y 
 
 
 
 
 
 
 
(j) 
x⎯⎯⎯⎯  
⎯⎯⎯⎯ 
⎯⎯⎯⎯? 
Y 
Y** 
Y** 
(k) 
 
x⎯⎯⎯⎯ 
⎯⎯⎯⎯? 
N 
Y 
Y** 
(l) 
 
 
x⎯⎯⎯? 
N 
N 
Y 
(m) 
?⎯⎯⎯⎯ 
 
⎯⎯⎯⎯ 
 
 
⎯⎯⎯⎯? 
Y*** 
Y*** 
Y*** 
 
 
 
 
 
 
 
 
 
 
(n) 
x⎯⎯⎯⎯ 
x 
 
 
 
 
Y 
Y 
N 
(o) 
?⎯⎯⎯⎯ 
x 
 
 
 
 
Y* 
Y 
N 
(p) 
 
x 
⎯⎯⎯⎯x 
 
 
 
N 
Y 
N 
(q) 
 
x 
⎯⎯⎯⎯ 
x 
 
 
N 
Y 
N 
(r) 
 
 
 
x 
⎯ 
⎯⎯⎯⎯x 
N 
Y 
Y 
(s) 
 
 
 
x 
⎯ 
⎯⎯⎯⎯? 
N 
Y 
Y** 
(t) 
 
 
 
 
x 
⎯⎯⎯⎯x 
N 
N 
Y 
(u) 
 
 
 
 
x 
⎯⎯⎯⎯? 
N 
N 
Y 
(v) 
 
 
x⎯⎯⎯⎯ 
⎯ 
x 
 
N 
Y 
Y 


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1. x = start/stop date of medication 
2. ? = missing start/stop date of medication 
3. * If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be assumed that the medication was ongoing from the Pre-treatment 
phase 
4. ** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then usage will be assumed to be ongoing for the remainder of the study 
5. *** If a medication has no start or stop date it will be assumed that the medication was ongoing from the Pre-treatment phase to the Post-treatment phase 
6.  
 
15.4.2. Combining Treatment Phases and States 
 
On-treatment and Post-treatment assessments and events will be classified as occurring during the Randomized or Continuation Phase of 
the study as follow: 
• 
If a subject did not enter the Continuation Phase, then any Post-treatment data will be assigned to the Randomized Phase.  
• 
For subjects who did enter the Continuation Phase, any Post-treatment data will be assigned to the Continuation Phase. 
 
For concomitant medication, if there is a duration overlapping any period then this should be reflected such that a concomitant medication 
(at time of the data cut): 
• Starting and ending before treatment start then phase is set to missing  
• Is taken at any point during the randomized phase only then phase is set to “Randomized Phase” 
• Is taken at any point during the continuation phase only then phase is set to “Continuation Phase” 
• Is taken at any point across the randomized and continuation phases then phase is set to “Randomized and Continuation Phase” 
 


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15.4.3. Emergent Flag for Adverse Events 
 
Flag 
Definition 
 Emergent 
• Emergent refers to AE Severity/ Lab toxicity that develops or increases in intensity after baseline 
 
For adverse events, partial AE start date will use imputation as described in Section 15.7.2.1. In the case of a completely missing start 
date, the event will be considered to have started On-treatment unless an end date for the AE is provided which is before start of 
investigational product; in such a case the AE is assigned as Pre-treatment. 
For laboratory data, there will be no imputation of dates, which are expected to be fully complete and available in SDTM transfers. Any 
laboratory dates that are partially missing will be queried.  


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15.5. 
Appendix 5: Data Display Standards & Handling Conventions 
15.5.1. Reporting Process 
Software 
• The currently supported versions of SAS software and any other statistical reporting software required for the analysis and reporting will be used. 
Reporting Area 
HARP Server 
 uk1salx00175 
HARP Compound 
 :\ARPROD\GSK3515864\mid208090\reporting_effort_number 
Analysis Datasets  
• Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG Version 1.1 or above).  
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be implemented as SDTM. 
Generation of RTF Files 
• RTF files will be generated for all reporting efforts. 
15.5.2. Reporting Standards 
General 
• The current GSK Statistical Display Standards Library 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  
• Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level listings should be located in the modular 
appendices as ICH or non-ICH listings 
• All data displays will use the term “subjects” rather than “participants”. 
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. 


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General 
• 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: 
• Actual 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 subject’s listings.  
Unscheduled Visits 
• Unscheduled visits will be assigned to a study visit using the all-inclusive windows defined in Section 15.3. 
• However, data summaries will only report visits that are planned assessment time points for each parameter (according to the Time and Events 
table). 
• Assessments at unscheduled visits will be included for ‘any time On-treatment’ time points and in data listings, as well any algorithms that make 
use of additional data (e.g., Snapshot). 
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 Statistical Display Standard Statistical Principals 7.01 to 7.13. 
 


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15.6. 
Appendix 6: Derived and Transformed Data 
 
15.6.1. General 
 
Multiple Measurements at One Time Point 
• If there are multiple assessments within Screening window, the last assessment before Day 
1 will be used 
• If there are multiple assessments within Day 1 window, the latest pre-dose assessment will 
be used 
• With the exception of the Snapshot endpoints, if after window assignment (see Section 
15.3), there are multiple valid assessments of a parameter within the same window, then the 
following hierarchy will be used to determine the value to be used for summary statistics of 
observed values: 
o the assessment closest to the window target Study Day; 
o if there are multiple assessments equidistant from the target Study Day, then for 
continuous variables the mean of these values will be used and for categorical 
variables the worse assessment. For HIV-1 RNA, the geometric mean of the 
number of copies will be used as opposed to the arithmetic mean 
• Assessments not chosen for use in summary statistics by this algorithm will still appear in 
the associated listings. Also, such valid assessments will be used when determining values 
of potential clinical concern for the ‘any time On-treatment’ time point, and for any algorithm 
that has specific rules for which observation to use (e.g., SNAPSHOT). 
• In the event of laboratory re-tests being performed the last re-test in the visit window will be 
used.  For example: 
• If a subject had a week 24 viral load and then two re-tests (i.e. three viral loads labeled as 
week 24, unscheduled 1 unscheduled 2). and the first two viral loads were within the upper 
bound of the week 24 visit (Day 210) but the last re-test was slotted to week 36 then the last 
re-test would not be used for the week 24 snapshot. 
• If a subject had a week 24 viral load but the re-test was performed on Day 220 (week 36) 
then the re-test viral load would not be used for the week 24 snapshot. 
Study Day 
• Calculated as the number of days from initial study treatment start date: 
• Ref Date = Missing                       → Study Day = Missing  
• Ref Date < Treatment Start Date   → Study Day = Ref Date –Treatment Start Date     
• Ref Data ≥ Treatment Start Date   → Study Day = Ref Date – (Treatment Start Date) + 
1   
 
Note that Treatment Start Date is considered to be on Study Day 1 and the day before this is 
Study Day -1; i.e., there is no Study Day 0. 
Post-baseline 
• Post-baseline refers to the combined time periods of On-treatment and Post-treatment. 
Post-baseline may be further specified according to phase of the study: Randomized Phase 
and Continuation Phase. 
Study Drug 
• Study Drug refers to either Investigational Product DTG/3TC or CAR. 


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15.6.2. Study Population 
 
Demographics 
Age 
• Age, in whole years, will be calculated with respect to the subject’s Screening visit where year 
of birth is collected.   
• GSK Statistical Display Standard algorithms will be used for calculating age where birth date will 
be imputed as follows: 
o For all subjects, the missing date and month will have this imputed as ‘30th June’. 
o For analysis purposes, if a subject did not fail to meet inclusion criteria #1 (aged 18 years or 
older), then set any age imputed as <18 by the GSK Statistical Display Standard algorithm 
to 18. If the subject failed to meet inclusion criteria #1 then the imputed age will not be 
reset. 
• 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. 
Framingham Risk Equation 
The predicted probability, 𝑝̂, of having a cardiovascular disease (CVD) within the next 10-years 
according to the Framingham formula [D’Agostino, 2008] is 
 
for females: 
𝑝̂F = 1 – S0(t)exp{ 2.32888 × log(age) + 1.20904 × log(TC) - 0.70833 × log(HDL) + 2.76157 × log(SBPu) + 2.82263 × log(SBPt) +  
0.52873 × Is + 0.69154 × Id - 26.1931}, 
 
for males: 
𝑝̂M = 1 – S0(t)exp{ 3.06117 × log(age) + 1.12370 × log(TC) - 0.93263 × log(HDL) + 1.93303 × log(SBPu) + 1.99881 × log(SBPt) +  
0.65451 × Is + 0.57367 × Id - 23.9802}, 
 
where 
S0(t) = {0.95012, females
0.88936, males  
TC = total serum cholesterol (mg/dL), 
HDL = serum HDL cholesterol (mg/dL), 
SBPu = systolic blood pressure (mmHg) if subject is not treated for high blood pressure (note 
that if a subject is treated for high blood pressure then log(SBPu) = 0) 
SBPt = systolic blood pressure (mmHg) if subject is treated for high blood pressure (note that if 
a subject is not treated for high blood pressure then log(SBPt) = 0) 



=
otherwise
smo
current
Is
,0
ker
,1
 



=
otherwise
diabetic
Id
,0
,1
 


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Demographics 
• 
A subject will be considered as treated for high blood pressure if at Screening/Day 1 visit the subject 
receives any medication for hypertension (need to check whether any of the terms “HYPERTENSION”, 
“HYPERTENTION”, “HIPERTENSION” or similar is included in the description of SDTM.CM.CMINDC 
variable) 
• 
Smoking status is collected on Screening/Day 1 visit as “Never smoked”, “Current smoker”, “Former 
smoker”. For “Current smoker” Is  should be set to 1 and for “Never smoked” and ”Former Smoker” Is  
should be set to 0. 
• 
A subject is classified as diabetic if “Current”  or “Past” has been selected in the medical history eCRF 
page completed on Screening/Day 1 visit; if “Not assessed” has been selected then the subject will be 
considered diabetic if the subject receives any medication for diabetes on Screening/Day 1 visit (need to 
check whether any of the terms “DIABETES” or “DIABETIC” is included in the description of 
SDTM.CM.CMINDC variable). 
• 
The 10-year probability of CVD will not be calculated for subjects who have indicated “Current “or “Past” 
myocardial infarction in the medical history eCRF page completed on Screening/Day 1 visit. These 
subjects will not be included in summary statistics (e.g. mean, sd, median) of 10-year CVD risk in 
‘Summary of Baseline Cardiovascular Risk Assessments Table’,but will be counted in the highest 
category of risk (i.e. >20%) in the summary by category. 
Extent of Exposure 
• Exposure to DTG/3TC will be calculated from the IP eCRF pages.  Exposure to CAR will be 
calculated from the CONART eCRF pages.  
• Subjects who were randomized to DTG/3TC but did not report a IP start date will be categorised 
as having zero days of exposure.  
• Subjects who were randomized to CAR but withdrew on Day1 will be categorised as having 
zero days of exposure 
• Missing Treatment Stop Date will be imputed, for purposes of calculating exposure, as the date 
of last visit or the recorded date of withdrawal/completion, whichever is earlier. 
• Actual exposure will be calculated where the duration of any dosing interruptions based on 
eCRF data will be subtracted from the result above. 
• The ratio (percentage) of the actual exposure to the overall exposure (i.e. study treatment stop 
date – study treatment start date+1) will be used to define protocol deviation leading to 
exclusion from PP Population due to study treatment interruption (i.e. >10%). 
Strata 
• For analysis purposes, randomization strata will be used from that derived using eCRF data, 
even if this differs from the strata captured in IVRS. 
• For patients randomized to DTG/3TC, baseline third agent class is collected on the prior ART 
history form. For patients randomized to current CAR, baseline third agent class is collected on 
the concomitant ART form. 
• Third agent class is identified using terms from the GSK Drug Dictionary 


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15.6.3. Efficacy 
 
HIV-1 RNA 
Snapshot  
• It is intended to be primarily a virologic assessment of the endpoint, and as such follows a 
“virology first” hierarchy. 
• Plasma HIV1-RNA < 50 c/mL or plasma HIV1-RNA ≥ 50 c/mL within an analysis window is 
typically determined by the last available plasma HIV-1 RNA measurement in that window while 
the subject is On-treatment. 
• When no HIV-1 RNA data is available within a window, a subject cannot be classified under 
HIV1-RNA < 50 c/mL.  Depending on the reason for lack of data, the subject will be classified as 
a HIV1-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 subject 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 subject withdraw for reasons other than AE and was not 
suppressed at the time, they will be a HIV1-RNA ≥ 50 c/mL. 
• For each scheduled assessment time, the snapshot response rate for a given threshold (e.g., 
<50 c/mL) is defined as: 
Snapshot Rate= Number of responders in that analysis window   
Number of subjects in the analysis population  
• Full details of the algorithm, including the handling of special cases, are included in Section 
15.11 of note, the date at which the subject ‘discontinue/withdrawn from the study’ in the 
Snapshot algorithm is the date of treatment discontinuation, rather than the date of study  
withdrawal, 
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.   
• Qualitive measures (i.e. “target detected” and “target non-detected”) may also be provided by 
the laboratory vendor for values <40 c/ml. When a measurement of plasma HIV-1 RNA is below 
the limit of quantification (i.e. 40 c/mL) and is qualitatively observable that will be denoted as a 
“Target Detected” measure, while HIV-1 RNA below the limit of quantification that is not 
qualitatively observable that will be denoted as “Target Not Detected”. Any measurements <40 
c/mL characterised as “Target Non-Detected” or “Target Detected” will be captured in the 
database. 
Confirmed Virologic Withdrawal (CVW), Suspected Virologic Withdrawal (SVW) and 
Precautionary Virologic Withdrawal (PVW) and potential Precautionary Virologic Withdrawal 
(pPVW) 
Please refer to the protocol, Section 7.1.1 for more details of the derivation of CVW, 
PVW, pPVW and SVWs.  


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HIV-1 RNA 
PVW (leading to discontinuation) 
• 
May be met after two consecutive assessments with HIV-1 RNA >=50 and <200 c/mL without an 
identifiable, non-virologic cause (immunization, illness, nonadherence) and after discussion with 
Medical Monitor, OR 
• 
Will be met with three consecutive on treatment assessments with HIV-1 RNA >=50 and <200 c/mL 
pPVW 
• 
Will be met after two consecutive assessments with HIV-1 RNA >=50 and <200 c/mL. The current 
HIV-1 RNA values must be below 200 c/mL, but the previous HIV-1 RNA can also have been 
>=200 c/mL    
SVW 
• 
One assessment with HIV-1 RNA >= 200 c/mL after Day 1 with an immediately prior HIV-1 RNA 
<50 c/mL. 
 
CVW 
• 
One assessment with HIV-1 RNA >= 200 c/mL after Day 1 with an immediately prior HIV-1 
RNA >=50 c/mL 
 
General Considerations 
• 
The subsequent HIV-1 RNA sample taken after SVW will be used for the determination of CVW.  
• 
Based on the protocol specific conditions outlined in the protocol, derivation of SVW and CVW will 
use nominal visits and unscheduled visits. 
• 
Visit windowing will not be applied.  
• 
The condition of 2-4 weeks between the suspected and confirmatory re-test (as described in 
protocol Section 7.1) will not be used when programmatically identifying CVW. 
• 
A patient can only be classified as CVW for the analyses if the patient has not withdrawn IP at the 
time of the HIV-RNA re-test value (at CVW value), where Treatment Start < HIV-1 RNA sample date 
<= Treatment Stop Date + 1 (if Treatment Stop date exists). Note: study drug interruptions will not 
be taken into account when programmatically identifying CVW. 
• 
Similarly, viral loads above criteria cut-offs resulting in SVW, CVW, PVW and pPVW need to have 
occurred post-Day 1 in order for the criteria to be met. For example an SVW can occur at Week 4 if 
Week 4 HIV-1 RNA >=200 i.e. the viral load above SVW criterion occurred post-Day 1.  
• 
Additional guidelines specified in the protocol related to patient management only and will not be 
taken into account when programmatically identifying CVW. 
• 
The SVW can become a pPVW, and then later a PVW, if the confirmatory viral loads are between 
50 and 200 c/mL 
• 
Please refer to Section 7.1.1 of the protocol for details of the derivation. 
 
CDC HIV-1 Classification and HIV-associated conditions 
• HIV associated conditions will be assessed according to the 2014 CDC Revised Classification 
System for HIV Infection in Adults (see protocol Section 11.12).  


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HIV-1 RNA 
• Any 'other’ conditions reported in the eCRFs will be identified programmatically before being 
sent for clinical review to determine whether they should be classed as stage 3 associated 
conditions. Review will be ongoing and as a minimum will take place prior to each reporting 
effort. 
 
15.6.4. Safety 
Extent of Exposure 
 
• Exposure to DTG/3TC will be calculated from the IP eCRF pages.  Exposure to CAR will be 
calculated from the CONART eCRF pages. Number of days of exposure to study drug will be 
calculated as: 
Duration of Exposure in Days = (Treatment Stop Date –Treatment Start Date) + 1 
 
For subjects randomized to DTG/3TC or CAR at Day 1: 
• For Randomized Phase: 
o For patients completing the Randomized Phase Exposure = IP Start Date  to (Week 
52 DOV -1) 
o If a subject discontinues prior to Week 52, the IP Stop Date recorded in the eCRF 
will be used. A partial or missing IP stop date is handled as described in Section 
15.7.2.1.  
o A Day 1 Date of Visit will be used for partial or missing IP start date. 
• The overall exposure is calculated as 
o Exposure = IP Stop Date – IP Start Date + 1 
 
• Duration of dosing in subject years will be calculated as the sum of subject duration of dosing in 
days (across all subjects)/365.25 
 
• Subjects who were randomized to DTG/3TC but did not report a IP start date will be categorised 
as having zero days of exposure.  
• Subjects who were randomized to CAR but withdrew on Day1 will be categorised as having zero 
days of exposure. 
• Missing Treatment Stop Date will be imputed, for purposes of calculating exposure, as the date 
of last visit or the recorded date of withdrawal/completion, whichever is earlier. 
• An alternative calculation of exposure will be performed where the duration of any dosing 
interruptions based on eCRF data will be subtracted from the result above. 
• The ratio (percentage) of the actual exposure to the overall exposure (i.e. study treatment stop 
date – study treatment start date+1) will be used to define protocol deviation leading to exclusion 
from PP Population due to study treatment interruption (i.e. >10%). 
Adverse Events 
AE Severity – DAIDS Grading 
• The DAIDS grading (VERSION 2.1, March 2017) for severity of clinical adverse events will be 
performed. 


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Extent of Exposure 
• See protocol for DAIDS grading criteria. 
Adverse Events of Special Interest (AESI) 
The preferred terms for each AESI will be review by safety and clinical team and updated before 
each formal analysis in a separate document. The following table below shows the AESI categories. 
AESI  
Anxiety 
Depression and hypomania 
Drug Hypersensitivity 
Insomnia 
Nightmare/Abnormal Dreams 
Rash 
Sleep disorder 
Suicidality and self-injury 
 
Laboratory Parameters 
• Additional non-protocol specified laboratory assessments performed at the institution’s local 
laboratory that are databased will not be included in the listings or analyses/summaries. All 
analyses will be based on central laboratory assessments only. 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.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> 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, as specified in the 
protocol.  
• 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 summarising toxicity grades for such parameters, they will be categorised as to whether 
they are above or below the midpoint of normal range. 
 
Parameter 
Below Midpoint 
Above Midpoint 
Calcium 
Hypocalcaemia 
Hypercalcaemia 
Fasted glucose 
Hypoglycaemia 
Hyperglycaemia 
Sodium 
Hyponatremia 
Hypernatremia 
Potassium 
Hypokalemia 
Hyperkalemia 
Lipid-Modifying Agents 
• The following ATC codes correspond to lipid-modifying agents: 
o ATC Level 2: C10 
o ATC Level 3: C10A, C10B (if Level 2 is not available) 


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Laboratory Parameters 
o ATC Level 4: C10AA, C10AB, C10AC, C10AD, C10AX, C10BA, C10BX (if level 2, 3 are not 
available) 
• Subjects are considered to have used a lipid modifying agent at baseline if they were taking the 
medication at the time of their baseline laboratory assessment or if they stopped their lipid 
modifying medication within 12 weeks of their baseline lipid testing date.  
National Cholesterol Education Program (NCEP) Lipids Categories 
• In addition to DAIDS toxicity scales (see protocol), lipid values will be categorized according to 
the 2001 NCEP Adult Lipid Guidelines [Grundy, 2001].  
Parameter 
Value Range 
(mmol/L) 
Value Range 
(mg/dL) 
Category 
Triglycerides 
<1.70 
<150 
Normal 
1.70 to <2.26 
150 to <200 
Borderline High 
2.26 to <5.65 
200 to <500 
High 
5.65 
500 
Very High 
Total Cholesterol 
<5.18 
<200 
Desirable 
5.18 to <6.21 
200 to <240 
Borderline High 
6.21 
240 
High 
HDL Cholesterol 
<1.04 
<40 
Low 
1.04 to <1.56 
40 to <60 
Normal 
1.56 
60 
High 
LDL Cholesterol 
<2.59 
<100 
Optimal 
2.59 to <3.37 
100 to <130 
Near/Above Optimal 
3.37 to <4.14 
130 to <160 
Borderline High 
4.14 to <4.92 
160 to <190 
High 
4.92 
190 
Very High 
Total Cholesterol / HDL Cholesterol Ratio 
• When both total cholesterol and HDL cholesterol results are available from the same date for a 
subject, then the ratio will be calculated by dividing the total cholesterol result by the HDL 
cholesterol result. The ratio can be classified as follows: 
 
Parameter 
Value Range 
Total Cholesterol / HDL Ratio 
< 3.5 
3.5 to < 4.4 
4.4 to < 5 
 5 
Glomerular Filtration Rate (GFR) 
• Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [Levey et al.] will be 
used by the central laboratory to provide an estimate of GFR, in mL/min per 1.73 m2, as follows 
for the CKD-EPI creatinine equation: 
 


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Laboratory Parameters 
where age (in years) is at time of assessment, κ = 0.7 if female or 0.9 if male, α = -0.329 if female 
and -0.411 if male, min() indicates the minimum of CRT/κ or 1, max() indicates the maximum of 
CRT/κ or 1, and CRTmg/dL is serum creatinine concentration in mg/dL. The serum creatinine 
concentration in mg/dL is obtained from GSK standard units of mol/L as CRTmg/dL =0.0113x 
CRTmol/L.  
CKD-EPI Cystatin C Equation (2012) 
The following will be used for the CKD-EPI Cystatin C Equation: 
eGFR = 133 x min(Scys/0.8, 1)-0.499 x max (Scys/0.8, 1)-1.328 x 0.996Age x 0.932 [if female] 
Abbreviations / Units  
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
Scys (standardized serum cystatin C) = mg/l 
min = indicates the minimum of Scys/0.8 or 1 
max = indicates the maximum of Scys/0.8 or 1 
age = years 
Assays 
Hepatitis Status 
• Hepatitis C status will be determined using antibody (IgM or IgG) and/or hepatitis C virus (HCV) 
RNA assessments performed during screening.  
• 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., ≥43 IU/mL 
[≥1.63 log IU/mL]) or not 
• Antibody (IgM or IgG) status with ‘BORDERLINE’ or ‘REACTIVE’ will be considered Positive 
• A subject will be considered positive for hepatitis B virus (HBV) if they have a positive surface 
antigen or detectable HBV DNA result during screening. Subjects positive for HBV are not 
allowed to enter the study. 
 
BMI 
• BMI classification is based on standard categories adopted by the WHO and FDA: 
Underweight = BMI of < 18.5 kg/m2 
Normal = BMI of 18.5 – 24.99 kg/m2 
Overweight = BMI of 25 – 29.99 kg/m2 
Obese = BMI of ≥ 30 kg/m2 
 


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Other Safety Endpoints 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• Missing data will not have any imputation performed. 
• A positive alert is triggered if a subject has reported suicidal ideation/behaviour in categories 4-
9. 
• Questions in categories 3-5 will be triggered if suicidal ideation is reported in categories 1 
or/and 2.  
• Incomplete calls: 
o when no complete call is databased on the same day, the data from the incomplete 
call will be used 
o if a subject has only an incomplete call, and it resulted in a positive alert, the 
relevant pages in the eCRF should be completed, even though the call was 
incomplete 
o when a complete call is databased on the same day, the data from the complete 
call will be used in the summaries. 
• Duplicate calls, if they occur on the same day: 
o Both calls will be reported in the listings. 
o For summary tables, the entry with latest time record will be used.  
o For summary tables at baseline, unscheduled repeat visits will not be summarised.  
o Relevant eCRF pages will be completed based on the latest entry (if it was a 
positive alert).  
• Late Day 1 assessments 
o Late DAY 1 assessments will be summarised as representing baseline status (i.e., 
treated as true DAY 1 assessments).  Where this leads to multiple DAY 1 
assessments, ‘complete’ assessments will be used over ‘incomplete’ assessments 
to represent baseline status. Such assessments will be considered DAY 1 if they 
occur by Day 14. 
• Day 1 assessments performed at later visits 
o DAY 1 assessments on (or close to) study day 1 will be accepted as DAY 1 
assessments (as above).  For DAY 1 assessments performed at later visits, the 
‘Lifetime’ assessment observation will not be summarised but the ‘Within the past 2 
months’ assessment will be used as a surrogate for the later post-baseline visit 
assessment. 
Homeostatic model assessment-Insulin Resistance (HOMA-IR) 


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• 
HOMA-IR = (fasting plasma insulin (mU/L) * fasting plasma glucose (mmol/L)) / 22.5. 
• HOMA-IR categories will be categorised as follows: 
o <2 
o 2 to <3 
o 3 to <4 
o >=4 
   
All HOMA-IR analyses will be based on fasting values and only patients with post-baseline 
values will be included in analyses (i.e. patients with missing post-baseline HOMA-IR will not be 
included in summary tables or figures). Additionally, patients who are diabetic as captured on 
the medical history form at screening will be excluded from all HOMA-IR analyses. Finally, any 
patient who has taken an anti-diabetic medication (ATC code “A10” (DRUGS USED IN 
DIABETES)) as captured on the medical history form up to screening will be removed from the 
analysis. 
 
 


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15.6.5. Viral Genotyping and Phenotyping 
 
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' 
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 RAL, EVG, BIC or DTG: 
 
Amino Acids in 
HIV Integrase for 
Analysis 
H51Y, T66A/I/K, L74M, E92Q/V/G, Q95K, T97A, G118R, F121Y, 
E138A/K/D, G140A/C/S, Y143C/H/R/K/S/G/A, P145S, Q146P, S147G, 
Q148H/K/R, V151I/L/A, S153F/Y, N155H/S/T, E157Q, G163R/K, S230R, 
R263K,  
L68V/I*, L74I*, E138T*, V151I*, G193E* 
NOTES: 
• 
Current listing includes INSTI mutations identified via the Stanford HIV Resistance database, or identified 
during in vitro passage of DTG*, or as seen in a previous DTG studies in INI-experienced subjects* (i.e. 
ING112574) and may be modified in case of additional substantive data availability. This table is updated 
only by Virologists. 
• 
INI mutations listed taken from Stanford HIV Resistance Database (http://hivdb.stanford.edu/DR/cgi-
bin/rules_scores_hivdb.cgi?class=INI cited 25 Oct 2019) and accessed on 28Oct/2020. 
• 
Each INI mutation listed had a score of 15. INI substitutions listed above in bold had a score for EVG or 
RAL of =60. 
• 
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. 


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Genotype 
Amino Acid Changes 
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, I54M/L/V, Q58E, T74P, L76V, 
V82A/T/F/L/S, N83D, I84V, N88S, L90M 
Note: List generated from IAS_USA Guideline, - 2019 Drug Resistance Mutations Update Volume 
27, Issue 3, September /October 2019 
 
Susceptibility Scores 
Stanford Genotypic Susceptibility Score (S-GSS) 
• To establish genotypic susceptibility to ART treatment, a genotypic sensitivity score will be 
calculated. 
• Genotypic sensitivity to each drug will be assessed using the HIVdb, the Integrated Genotypic 
Resistance Interpretation System [Liu, 2006]. 
• In the Stanford HIVdb system, each HIV-1 drug resistance mutation is assigned a drug penalty 
score. Also, for combination of specific mutations an extra penalty is assigned. The penalty 
scores for each drug resistance mutation and for combination of drug resistance mutations at 
different positions within each genomic region are available here 
NNRTI: https://hivdb.stanford.edu/dr-summary/mut-scores/NNRTI/ 
NRTI:  https://hivdb.stanford.edu/dr-summary/mut-scores/NRTI/ 
PI:  https://hivdb.stanford.edu/dr-summary/mut-scores/PI/ 
INSTI:  https://hivdb.stanford.edu/dr-summary/mut-scores/INSTI/.  
 
• 
Any mutations that are not included the Stanford database will contribute 0 to the GSS calculations. 
• 
The drug resistance estimate is obtained by adding together the penalty scores from all mutations 
associated with resistance to that drug and by adding also the penalty for combinations of certain 
mutations, if present, and then a numeric score (S-GSS) is applied for each drug as shown in the Table 
below. 
• 
When there's a mixture of two or more mutations at the same position, the mutation associated with the 
largest penalty is scored.  
• 
The HIVdb S-GSS will be calculated for all subjects with genotypic data at all time points from when 
genotypic data are available for all drugs in the Stanford database. However, Tables will report S-GSS 
scores only for drugs that have been taken by at least one subject during the study. Listings will report S-
GSS scores for all drugs in the Stanford database. 
 
• 
Examples 
 Example 1: Assume a subject at a specific time point has the INSTI mutations G140S and Q148H. The 
following Table shows the calculation of drug resistance estimate score for drugs DTG and EVG.  
 


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Genotype 
Amino Acid Changes 
 
Penalty Scores 
INSTI mutations 
DTG 
EVG 
G140S 
10 
30 
Q148H 
25 
60 
G140S + Q148H 
10 
0 
Total  
(drug resistance estimate) 
45 
90 
 
For DTG, mutation G140S has a penalty score of 10, mutation Q148H has a penalty score of 25. One need 
also to account for the penalty score for the combination of the two mutations which is 10. The sum of all 
penalties scores gives the drug resistance estimate score which is 45 in this case. Similar calculation for 
EVG applies.  
 
Example 2: Assume a subject at a specific time point has the INSTI mutations: G140A/C/S (i.e. recorded as 
G140A, G140C and G140S in SDTM.PF) and Q148H/K/R. The following Table shows the calculation of drug 
resistance estimate score for DTG. 
 
DTG 
INSTI mutations 
Individual Mutation 
Penalty Score 
Penalty scores used for drug 
resistance calculation 
G140A 
10 
10 
G140C 
10 
G140S 
10 
Q148H 
25 
30 
Q148K 
30 
Q148R 
25 
G140A/C/S + Q148H/K/R 
10 
10 
Total  
(drug resistance estimate) 
 
50 
 
For mixture of mutations at the same position, the mutation associated with the largest penalty is used, 
hence for Q148H/K/R the penalty score of 30 for Q148K is used. For G140A/C/S all mutations have the 
same score 10 so, 10 is used. The penalty score for the combination of mutations at codon positions 140 and 
148 is 10. The sum of the three penalties scores gives the drug resistance estimate score which is 50. 
• 
Scores for particular patterns of INSTI, NNRTI, NRTI and PI mutations have been calculated and are 
readily available here  
NNRTI: https://hivdb.stanford.edu/dr-summary/pattern-scores/NNRTI/ 
NRTI: https://hivdb.stanford.edu/dr-summary/pattern-scores/NRTI/ 
PI: https://hivdb.stanford.edu/dr-summary/pattern-scores/PI/ 
INSTI: https://hivdb.stanford.edu/dr-summary/pattern-scores/INSTI/ 
 
• The drug resistance estimate is obtained by adding together the penalty scores from all 
mutations associated with resistance to that drug and then a numeric score (S-GSS) is applied 
for each drug as shown below. Any mutations that are not included the Stanford database will 
contribute 0 to the GSS calculations. When there's a mixture of two or more mutations at the 


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Genotype 
Amino Acid Changes 
same position, the mutation associated with the largest penalty is scored. The sum scores are 
titrated to fall within the following ranges: susceptible, potential low-level resistance, low-level 
resistance, intermediate resistance, and high-level resistance (see table below). 
•  
 
Resistance 
Estimate 
S-GSS Score Sensitivity 
• 
The HIVdb GSS will then be calculated for each subject defined as the sum of the resistance 
scores for each of their background drugs. 
Monogram Genotypic Susceptibility Score (M-GSS) 
• Genotypic sensitivity to each drug will be assigned using the Monogram resistance score 
and will be reported in a listing for all drugs where Monogram resistance score is available 
in the database. 
• Assays PSGT, GSIN, PSGTIN denote Genotypic Sensitivity as 'Sensitive' or 'Resistance' 
whereas assay GSARC as 'Sensitive', 'Resistance Possible' or 'Resistance'. 
• Genotypic Sensitivity provided by Monogram based on assays PSGT, GSIN, PSGTIN is 
translated to a Genotypic Sensitivity Score (M-GSS) according to the table below.  
• For the DTG/3TC arm a subject might have a M-GSS score of 0, 1 or 2, and in the CAR 
arm a subject might have a M-GSS score of 0, 1, 2, or 3 (since CAR is a 3-drug regimen). 
Score 
Sensitivity 
 
 
 
Phenotype 
Phenotypic Susceptibility Scores (PSS) 
• 
Phenotypic susceptibility to all licensed antiretroviral drugs and DTG will be determined using PhenoSense HIV 
assays from Monogram Inc. and will be reported as fold change (FC) in IC50 relative to wild-type control virus NL4-
3, i.e., FC of sample virus = IC50 of sample virus/IC50 of control virus. 
• 
Since the maximum assay limit for FC for each ART varies from subject to subject, FC values that are greater than 
the maximum assay limit (e.g., ‘>100’) will be interpreted as having a value equal to the smallest maximum assay 
limit for that ART in the study population for data analysis.  Censored values will be presented ‘as is’ in the listings. 
• 
Phenotypic susceptibilities will be categorised according to FC (based on Monogram PhenoSense assay). Clinical 
cut-offs (where available) or biological cut-offs by PhenoSense will be used to define the phenotypic susceptibility 
of background treatment. 
• 
Replication capacity is generated as part of standard phenotypic assays. 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.
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Phenotype 
• To establish susceptibility to background treatment, a phenotypic sensitivity score will be calculated. 
Phenotypic susceptibility to each drug in a subject’s background regimen will be determined by 
applying drug-associated cutoffs as defined by the PhenoSense algorithm to the phenotypic fold 
resistance to that drug at a certain timepoint (e.g., Screening or Baseline). A numeric score will be 
assigned to each background drug using two different methods: one with full sensitivity only (PSSf) and 
one with partial sensitivity included (PSSp). 
 
PSS with Full Sensitivity Only (PSSf) 
Fold Change 
Score 
Interpretation 
> clinical lower cutoff or biologic cutoff 
➢ clinical lower 
cutoff or biologic 
cutoff 
 
PSS with Partial Sensitivity Included (PSSp) 
Fold Change 
Score 
Interpretation 
> clinical higher cutoff 
 clinical higher cutoff and > clinical lower cutoff 
 clinical lower cutoff 
 
• Both PSSf and PSSp will be calculated separately for each subject defined as the sum of the 
resistance scores for each background drug. 
 
Drug 
Abbreviation 
Class 
PhenoSense cutoff 
Abacavir 
ABC 
NRTI 
(4.5 – 6.5)a 
Lamivudine 
3TC 
NRTI 
3.5 a 
Didanosine 
ddI 
NRTI 
(1.3 – 2.2) a 
Stavudine 
d4T 
NRTI 
1.7 a 
Zidovudine 
AZT (ZDV) 
NRTI 
1.9 
Emtricitabine 
FTC 
NRTI 
3.5 
Tenofovir 
TDF 
NRTI 
(1.4 – 4) a 
Delavirdine 
DLV 
NNRTI 
6.2 
Efavirenz 
EFV 
NNRTI 
3 
Nevirapine 
NVP 
NNRTI 
4.5 
Etravirine 
ETR 
NNRTI 
(2.9-10) a 
Rilpivirine 
RPV 
NNRTI 
2.0 
Fosamprenavir/r 
FPV/r 
PI 
(4-11) a 
Atazanavir/r 
ATV/r 
PI 
5.2 a 
Indinavir/r 
IDV/r 
PI 
10 a 
Lopinavir/r 
LPV/r 
PI 
(9 – 55) a 
Nelfinavir 
NFV 
PI 
3.6 
Saquinavir/r 
SQV/r 
PI 
(2.3 – 12) a 
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Phenotype 
Tipranavir/r 
TPV/r 
PI 
(2 – 8) a 
Darunavir/r 
DRV/r 
PI 
(10 – 90) a 
Ritonavir 
RTV 
PI 
2.5 
Enfuvirtide 
T20 
FI 
6.48 
Raltegravir 
RAL 
INI 
1.5 
Elvitegravir 
EVG 
INI 
2.5  
Dolutegravir 
DTG 
INI 
(4-13) a 
Bictegravir 
BIC 
INI 
(2.5-10) 
a. 
clinical cutoff (lower cutoff – higher cutoff) 
 
 
Phenotypic Susceptibility Score (PSS) 
Net Assessment and Overall susceptibility of ARTs 
• Net assessment is an assessment of antiviral activity of ARTs using both genotypic and phenotypic 
test results interpreted through a proprietary algorithm (from Monogram Biosciences) and provides 
the overall susceptibility of the drug (Note: partially sensitive and resistant calls are considered 
resistant in this analysis).  
• For determining overall susceptibility of ARTs (OSS), a binary scoring system (0= 
, 
1=
) for each antiretroviral agent was used and will be provided in the Monogram dataset. 
OSS will be calculated as the sum of the net assessment scores of ARTs comprising the subject’s 
ART and categorised as 0, 1, 2, or 3. OSS values will be calculated only for the time of CVW when 
net assessment is available. 
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Phenotype 
Decision tree approach for Monogram resistance data analyses 
• We might have resistance data that come from mixed datasets: PSGT, PSIN, GSIN (primary assays) 
vs PSGT+IN (secondary assay) 
• If one of the primary assay does not work for a specific timepoint, we might report the secondary 
assay if data is available. If all primary assays for a specific timepoint work then we report primary. 
For example, for baseline if the same assay section (PSGT, PSIN, GSIN) worked then we report 
primary. If at least one of PSGT or PSIN or GSIN didn’t work then we report secondary PSGT+IN.  
• Secondary assay testing results might not always be available. 
Background :  
• PSGT - provides both geno and pheno data for PRO/RT (NRTI and NNRTI) only, with pheno 
including PRO/RT Replication Capacity (RC) 
• PSIN - Provides pheno data on Integrase only, with pheno including IN RC   
• 
GSIN - Provides geno data on Integrase only, This assay provides NO RC data. 
• 
PSGT+IN - Secondary assay used if PSGT or GSIN assay fails; it provides both geno and pheno 
data on PRO, RT and Integrase  
• 
If one of the primary assays does not work for a specific timepoint, we might report the data from the secondary 
assay, if available. If all primary assays for a specific timepoint work, then we use the data from the primary 
assays, as secondary assay analysis is not performed. If at least one of PSGT or PSIN or GSIN haven’t worked 
for a specific time point (e.g. Baseline, CVF or time of switch from DTG + 3TC FDC), then we use data from the 
secondary PSGT+IN and the data from any primary assay that worked from this time point are ignored.  
• 
Secondary assay testing results might not always be available. 
• 
The decision tree algorithm will be used for data summaries in Tables. Listings will report all data from all assays 
that worked at a specific time point.  
• 
For examples please refer to decision tree below. 
 
Table Symbol Key: 
Y = assay test successful 
N = assay test failure 
2nd  = back up test performed 
bold = assay to use for analysis 
 
How to make decisions:  
Scenario 1: if primary PSGT, PSIN and GSIN assays all work for both Baseline and CVF or at time to switch due to 
Baseline resistance mutations samples, then PSGT+IN assay will not be performed and no PSGT+IN data should be 
generated.  
Assays  
Baseline  
CVF or Switch 
PSGT 
Y 
Y 
PSIN 
Y 
Y 
GSIN  
Y 
Y 


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Phenotype 
Scenario 2:  If PSGT, PSIN and GSIN all work for Baseline sample; PSGT works for CVF or at time of Switch sample 
but PSIN and GSIN fail, while PSGT+IN works, then use PSGT+IN (PR, RT and INSTI) for CVF/Switch and a PSGT, 
PSIN, GSIN for Baseline; do not use PSGT data at CVF/Switch. 
Assays  
Baseline  
CVF or Switch 
PSGT 
Y 
Y 
PSIN 
Y 
N 
GSIN  
Y 
N 
2nd PSGT+IN 
- 
Y 
 
Scenario 3: If PSGT works for Baseline, but PSIN and GSIN fail, then secondary PSGT+IN assay will be performed on 
Baseline sample. Similarly, if PSGT works for CVF or switch sample but PSIN and GSIN fail to work, in this scenario, 
use data generated from PSGT+IN assay on both Baseline and CVF/switch sample for analyses, regardless of 
obtained PSGT assay data. Same is the case if PSGT fails in both time points and PSIN and GSIN do not fail; the data 
from PSGT+IN from both time points will be used.  
Assays  
Baseline  
CVF or Switch 
PSGT 
Y 
Y 
PSIN 
N 
N 
GSIN  
N 
N 
2nd PSGT+IN  
Y 
Y 
 
Scenario 4: If PSGT works but GSIN and PSIN both fail on Baseline sample, then 2nd PSGT+IN assay might be 
performed. If PSGT, PSIN and GSIN all work for CVF or Switch sample, then use Baseline PSGT+IN data from 
Baseline, regardless of PSGT Baseline data.  
Assays  
Baseline  
CVF or Switch 
PSGT 
Y 
Y 
PSIN 
N 
Y 
GSIN  
N 
Y 
2nd PSGT+IN  
Y 
- 
 
 


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15.6.6. Health Outcomes 
 
HIV Treatment Satisfaction Questionnaire (
) 
Questionnaire (Questions 1-10 are scored 0-6) 
Treatment Satisfaction Score 
• Total Treatment Satisfaction Score is computed with items 1-10. Items 1-10 are summed to 
produce a score with a possible range of 0 to 60.  
• Higher scores represent greater treatment satisfaction as compared to the past few weeks. 
• A maximum of 5 items can be missing, which can be imputed to reflect the mean of the 
completed item scores. If 6 or more items are missing, then the treatment satisfaction scale 
score should not be computed.  
• General Satisfaction/Clinical sub-score is computed with items 
 and 
 . These items 
are summed to produce a score with possible range of 0 to 30 
• Lifestyle/ease sub-score is computed with items 
 and . These items are summed to 
produce a score with possible range of 0 to 30. 
Individual Item Scores 
• Items are rated as 6 (very satisfied, convenient, flexible, etc.) to 0 (
, 
.).  
• Higher scores represent greater satisfaction with each aspect of treatment 
• For individual item scores outputs, missing scores will not be computed (according to Page 7 of 
the [HIVTSQ User Guidelines]). 
• If multiple assessments equidistant from the target Study Day, the assessments with worst 
score will be used. 
 
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Symptom Distress Module 
Questionnaire (Questions 1-20 are scored 
) 
• The Symptom Distress Module (also referred to as HIV Symptom Index) is a 20-item self-
reported measure that addresses the presence and perceived distress linked to symptoms 
commonly associated with HIV or its treatment.  
• The aggregate scores are derived from the individual scores: 
• symptom count: unweighted sum of the number of symptoms which are present; 
• symptom bother score: unweighted sum of the bother item scores for each symptom. 
• These aggregate scores are considered assessable only if less than 10% of the symptom items 
(i.e. one or two symptom items) are missing. The missing items are then considered as the “I do 
not have this symptom” option as this would be interpreted as the symptom was either not 
applicable or unimportant to the subject. 
• If more than two symptoms are missing, the aggregated scores (symptom bother score and 
symptom count) are set to missing. 
• If multiple assessments equidistant from the target Study Day, the assessments with worst 
score will be used. 
Symptom count 
• The “symptom count” based on which of the 20 symptoms were present in the subject.  
• The symptom count ranges from 0 to 20. 
Symptom bother score 
• The symptom bother score ranges from 0 to 80. 
• If the subject ticked 
”, the bother score is 0 
• If the subject gave a bother rating, then it is based on ranging from 1 
) to 4 
(
).   
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copyright laws and therefore have been excluded.
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Symptom Distress Module 
• If the subject ticked two boxes, the worst case is considered. In particular, if the option “I do not 
have this symptom” is ticked conjointly with a bother rating, the bother score is defined 
according to the bother rating. 
 
Willingness to switch survey 
Questionnaire (Questions 1-7) 
• Assess the reason(s) for their participation and facilitate an understanding of subject’s 
willingness to switch  
• A single item question prior to randomisation. 
• 7 reasons for willingness to participate in a clinical study where the current HIV medication may 
be switched check all that apply 
• Any missing values will remain missing 
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15.6.7. Cut-off date for protocol deviations  
 
Cut-off date 
The following rules should be used to calculate cut-off date for protocol deviations up to and 
including Week 24:  
• 
For subjects who have Week 24 viral load date (cut-off 1):  
- cut-off = Week 24 viral load date (used for snapshot algorithm) from LB (laboratory) dataset, or 
date of re-test date if patient had a re-test 
• For subjects who do not have Week 24 viral load date (cut-off 2): 
- cut-off date = the earliest of (Day of Study Discontinuation from DS, date of Withdrawal 
Visit from SV, Study day of permanent treatment discontinuation from EX (for subjects 
randomized to DTG/3TC) or CM (for patients randomized to CAR), study treatment start 
date + 210* -1). 
*upper bound of week 24 window 
 
Additional Statistical Programming Checks to identify ‘Subjects with study withdrawal due to a 
reason of “Protocol Deviation” (as recorded in the eCRF) at or prior Week 24’ will be performed.  
 
• 
Consider subjects that have discontinued from the study prior or at Week 24 with ‘Protocol 
deviation’ as a reason in DS (study discontinuation).  
• 
Cut-off date (cut-off 3):  
 
• 
For subjects who have Week 24 viral load date -> cut-off = Week 24 viral load date (used for 
snapshot algorithm) from LB (laboratory) dataset.  
• 
For subjects who withdrawn before Week 24 Snapshot HIVRNA sample taken or if missing data 
during week 24 window but on study-> cut-off = IP start date + 210* - 1  
 
• 
Compare the PD occurrence date (Day of Study Discontinuation from DS) to cut-off date (see 
paragraph above, please note: cut-off rules 1 and 2 defined above do not apply here)  
• 
If cut-off date ≥ PD occurrence date, then deviations will result in exclusion from the per protocol 
set.  
 
*upper bound of week 24 window  
 
Similar rules will be followed for Week 48 and subsequent time points and will be detailed in a 
separate Protocol Deviation specification document. Please refer to latest version of the Protocol 
Deviation specification document prior to the analysis for full details of protocol deviation 
identification, 
 


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15.6.8. eCRF Baseline Third Agent Class Determination 
 
Baseline third agent will be determined as the third agent ingredient: 
• 
still being taken at randomization for CAR patients 
• 
discontinued immediately prior to randomization for DTG/3TC patients. 


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15.7. 
Appendix 7: Reporting Standards for Missing Data 
15.7.1. Premature Withdrawals 
Element 
Reporting Detail 
General 
Subject study completion (i.e. as specified in the protocol) was defined as: 
• Randomly assigned to either treatment group, completed the Randomized 
Phase including the Week 52 visit, and did not enter the Continuation Phase; 
• Subjects randomized to DTG/3TC treatment group, completed the Randomized 
Phase including the Week 52 visit, entered and completed the Continuation 
Phase, defined as remaining on study until:  
o DTG and 3TC FDC tablet is locally approved for use as a 2-drug 
regimen, and available through public health services or through the 
subject’s usual health insurance payer, or 
o the actual FDC tablet, if required by local regulations, is available, or 
o the subject no longer derives clinical benefit, or  
o the subject meets a protocol-defined reason for discontinuation, or 
o development of the DTG/3TC dual regimen is terminated.  
• Withdrawn subjects will not be replaced in the study. 
• All available data from subjects who were withdrawn from the study will be 
listed. 


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15.7.2. Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data are not provided, leading to blank 
fields on the collection instrument:  
• These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data are 
excluded from the table. 
• Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should not be displayed as such.  
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) are classified as either  ‘HIV-1 RNA ≥50 c/mL’) or ‘No 
Virologic Data’. For full details of the Snapshot algorithm see Appendix 11 
Observed 
Case (OC) 
• This dataset uses only the data that is available at a particular timepoint, with no 
imputation for missing values. 
 
15.7.2.1. 
Handling of Missing and Partial Dates 
 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in subject 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. 
Exposure 
• If study treatment stop date is missing, then for the purposes of calculating 
exposure, it will be imputed using the date of last visit or the recorded date of 
withdrawal/completion whichever is earlier.  
• Partially Missing Stop Day: Last day of the month or last month of the year will 
be used, unless this is after the stop date of study treatment or withdrawal date; 
in this case the earliest of the two dates will be used. Note Study Treatment 
DTG/3TC is recorded on the Study Treatment eCRFs and CAR treatment is 
recorded on the CONART eCRFs. 
Adverse 
Events and 
Clinical 
Events 
• The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE and Clinical Event start and end dates; that is, the day of the 
month may be missing: 
o If the full date cannot be ascertained, the following conventions will be 
applied for calculating the time to onset and the duration of the event: 
Completely missing dates: (i.e. no year specified) will remain missing, with 
no imputation applied. Consequently, time to onset and duration of such 
events will be missing. 
o Partially Missing Start Day: First day of the month or first month of the year 
will be used unless this is before the start date of study treatment; in this 


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Element 
Reporting Detail 
case the study treatment start date will be used and hence the event is 
considered On-treatment as per Appendix 4: Treatment States and Phases 
o Partially Missing Stop Day: Last day of the month or last month of the year 
will be used, unless this is after the stop date of study treatment or 
withdrawal date; in this case the earliest of the two dates will be used. 
Otherwise, if patient hasn't withdrawn, last visit date will be used. 
o The recorded partial date will be displayed in listings. 
Concomitan
t 
Medications 
• Partial dates for any concomitant medications recorded in the eCRF will be 
imputed using the following convention: 
o If the partial date is a start date, the first day of the month will be used for 
the day and ‘Jan’ will be used for the month 
o If the partial date is a stop date, last day of the month will be used for the 
day and 'Dec' will be used for the month. 
o For medications recorded in the eCRF as prior ART, the earlier of this 
imputed date or the day before IP start will be used. 
 
• The recorded partial date will be displayed in listings. 
 
 


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15.8. 
Appendix 8: Values of Potential Clinical Importance 
 
Element 
Reporting Detail 
Laboratory 
Values 
(Chemistry 
(Including 
Lipids), 
Hematology 
and 
Urinalysis) 
• The DAIDS grading for severity of laboratory toxicities and clinical adverse 
events is included in the protocol.  
• The central laboratory will flag laboratory parameter toxicities directly in the 
provided datasets for subjects with any value outside normal range. 
• Abnormalities for potential clinical concern/importance will be defined as 
any Grade1-5 toxicity. 
 
 


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15.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
There is no population pharmacokinetic analysis planned in this study. 
 


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15.10. 
Appendix 10: Time to Event Details 
15.10.1. TRDF Detailed Steps 
TRDF Detailed steps 
The steps below are for the derivation of TRDF at specific timepoints when the upper bound of the 
analysis window is used as a cut-off i.e. for the table only.  
Randomized Period denotes period where subjects are still on their randomized treatment, prior to entering 
Continuation Phase for DTG/3TC subjects. This is also irrespective of blinding.  
Final step of the derivation is made in following order:  
[1] When one EVENT (1.2, 2.2, 3.2, 4.2) criterion is satisfied, select. In situations where more than one 
EVENT criteria satisfied, select the earliest event. If the earliest event date satisfies more than one 
criteria (e.g. subject had CVW and discontinuation), select CVW. 
[2] When one CENSOR (1.1, 2.1, 3.1, 4.1, 5.x) criterion is satisfied, select. Else in situations where more 
than one CENSOR criteria satisfied, select the latest censor day. If the latest event date satisfies more 
than one criteria, apply the ordering below. 
  
Condition 
Censor 
Status  
Event Description/AVAL 
1. Subjects met CVW event criteria during the 
randomized period.  
(Based on derived CVW confirmed prior to cut-
off used for the analysis) 
 
Then set tempAVAL= Study Day of SVW 
immediately preceding CVW 
 
 
1.1 Initial elevation/SVW immediately 
preceding CVW event date is after the upper 
bound of the analysis visit window  
i.e tempAVAL > upper bound of the analysis 
visit window for Week X 
 
CNSR=1 
EVNTDESC=Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 
 


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TRDF Detailed steps 
1.2 Initial elevation/SVW immediately 
preceding CVW event date is on or before the 
upper bound of the analysis visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window for Week X 
 
CNSR=0 
EVNTDESC=CVW. 
AVAL= tempAVAL. 
 
2. Subjects with study withdrawal due to 
treatment related adverse events during the 
randomized period  
(defined as subjects that have reason for 
withdrawal =AE on disposition page and that 
the subject has at least one AE considered both: 
i) drug related (AEREL=Y) and ii) result in 
withdrawal from study (AEWD=Y))  
Then set tempAVAL= Earliest of (Day of 
Study Discontinuation [from Disposition 
page]), date of Withdrawal Visit [from Study 
Visit domain], Study day of permanent 
treatment discontinuation [from Exposure and 
Concomitant ART domains]). 
Assumption: Study day of permanent treatment 
discontinuation is included in the definition to 
account for cases where discontinuation 
information is recorded later. This is a 
conservative approach consistent with treatment 
discontinuation preceding withdrawal.  
 
 
2.1 Study withdrawal is after the upper bound 
of the analysis visit window 
i.e tempAVAL > upper bound of the analysis 
visit window 
CNSR=1 
EVNTDESC=Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 
2.2 Study withdrawal is on or before the upper 
bound of the analysis visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
CNSR=0 
EVNTDESC=Study Withdrawal Due to 
Treatment Related AE. 
AVAL= tempAVAL 


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TRDF Detailed steps 
 
3:  Subjects met protocol defined stopping 
criteria during the randomized period.,  
(Based on disposition page) 
 
Then set tempAVAL=Earliest of (Day of Study 
Discontinuation [from Disposition page]), date 
of Withdrawal Visit [from Study Visit domain], 
Study day of permanent treatment 
discontinuation [from Study Treatment or 
CONART eCRF pages]). 
 
 
 
3.1 Protocol defined stopping criteria were met 
after the upper bound of the analysis visit 
window 
i.e tempAVAL > upper bound of the analysis 
visit window 
 
CNSR=1 
EVNTDESC=Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 
3.2 Protocol defined stopping criteria were met 
on or before the upper bound of the analysis 
visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
 
CNSR=0 
EVNTDESC=Study Withdrawal Due to 
Protocol Defined Criteria. 
AVAL=tempAVAL 
4: Subjects with study withdrawal due to lack 
of efficacy during the randomized period. 
(Based on disposition page) 
 
Then set tempAVAL= Earliest of (Day of 
Study Discontinuation [from Disposition 
page]), date of Withdrawal Visit [from Study 
 
 


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TRDF Detailed steps 
Visit domain], Study day of permanent 
treatment discontinuation [from Study 
Treatment or CONART eCRF pages]) 
4.1 Study withdrawal is after the upper bound 
of the analysis visit window 
i.e tempAVAL > upper bound of the analysis 
visit window 
 
CNSR=1 
EVNTDESC=Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 
4.2 Study withdrawal is on or before the upper 
bound of the analysis visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
 
CNSR=0 
EVNTDESC=Study Withdrawal Due to 
Lack of Efficacy 
AVAL= tempAVAL  
If none of the above conditions met 
 
 
5: Subjects with study withdrawal for other reasons 
during the randomized period. 
(Based on disposition page) 
 
Then set tempAVAL= Earliest of (Day of 
Study Discontinuation [from Disposition 
page]), date of Withdrawal Visit [from Study 
Visit domain], Study day of permanent 
treatment discontinuation [from Study 
Treatment or CONART eCRF pages]) 
 
 
5.1 Study withdrawal is after the upper bound 
of the analysis visit window 
i.e tempAVAL > upper bound of the analysis 
visit window 
 
CNSR=1 
EVNTDESC=Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 
 
5.2 Study withdrawal is on or before the upper 
bound of the analysis visit window 
CNSR=1 
EVNTDESC=Censored due to Study 
Discontinuation for Other Reasons. 


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TRDF Detailed steps 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
 
AVAL=tempAVAL 
6: Subject completed the randomized period 
of the study. 
(Based on disposition page) 
 
 
CNSR=1 
EVNTDESC= Censored as completed 
the Randomized Period. 
AVAL= Date of end of Treatment Phase 
7: Subject is ongoing in the study during the 
randomized period and have not yet 
completed the randomized period  
 
Assumption: this will only be in cases where 
the reporting effort/analysis is performed 
midway through the randomized period 
CNSR=1 
EVNTDESC= Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 


 
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15.10.2. TRDF Detailed Steps for the Kaplan-Meier plot 
TRDF Detailed steps 
The steps below are for the derivation of TRDF overall i.e. for the Kaplan-Meier plot only.  
Final step of the derivation is made in following order:  
[1] When one EVENT (conditions 1-4) criterion is satisfied, select. In situations where 
more than one EVENT criteria satisfied, select the earliest event. If the earliest event 
date satisfies more than one criteria (e.g. subject had CVW and discontinuation), 
select CVW. 
[2] When one CENSOR (conditions 5.x) criterion is satisfied, select. Else in situations 
where more than one CENSOR criteria satisfied, select the latest censor day. If the 
latest event date satisfies more than one criteria, apply the ordering below. 
  
Condition 
Censor 
Status  
Event Description/AVAL 
1. Subjects met CVW event criteria 
during the randomized period.  
(Based on derived CVW confirmed 
prior to cut-off used for the analysis) 
CNSR=0 
EVNTDESC=CVW. 
AVAL=Study Day of SVW 
immediately preceding CVW. 
 
2. Subjects with study withdrawal due 
to treatment related adverse events 
during the randomized period  
 (defined as subjects that have reason 
for withdrawal =AE on disposition 
page and that the subject has at least 
one AE considered both: i) drug related 
(AEREL=Y) and ii) result in 
withdrawal from study (AEWD=Y))  
 
CNSR=0 EVNTDESC=Study Withdrawal 
Due to Treatment Related AE. 
AVAL=Earliest of (Day of Study 
Discontinuation [from 
Disposition page]), date of 
Withdrawal Visit [from Study 
Visit domain], Study day of 
permanent treatment 
discontinuation [from Study 
Treatment or CONART eCRF 
pages]). 
3:  Subjects met protocol defined 
stopping criteria during the 
randomized period.,  
(Based on disposition page) 
CNSR=0 EVNTDESC=Study Withdrawal 
Due to Protocol Defined Criteria. 
AVAL=Earliest of (Day of Study 
Discontinuation [from 
Disposition page]), date of 
Withdrawal Visit [from Study 


 
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Visit domain], Study day of 
permanent treatment 
discontinuation [from Study 
Treatment or CONART eCRF 
pages]). 
4: Subjects with study withdrawal due 
to lack of efficacy during the 
randomized period. 
(Based on disposition page) 
CNSR=0 
EVNTDESC=Study Withdrawal 
Due to Lack of Efficacy 
AVAL= Earliest of (Day of Study 
Discontinuation [from 
Disposition page]), date of 
Withdrawal Visit [from Study 
Visit domain], Study day of 
permanent treatment 
discontinuation [from Study 
Treatment or CONART eCRF 
pages]) 
If none of the above conditions met 
 
 
5: Subjects with study withdrawal 
for other reasons on or before the 
end of randomized period. 
(Based on disposition page) 
CNSR=1 
EVNTDESC=Censored due to 
Study Discontinuation for Other 
Reasons. 
AVAL=Earliest of (Day of Study 
Discontinuation [from 
Disposition page]), date of 
Withdrawal Visit [from Study 
Visit domain], Study day of 
permanent treatment 
discontinuation [from Study 
Treatment or CONART eCRF 
pages]) 
6: Subject completed the 
randomized period of the study. 
(Based on disposition page) 
CNSR=1 
EVNTDESC= Censored as 
completed the Randomized 
Period. 
AVAL= Date of completion of 
randomized study period 
7: Subject is ongoing in the study 
during the randomized period and 
have not yet completed the 
randomized period 
CNSR=1 
EVNTDESC= Ongoing in the 
Study. 
AVAL=Last visit date 
 
Notes: 


 
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1. Randomized Period = Randomized Phase  
2. Efficacy visit windows should be used throughout for the upper bound of the analysis visit window 
3. Subjects are considered to have completed the randomized period if they completed the Randomized Phase. 
4. By definition, a subject must be on-treatment for a CVW to be recorded therefore inclusion of study date of 
treatment discontinuation in the derivation is not required  
5. EVNTDESC, AVAL & CNSR variables created for the following timepoints:  
6. Week 24 or 48 – for the table analysis 
7. Overall – for the Kaplan-Meier plot  
 


 
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15.10.3. ERDF Detailed Steps 
 
Similar algorithm will be applied for ERDF analyses and  Kaplan-Meier figure, where 
condition 2 and 3 in Section 15.10.1 and Section 15.10.2 will not be considered.  
 
 


 
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15.11. 
Appendix 11: Snapshot Algorithm Details 
 
• Consider an analysis visit window, Week X (e.g. Week 24, Week 48). The 
Window for Week 24/48 visit is defined in Appendix 3. e.g. Week 48 (+/- 6 
Week:  295  Study Day  378) 
• Consider an HIV1-RNA threshold (e.g. 40, 50, 200 copies/mL …) in analysis,  
• The analysis window ‘Week 48’ and HIV1-RNA threshold of ’50 c/mL’ are used 
for the purpose of illustration. A subject’s Snapshot response and reason at Week 
48 are categorized as below. 
 
o HIV1-RNA < 50 copies/mL 
o HIV1-RNA ≥ 50 copies/mL 
Data in window not below 50 
Discontinued for lack of efficacy 
Discontinued for other reason while not below 50 
Change in background therapy* 
 
o 
No Virologic Data at Week 48 Window 
Discontinued study due to AE or death 
Discontinued study for other reasons 
On study but missing data in window 
 
* Note: since changes in ART or dose modification are not permitted in this protocol, all 
such subjects who change ART during Randomized Phase will be considered ‘HIV1-RNA 
≥ 50 c/mL’. if the change in ART is made prior to an analysis timepoint.  For subjects on 
CAR, a switch from a PI boosted with ritonavir to the same PI boosted with cobicistat 
(and vice versa) is permitted per protocol and a switch from lamivudine to emtricitabine 
and vice versa will not be considered ‘HIV1-RNA ≥ 50 copies/mL’ due to ‘change in 
ART’. 
 
The steps in determining response and reasons are indicated in Table below, in the order 
stated. 
 
Detailed steps 
• 
Please note that the following scenarios will NOT be penalized Per Snapshot algorithm (i.e. 
please excluding these scenarios from Condition 1-4).  
• 
Dose reduction, dropping a component, or change in formulation (e.g. ‘Tivicay + Kivexa’ to 
‘Triumeq’ with the identical ingredients)  
• 
Permitted Change (if a decision date is not collected in eCRF) / decision to permitted 
change is made prior to/on the first on-treatment viral load result 
• 
Permitted change is made after the first on-treatment viral load result AND last on-
treatment viral load prior to/on the date of change is <50 c/mL 


 
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Condition  
(‘Week 48’ indicates Week 48 window) 
Response  
Reasons 
1. If non-permitted change in background therapy prior 
to Week 48  
HIV1-RNA ≥ 
50  
Change in 
background 
therapy 
2.    If permitted change in background therapy prior to 
Week 48 AND the latest on-treatment VL prior to/on 
the date of change is ≥ 50 c/m [a] 
HIV1-RNA ≥ 
50  
Change in 
background 
therapy 
3. If non-permitted change in background therapy 
during Week 48    
 
 
•      3.1  Last on-treatment VL during Week 48 prior 
to/on the date of change ≥ 50 c/mL 
HIV1-RNA ≥ 
50  
Data in window 
not below 50 
•      3.2  Last on-treatment VL during Week 48 prior 
to/on the date of change <50   c/mL 
HIV1-RNA < 
50  
 
•      3.3  No VL during Week 48 prior to/on the date 
of change     
HIV1-RNA ≥ 
50  
Change in 
background 
therapy 
4. If permitted change in background therapy during 
Week 48 AND the last on-treatment VL prior to/on the 
date of change is ≥ 50 c/mL [a] 
 
 
4.1    this last on-treatment VL occurs prior to Week 48  HIV1-RNA ≥ 
50  
Change in 
background 
therapy  
4. 2   this last on-treatment VL occurs during Week 48 
but prior to/on the date of change 
HIV1-RNA ≥ 
50  
Data in window 
not below 50 
5.  If none of the above conditions met 
 
 
5.1   VL available during Week 48  
 
 
      5.1.1 Last on-treatment VL during Week 48 ≥ 50 c/mL 
HIV1-RNA ≥ 
50  
Data in window 
not below 50 
      5.1.2 Last on-treatment VL during Week 48 <50 c/mL 
HIV1-RNA < 
50  
 
5.2   No VL during Week 48    
 
 
 
5.2.1     If subjects still on study (i.e. The on-treatment 
period has not been ended up to the upper 
bound of Week 48 window. For example, for 
oral treatment, the on-treatment period ends at 
permanently IP stop date+1) 
No virologic 
data at Week 
48 Window  
On study but 
missing data in 
window 
5.2.2     If subjects withdraw before/during Week 48 
due to :- 
 
 
5.2.2.1  Safety reasons (e.g. AE/death, liver chemistry 
stopping criteria, renal toxicity withdrawal 
criteria, QTc withdrawal criteria et al,  as 
recorded in eCRF Study Conclusion form) 
No virologic 
data at Week 
48 Window 
Disc. due to 
AE/death 
5.2.2.2  Non-safety related reasons (e.g. Lack of 
efficacy, protocol deviation, withdrew consent, 
 
 


 
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loss to follow-up, study closed/terminated, 
investigator discretion et al, as recorded in 
eCRF Study Conclusion Form) 
5.2.2.2.1 Last on-treatment VL <50 c/mL OR no 
on-treatment VL available during study   
No virologic 
Data at Week 
48 Window 
Disc. for other 
reasons 
5.2.2.2.2 Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to Lack of efficacy 
HIV1-RNA ≥ 
50  
Disc. for lack of 
efficacy 
5.2.2.2.3 Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to all other non-safety related 
reasons 
HIV1-RNA ≥ 
50  
Disc. for other 
reason while not 
below 50 
1. [a]: Excluding permitted change in background therapy where change or decision to change is made prior 
to/on the first on-treatment viral result  
 
 


 
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Snapshot outcomes are shown below and are to be used in conjunction with the steps in the Snapshot algorithm  
Figure 1 
Flowchart of Snapshot Outcome  
 
 
 
Yes 
Week 48 VL 1 
Available? 
No 
Yes 
No (meet Cond. 1, 2, or 3.3, 4.1) 
No 
(meet Cond. 3.1, 4.2) 
Yes  
(meet  
Cond. 
3.2) 
HIV-1 RNA< 50 
HIV-1 RNA≥ 
50 9 
HIV-1 
RNA>=50 3 
Yes 
Week 48 VL 1 
< 50 c/mL ? 
No  
(meet Cond. 5.1.1) 
Yes  
(meet Cond. 5.1.2) 
No 
Withdrawal before/ 
during Week 48 
No 
(meet Cond. 5.2.1) 
No Virologic data 
at Week 48 6 
Due to AE or Death? 
Yes 
Yes 
(meet Cond. 5.2.2.1) 
No Virologic data 
at Week 48 4 
Last VL2 < 50 c/mL 
or missing? 
No 
Yes 
(meet Cond. 5.2.2.2.1) 
No Virologic data at 
week   50 5 
No 
Yes 
(meet Cond. 5.2.2.2.2) 
HIV-1 RNA ≥ 50 7 
HIV-1 RNA ≥ 50 8 
No 
(meet Cond. 5.2.2.2.2) 
 
Withdrawal reason in 
eCRF: lack of efficacy? 
 
Permitted/non-permitted change in ART 
during Week 48, & VL available on/prior to 
change in the same window? 
 
(Prior to or during Week 48 window) 
Non-permitted change in ART 
or 
Permitted change in ART & the latest on-treatment viral 
load (VL) on/prior to change is ≥ 50 c/mL? 
 
Week X latest VL (on/prior to 
change in ART) < 50 c/mL 
1: Last on-treatment VL in 
Week 48 window    
2: Last on-treatment VL prior 
to Week 48 
 
Reasons for HIV-1 RNA≥ 50 
c/mL 
3: Change in background 
therapy  
7: Discontinued for lack of 
efficacy 
8: Discontinued for other 
reason while not below 50  
9: Data in window not below 
50   
 
Reasons for ‘No Virologic 
data at Week 48’   
4: Discontinued due to 
AE/death 
5: Discontinued for other 
reasons 
6: On study but missing data in 
window 


 
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A dataset will be created based on the Snapshot algorithm, where the dataset contains the 
following information, as a minimum: 
Study identification 
Subject identification  
Study day and date of last blinded treatment  
Virologic outcome based on the snapshot approach (i.e., HIV-1 RNA < 50 c/mL, HIV-1 
RNA ≥ 50 c/mL, discontinued due to AE or death, discontinued for other reasons, on 
study but missing data during window)  
The HIV-1 RNA measurement and the corresponding study day and date used to 
determine the above virologic outcome if the measurement was not missing 
Study day and date when the subject switched to open-label treatment due to lack or loss 
of virologic suppression, if applicable 
Discontinuation study day and date, reason for discontinuation, and last blinded treatment 
measurement before discontinuation for subjects who discontinued study drug 


 
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15.12. 
Appendix 12: Modified Snapshot Algorithm Details 
 
The below Modified Snapshot Algorithm will be used to determine Snapshot outcomes 
taking into account COVID-19 related events. The Modified Snapshot Estimand still 
reports high-level categories (>=50 c/mL, <50 c/mL and No Virologic Data) in exactly 
the same way as the standard FDA Snapshot Algorithm in Section 15.11, however it 
reports additional subcategories to account for outcomes related to COVID-19. 
• Consider an analysis visit window, Week X (e.g. Week 24, Week 48). The 
Window for Week 24/48 visit is defined in Appendix 3. e.g. Week 48 (+/- 6 
Week:  295  Study Day  378) 
• Consider an HIV1-RNA threshold (e.g. 40, 50, 200 copies/mL …) in analysis,  
• The analysis window ‘Week 48’ and HIV1-RNA threshold of ’50 c/mL’ are used 
for the purpose of illustration. A subject’s Modified Snapshot response and reason 
at Week 48 are categorized as below. 
 
o HIV1-RNA < 50 copies/mL 
o HIV1-RNA ≥ 50 copies/mL 
Data in window not below 50 
Non-COVID-19 related                                               
   Discontinued for lack of efficacy 
   Discontinued for other reason and HIV-1 RNA >= 50 copies/mL      
   Change in ART* 
COVID-19 related                                               
   Discontinued for lack of efficacy 
   Discontinued for other and HIV-1 RNA >= 50 copies/mL      
   Change in background therapy* 
 
o No Virologic Data at Week 48 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 
 
* Note: since changes in ART or dose modification are not permitted in this protocol, all 
such subjects who change ART during Randomized Phase will be considered ‘HIV1-RNA 
≥ 50 c/mL’ if the change in ART is made prior to an analysis timepoint.  For subjects on 
CAR, a switch from a PI boosted with ritonavir to the same PI boosted with cobicistat 
(and vice versa) is permitted per protocol and a switch from lamivudine to emtricitabine 
and vice versa will not be considered ‘HIV1-RNA ≥ 50 copies/mL’ due to ‘change in 
ART’. 
 


 
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115 
The steps in determining response and reasons are indicated in Table below, in the order 
stated. 
 
Detailed steps 
• 
Please note that the following scenarios will NOT be penalized Per Modified Snapshot 
algorithm (i.e. please excluding these scenarios from Condition 1-4).  
• 
Dose reduction, dropping a component, or change in formulation (e.g. ‘Tivicay + Kivexa’ to 
‘Triumeq’ with the identical ingredients)  
• 
Permitted Change (if a decision date is not collected in eCRF) / decision to permitted 
change is made prior to/on the first on-treatment viral load result 
• 
Permitted change is made after the first on-treatment viral load result AND last on-
treatment viral load prior to/on the date of change is <50 c/mL 
 
Condition  
( ‘Week 48’ indicates Week 48 window) 
Response  
Reasons 
1.1 If non-permitted change in background therapy prior 
to Week XX (Non-COVID-19 switch) 
HIV1-RNA ≥ 
50  
Change in 
background 
therapy (Non-
COVID-19 
related) 
1.2  If non-permitted change in background therapy prior 
to Week XX (COVID-19 switch) 
HIV1-RNA ≥ 
50  
Change in 
background 
therapy (COVID-
19 related) 
2. 1 If permitted change in background therapy prior to 
Week 48 AND the latest on-treatment VL prior to/on 
the date of change is ≥ 50 c/mL (not related to 
COVID-19) [a] 
HIV1-RNA ≥ 
50  
Change in 
background 
therapy(Non-
COVID-19 
related) 
2. 2 If permitted change in background therapy prior to 
Week 48 AND the latest on-treatment VL prior to/on 
the date of change is ≥ 50 c/mL(related to COVID-
19)  [a] 
HIV1-RNA ≥ 
50  
Change in 
background 
therapy(COVID-
19 related) 
4. If non-permitted change in background therapy 
during Week 48    
 
 
•      3.1  Last on-treatment VL during Week 48 prior 
to/on the date of change ≥ 50 c/mL 
HIV1-RNA ≥ 
50  
Data in window 
not below 50 
•      3.2  Last on-treatment VL during Week 48 prior 
to/on the date of change <50   c/mL 
HIV1-RNA < 
50  
 
•      3.3.1  No VL during Week 48 prior to/on the 
date of change  (non-related to COVID-19)     
HIV1-RNA ≥ 
50  
Change in 
background 
therapy(Non-
COVID-19 
related) 


 
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•      3.3.2  No VL during Week 48 prior to/on the 
date of change (related to COVID-19)      
HIV1-RNA ≥ 
50  
Change in 
background 
therapy( COVID-
19 related) 
5. If permitted change in background therapy during 
Week 48 AND the last on-treatment VL prior to/on the 
date of change is ≥ 50 c/mL [a] 
 
 
4.1.1    this last on-treatment VL occurs prior to Week 
48  (non- COVID-19 related switch)     
HIV1-RNA ≥ 
50  
Change in 
background 
therapy (Non-
COVID-19 
related) 
4.1.2    this last on-treatment VL occurs prior to Week 
48  (COVID-19 related switch)     
HIV1-RNA ≥ 
50  
Change in 
background 
therapy (COVID-
19 related) 
4. 2   this last on-treatment VL occurs during Week 48 
but prior to/on the date of change 
HIV1-RNA ≥ 
50  
Data in window 
not below 50 
5.  If none of the above conditions met 
 
 
5.1   VL available during Week 48  
 
 
      5.1.1 Last on-treatment VL during Week 48 ≥ 50 c/mL 
HIV1-RNA ≥ 
50  
Data in window 
not below 50 
      5.1.2 Last on-treatment VL during Week 48 <50 c/mL 
HIV1-RNA < 
50  
 
5.2   No VL during Week 48    
 
 
 
5.2.1     Participants unable to attend Week 48 visit due 
to COVID-19, but otherwise considered still on-
study (i.e. The on-treatment period continues 
beyond the upper bound of Week 48 window. 
For example, for oral treatment, a participant 
with IP stop date+1> Day 378 of the upper 
bound of Week 48 window, would be 
considered ‘on study’ for Week 48 snapshot 
assessment) 
No virologic 
data at Week 
48 Window  
On study but 
missing data in 
window(COVID-
19 related) 
5.2.2     If participants still on study but participant has 
not missed visit due to COVID-19 (i.e. The on-
treatment period continues beyond the upper 
bound of Week 48 window. For example, for 
oral treatment, a participant with IP stop 
date+1> Day 378 of the upper bound of Week 
48 window, would be considered ‘on study’ for 
Week 48 snapshot assessment) 
No virologic 
data at Week 
48 Window  
On study but 
missing data in 
window(Non- 
COVID-19 
related) 
5.3.2     If participants withdraw before/during Week 48 
due to: 
 
 


 
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5.3.2.1  Non-COVID-19 Safety reasons (e.g. non-
COVID-19 AE/death, liver chemistry stopping 
criteria, renal toxicity withdrawal criteria, QTc 
withdrawal criteria,  as recorded in eCRF 
Conclusion form) 
No virologic 
data at Week 
48 Window  
Disc. due to 
AE/death(Non- 
COVID-19 
related) 
5.3.2.2  COVID-19 safety reasons eCRF (e.g. 
AE/death resulting from COVID-19 as 
recorded in the eCRF Conclusion form). If 
subject has AE or death recorded as primary 
reason for discontinuing (not captured as 
COVID-19 related), but subject has at least 
one COVID-19 related AE/death leading to 
withdrawal per AE eCRF page, the subject will 
assumed to have discontinued as a result of 
COVID-19 AE/death and hence will be 
captured in this Snapshot category. 
No virologic 
data at Week 
48 Window  
Disc. due to 
AE/death(COVID-
19 related) 
5.3.2.3  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 et al, 
as recorded in eCRF Study Conclusion Form) 
 
 
5.3.2.3.1 Last on-treatment VL <50 c/mL OR no 
on-treatment VL available during study   
No virologic 
Data at Week 
48 Window  
Disc. for other 
reasons(Non- 
COVID-19 
related) 
5.3.2.3.2 Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to Lack of efficacy 
HIV1-RNA ≥ 
50   
 
Disc. for lack of 
efficacy(Non- 
COVID-19 
related) 
5.3.2.3.3 Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to all other non-safety related 
reasons 
HIV1-RNA ≥ 
50  
 
Disc. for other 
reason while not 
below 50(Non- 
COVID-19 
related) 
5.3.2.4  Non-safety and COVID-19 related reasons 
(e.g. Withdrawal of consent, protocol deviation 
(where subreason is COVID-19), investigator 
discretion (where Other text is recorded as 
‘COVID-19’), as recorded in eCRF Conclusion 
Form) 
 
 
5.3.2.4.1 Last on-treatment VL <50 c/mL OR no 
on-treatment VL available during study   
No virologic 
Data at Week 
48 Window  
Disc. for other 
reasons(COVID-
19 related) 
5.3.2.4.2 Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to all other non-safety related 
reasons 
HIV1-RNA ≥ 
50  
 
Disc. for other 
reason while not 
below 50(COVID-
19 related) 


 
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15.13. 
Appendix 13: Abbreviations & Trade Marks 
 
15.13.1. Abbreviations 
 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CAR 
Current ART regimen 
cART 
Combination ART  
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) 
DOB 
Date of Birth 
DP 
Decimal Places 
DOV 
Date of Visit 
eCRF 
Electronic Case Record Form 
ERDF 
Efficacy Related Discontinuation Failure 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
GUI 
Guidance 
LOC 
Last Observation Carries Forward 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance  
PD 
Protocol Deviation 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 


 
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Abbreviation 
Description 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TAF 
Tenofovir alafenamide fumarate 
CAR 
Current antiretroviral regimen 
TFL 
Tables, Figures & Listings  
TRDF 
Treatment Related Discontinuation Failure 
GSK 
GlaxoSmithKline 
15.13.2. Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
Epivir 
 
Monogram Inc 
Tivicay 
 
NONMEM 
 
 
SAS  
 
 
WinNonlin 
 


 
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15.14. 
Appendix 14: Model Checking and Diagnostics for 
Statistical Analyses 
15.14.1. Statistical Analysis Assumptions 
Endpoint(s) 
Change from Baseline in bone/renal/inflammatory biomarkers, weight, 
BMI, HOMA-IR, HbA1c, lipids and health outcomes 
Analysis 
      MMRM/ANCOVA 
• Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used for 
MMRM models. 
• An unstructured covariance structure for the R matrix will be estimated by treatment group by 
specifying ‘type=UN’ and ‘group=treat’ on the REPEATED line for MMRM models. 
o In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS.  
o Akaike's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure. 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
 
Endpoint(s) 
Change from Baseline in Lipids 
Analysis 
      Multiple Imputation 
• Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals (i.e. checking the normality assumption) to 
gain confidence that the model assumptions are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
• Diagnostic plots (trace and autocorrelation plots) will be checked to verify that the number of 
burn-in iterations and MCMC steps between imputed datasets are sufficient. If the trace plots 
show apparent trend or the autocorrelation plots show significant positive or negative 
autocorrelation, number of iterations will be increased until the diagnostic plots are acceptable. 
 


 
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15.15. 
Appendix 15: Test of Homogeneity: Fleiss, Liu & Kelly 
Method 
15.15.1. Statistical Analysis Method for Test of Homogeneity by Fleiss, Liu 
& Kelly 
Analysis 
      Test of Homogeneity by Fleiss, Liu & Kelly 
 
Subgroup  i  (i= 1 to K categories) 
Treatmentj (j=1,2) 
Outcome of 
Interest 
Not 
Outcome of 
Interest 
Total 
 
 Non-Sparse cells (If both π̂i1 or π̂i2 (proportion of outcome in either treatment for level i) is 
not 0 or 1 no modification is made to counts of outcome): 
Trtj=Trt1 
xij = x11 
nij - xij  
= n11 – x11 
nij = n11 
Trtj=Trt2 
xij = x12 
nij - xij 
= n12 – x12 
nij = n12 
 
Sparse cells:  
If either π̂i1 or π̂i2 (proportion of outcome in either treatment for level i) is 0 or 1 add 0.5 to 
each cell in level i (for level i only) 
Trtj=Trt1 
xij = x11 + 0.5 
n11 – x11 + 0.5 
nij = n11 + 1 
Trtj=Trt2 
xij = x12 + 0.5 
n12 – x12 + 0.5 
nij = n12 + 1 
 
 
 
π̂ij = 
xij
nij     
 
 
H0:  Risk differences in each level are equal. 
 
Test Statistic:   Qwls  = ∑
(Yi− τ̂)2
ŵ I
K
i=1
 ~ ChiSq(K-1)     
  
         
Yi = π̂i1 − π̂i2 
 
   
τ̂ = 
∑
Yi
ŵ i
K
i=1
∑
1
ŵ i
K
i=1
      
 
 
wi =
π̂i1 (1−π̂i1)
ni1−1
+ 
π̂i2 (1−π̂i2)
ni2−1
      
 
 


 
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15.16. 
Appendix 16: Final (End of Study) Analysis 
This appendix provides the details of the planned analyses and data displays for 
End of Study (EoS) reporting. These analyses may be included in regulatory submissions, 
study reports and publications 
 
The primary analysis at Week 48 have been completed based on the original RAP.  This 
present appendix is written to cover only analyses included in the final end of study 
reporting. All derivations described in the study analysis plan will be re-used for end of 
study reporting and only those definitions and derivations that have changed since the 
previous interim and primary analysis are described below. This additional appendix 
summarizes only the key endpoints of interest for the final analysis and explain any 
deviations from the primary analysis.  
 
The details of the final EOS reporting and analysis plan are described below: 
 
1. The analysis for which the data have not been changed since the last interim 
analysis (Week 48 analysis) will not be reported to avoid redundancy.  
2. No subgroup analysis, hypotheses testing, or statistical analyses will be 
performed. 
3. The Continuation Phase is not applicable for participants in Sweden and 
Denmark. 
4. All required disclosure outputs following the FDAAA and EudraCT 
guidelines will be produced. These outputs will include data from both 
Randomized and Continuation phase. 
5. For the purpose of creation of Mexico Final Safety Report and submission to 
Ministry of Health, some listings at Mexico sites will be reported separately. Such 
listings are identified in the Programming notes in Section 15.16.9. These listings 
will include data from both Randomized and Continuation Phase 
 
15.16.1. Study Phases 
In the previous analysis (Week 48 analysis), data were summarized for the Randomized 
Phase of the study. However, when data from the Continuation Phase were available, 
Continuation Phase was also included. For the EOS reporting, data to be analysed/ 
reported are from Continuation Phase unless specified otherwise, and this will be noted in 
the title of the output. Listings containing data from both the Randomized and 
Continuation Phases will have a column added to specify the phase of the study for each 
record. Continuation Phase is defined as below:  
Phase 
Start 
End  
Continuation Phase 
Date of exposure after 
Week 52 in the 
DTG/3TC arm. 
Study completion/discontinuation date 
1. 
Notes:  
• 
A participant enters the Continuation Phase if they have at least one exposure to the Investigational Product 
after analysis visit Week 52.  
• 
There will be no Continuation Phase in the CAR Treatment arm.  


 
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15.16.2. Analysis Populations for the Continuation Phase  
In addition to the populations defined in Section 4 of the RAP, the following populations 
were defined for the End of Study Analysis: 
Population  
Definition/ Criteria.  
Analysis Evaluated  
Safety - Continuation Phase Comprises all participants in 
the Safety Population who 
receive at least one dose of 
Investigational Product after 
entering the Continuation 
Phase.  
• 
Safety  
Intent-to-Treat Exposed (ITT-
E) - Continuation Phase 
Comprises all participants in 
the ITT-E Population who 
enter the Continuation 
Phase.  
• 
Efficacy  
• 
Study Population 
• 
Virology 
CVW- Continuation Phase 
Comprises all subjects in the 
ITT-E- Continuation Phase 
population who have met the 
derived CVW criteria 
• 
Virology 
15.16.3. Study Population  
The study population summaries and data listings will be based on the All Subjects 
Screened or ITT-E- Continuation Phase population, unless otherwise specified. 
Demographic and baseline characteristics will be reported only for the subjects who 
entered the Continuation Phase. Overview of the key planned study population 
endpoints:  
• Study Populations  
• Summary of Number of Subjects Enrolled by Country and Site ID for the 
Continuation Population. 
• Concomitant and Antiretroviral Medications 
• Protocol deviations 
• Full details of the data displays are given in Section 15.16.9 
 
15.16.4. Efficacy Analysis  
The efficacy summaries and data listings will be based on the ITT-E-Continuation Phase 
Population. HIV-1 RNA viral load will be summarized using observed data (i.e., subjects 
with missing data at a time point are excluded). A figure will be reported to present 
Individual Plasma HIV-1 RNA and CD4+ Profiles by Visit for Subjects with at least One 
Confirmed Virologic Withdrawal Visit in the Continuation Phase  
Overview of the key planned efficacy endpoints: 


 
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• Proportion of Participants with Plasma HIV-1 RNA < 50 c/ mL/ >= 50 c/mL-  
observed data 
• Proportion of Participants with Confirmed Virologic Withdrawal – observed 
data  
• Incidence of disease progression and HIV-associated conditions 
• Distribution of Quantitative Plasma HIV-1 RNA Results at Suspected and 
Confirmed Virologic Withdrawal 
• Full details of the data displays are given in Section 15.16.9. 
 
15.16.5. Safety Analysis 
All safety displays will be based on the Safety population or Safety- Continuation Phase 
Population. The core adverse event displays for the final report have been identified 
based on the IDSL library required tables. For AE data (including COVID-19), unless 
stated otherwise, the summaries and listings will include only those AEs that occurred 
during Continuation Phase.  
Summaries of AE required for the FDAAA and EudraCT will be generated in this 
reporting effort. Such summaries are identified in the Programming notes. These 
summaries will include events from both Randomized and Continuation Phase.  
Common AEs are those with >=1% (without rounding) incidence for any treatment. For 
drug related grade 2-5 AEs, the common threshold is defined as 0.5%.  
Overview of the key planned safety endpoints: 
• Extent of Exposure 
• Adverse Events 
• Absolute values and Change from Baseline in Weight and BMI for subjects 
entering the Continuation Phase.  
• Patient profiles for subjects meeting Protocol defined liver stopping criteria in the 
Continuation Phase.  
• Positive Suicidal indication Alerts based on eC-SSRS occurring in the 
Continuation Phase.  
• For subjects at Mexico sites the following listings will be generated in this 
reporting effort. These listings will include data from both Randomized and 
Continuation Phase for both DTG/3TC and CAR arms.  
▪ Listing of Non-Serious AEs of Subjects at Mexico sites  
▪ Listing of SAEs of Subjects at Mexico sites 
▪ Full details of the data displays are given in Section 15.16.9. 
 
15.16.6. Virology Analysis 
The Virology displays will be based on CVW- Continuation Phase Population and ITT- E 
Continuation Phase - population. All virology summaries and Listings will include 
subjects who met Confirmed Virologic Withdrawal criteria during the Continuation 
phase. 


 
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Overview of the key planned virology endpoints:  
Refer to the Section 9.2.1 of this document.  
Full details of the data displays are given in Section 15.16.9. 
 
15.16.7. COVID - 19 analysis 
This study was started in 2019 and continued during the COVID -19 pandemic. The 
information regarding the number of participants affected by COVID-19 and its 
symptoms will be reported according to GSK core standards. The visits impacted due to 
the pandemic outbreak will be reported. Protocol deviations or adverse events related to 
COVID-19 if any, will also be reported according to GSK core standards.  
15.16.8. Other Analyses (Health Outcomes) 
Overview of the key planned analysis: 
• Change from Baseline in SDM for subjects entering the Continuation Phase. 
15.16.9. List of Data Displays for End of Study (EOS) Final Report 
Outputs that were not reported in previous reporting effort are identified in Programming 
Notes as ‘New output’. 
 
Study Population 
Type 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Table  
1.36 
ITT-E -
Continuation 
Phase 
Same shell as 
week 48, table 
1.3 
Summary of Number of Subjects 
Enrolled by Country and Site ID 
 
Table  
1.37 
All Subjects 
Screened  
SA1 
Summary of Study Populations 
CS CORE; 
 
Table  
1.38 
ITT-E-
Continuation 
Phase 
DV1a 
Summary of Important Protocol 
Deviations by relationship to 
COVID-19 Pandemic- 
Continuation Phase 
CS CORE 
 
 
 
 
 
 
Table 
1.39 
ITT-E-
Continuation 
Phase 
ES1 
Summary of Subject Status and 
Subject Disposition by relationship 
to COVID-19 Pandemic- 
Continuation Phase 
FDAAA, EudraCT 
Summarise by: i) 
Overall ii) Related to 
COVID-19, ii) Not 
related to COVID-19 
Table 
1.401 ITT-E- 
Continuation 
Phase 
DM1 
Summary of Demographic 
Characteristics - Continuation 
Phase 
 
Table 
1.41 
ITT-E- 
Continuation 
Phase 
CM1 
Summary of Concomitant 
Medication by ATC Level 1 and 
Ingredient – Continuation Phase 
 


 
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Study Population 
Listing-
ICH 
87 
ITT-E- 
Continuation 
Phase 
ES2 
Listing of Study Conclusions 
Reasons for Study Withdrawal – 
Continuation Phase 
 
Listing-
ICH 
88 
ITT-E- 
Continuation 
Phase 
DV2 
Listing of Important Protocol 
Deviations – Continuation Phase 
 
Listing-
Other 
89 
ITT–E-
Continuation 
Phase 
Same shell as 
week 48, 
Listing 28 
Listing of Visit Dates - 
Continuation Phase 
 
Listing - 
Other 
90 
All Subjects 
Screened 
Same shell as 
week 48, 
Listing 29 
Listing of Study Populations 
 
Listing - 
Other 
91 
ITT-E- 
Continuation 
Phase 
CM2 
Listing of Concomitant 
Medications – Continuation Phase 
 
Listing - 
Other 
92 
ITT-E- 
Continuation 
Phase 
Same shell as 
week 48, 
Listing 39 
Listing of on-treatment 
Concomitant ART Medications – 
Continuation phase 
 
Listing - 
Other 
92.1 
ITT-E- 
Continuation 
Phase 
Same shell as 
week 48, 
Listing 40 
Listing of Antiretroviral Therapy 
Starting after Treatment 
Discontinuation - Continuation 
phase 
 
Efficacy 
Type 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Table 
2.33 
ITT-E- 
Continuation 
Phase 
gsk3515864/mi
d204861/ 
primary_05/Tab
le 2.15 
Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL by 
Visit -Observed Data  
 
Table 
2.34 
ITT-E- 
Continuation 
Phase 
 
Same as above 
Proportion of Subjects with 
Plasma HIV-1 RNA >=50 c/mL by 
Visit -Observed Data 
 
Table 
2.35 
ITT-E 
Continuation 
Phase 
Same shell as 
week 48, Table 
2.14 
Summary of Change from 
Baseline in Plasma HIV-1 RNA 
(log10 c/mL) by Visit  
 
Table 
2.36 
ITT-E 
Continuation 
Phase 
Same shell as 
week 48, Table 
2.21 
Proportion of Subjects Meeting 
Confirmed Virologic Withdrawal 
Criteria by Visit by Type of Criteria  
 
Table 
2.37 
ITT-E- 
Continuation 
Phase 
Same shell as 
week 48, Table 
2.22 
Distribution of Quantitative 
Plasma HIV-1 RNA Results at 
Suspected and Confirmed 
Virologic Withdrawal  
 
Table 
2.38 
ITT-E- 
Continuation 
Phase 
Same shell as 
week 48, Table 
2.18 
Summary of Post-Baseline HIV-1 
Associated Conditions Including 
Recurrences - Continuation 
Phase 
 


 
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Study Population 
Table 
2.39 
ITT-E- 
Continuation 
Phase 
Same shell as 
week 48, Table 
2.19 
Summary of Post-Baseline HIV-1 
Associated Conditions Excluding 
Recurrences – Continuation 
Phase 
 
Table 
2.40 
ITT-E- 
Continuation 
Phase 
Same shell as 
week 48, Table 
2.20 
Summary of Post-Baseline HIV-1 
Disease Progressions - 
Continuation Phase 
 
Figure 
2.5 
ITT-E- 
Continuation 
Phase  
Same shell as 
week 48, 
Figure 2.2 
Individual Plasma HIV-1 RNA and 
CD4+ Profiles by Visit for Subjects 
with at least One Suspected 
Virologic Withdrawal Visit  
Include all visits 
Listing - 
ICH 
93 
ITT-E- 
Continuation 
Phase 
Same shell as 
Week 48, 
Listing 10 
Listing of Quantitative and 
Qualitative Plasma HIV-1 RNA 
Data- Continuation Phase 
 
Listing - 
Other 
94 
ITT-E- 
Continuation 
Phase 
Same shell as 
week 48, 
Listing 43 
Listing of Plasma HIV-1 RNA Data 
and CD4+ cell count data for 
Subjects with Confirmed Virologic 
Withdrawal- Continuation Phase 
 
 
Safety 
Type 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming 
Notes 
Table 
3.67 
Safety 
EX1 
Summary of Extent of Exposure to 
Investigational Product 
Including all 
phases 
 
3.69 
Safety- 
Continuation 
Phase 
Same shell as 
Week 48, 
Table 3.2 
Summary of All Adverse Events by System 
Organ Class and Preferred Term – 
Continuation Phase 
 
Table 
3.70 
Safety- 
Continuation 
Phase   
AE3 
Summary of Common (>=1%) Adverse 
Events by Preferred Term and Overall 
Frequency - Continuation Phase 
 
Table 
3.71 
Safety- 
Continuation 
Phase 
AE3 
Summary of Common (>=1%) Grade 2-5 
Adverse Events by Preferred Term and 
Overall Frequency - Continuation Phase 
 
Table 
3.72 
Safety- 
Continuation 
Phase 
AE5A 
Summary of All Drug-related Adverse 
Events by System Organ Class, Preferred 
Term and Maximum Toxicity - Continuation 
Phase 
 
Table 
3.73 
Safety- 
Continuation 
Phase   
AE3 
Summary of Common (>=0.5%) Drug-
related Grade 2-5 Adverse Events by 
Overall Frequency - Continuation Phase 
 
Table 
3.74 
Safety- 
Continuation 
Phase 
AE3 
Summary of Serious Adverse Events by 
System Organ Class and Preferred Term - 
Continuation Phase 
 
Table 
3.75 
Safety- 
Continuation 
Phase 
AE15 
Summary of Serious Adverse Events by 
System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
FDAAA, EudraCT, 
Ct.gov 
 


 
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Safety 
Table 
3.76 
Safety- 
Continuation 
Phase 
AE16 
Summary of Non-serious Adverse Events 
by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 FDAAA, EudraCT 
Table 
3.77 
Safety- 
Continuation 
Phase 
Same shell as 
week 48, Table 
3.18 
Number of Subjects with an Adverse Event 
of Suspected, Probable, Confirmed for 
COVID-19 Infection – Continuation Phase 
 
Table 
3.82 
Safety- 
Continuation 
Phase 
Same shell as 
week 48, Table 
3.42 
Summary of Weight (kg) by Visit 
 
Table 
3.83 
Safety- 
Continuation 
Phase 
Same shell as 
week 48, Table 
3.43 
Summary of Change from Baseline in 
Weight (kg) by Visit 
 
Table 
3.84 
Safety- 
Continuation 
Phase 
Same shell as 
week 48, Table 
3.46 
Summary of BMI (kg/m2) by Visit 
 
Table 
3.85 
Safety- 
Continuation 
Phase 
Same shell as 
week 48, Table 
3.47 
Summary of Change from Baseline in 
BMI (kg/m2) by Visit 
 
Table 
3.87 
Safety- 
Continuation 
Phase 
Same shell as 
week 144, 
Table 3.58 
Summary of True Positive Suicidal 
Indication/ Behaviour Alerts based on 
eCSSRS by Visit – Continuation Phase 
 
Table 
3.88 
Safety- 
Continuation 
Phase 
Same shell as 
week 48, Table 
3.59 
Summary of Subjects with Post-Baseline C-
SSRS Suicidal Ideation or Behaviour – 
Continuation Phase 
 
Listing - 
ICH 
95 
Safety-  
Continuation 
Phase 
Same shell as 
week 48, 
Listing 12 
Listing of Investigational Product Exposure 
Data – Continuation Phase 
 
Listing - 
ICH 
96 
Safety- 
Continuation 
Phase 
AE8 
 
Listing of All Adverse Events – Continuation 
Phase 
 
Listing - 
ICH 
97 
Safety- 
Continuation 
Phase 
AE8 
Listing of Adverse Events Leading to 
Withdrawal/Permanent Discontinuation of 
Investigational Product – Continuation 
Phase 
 
Listing-
ICH 
98 
Safety- 
Continuation 
Phase 
Same shell as 
Week 48, 
Listing 20 
Listing of All Laboratory Data for Subjects 
with Any Value of Potential Clinical 
Importance - Continuation Phase 
 
 
Listing-
ICH 
98.1 
Safety- 
Continuation 
Phase 
Same shell as 
Week 48, 
Listing 21 
Listing of Urinalysis Data for Subjects with 
Any Value of Potential                             
Clinical Importance - Continuation Phase 
 
Listing - 
Other 
99 
Safety- 
Continuation  
Phase 
LIVER5 
 
Patient Profiles for Subjects Meeting 
Protocol Defined Liver Stopping Criteria – 
Continuation Phase 
 
Listing - 
Other 
100 
Safety- 
Continuation  
Phase 
Same shell as 
week 48, 
Listing 58 
Patient Profiles for Subjects Meeting 
Confirmed Virologic Withdrawal Criteria – 
Continuation Phase 
 
Listing - 
102 
Safety- 
PREG1a 
Listing of Subjects Who Became Pregnant 
 


 
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Safety 
Other 
Continuation 
Phase 
During the Study – Continuation Phase 
Listing - 
Other 
103 
Safety- 
Continuation  
Phase 
Same shell as 
week 48, 
Listing 52 
Listing of eC-SSRS Suicidal Ideation and 
Behaviour Positive Alerts (4-9) – 
Continuation Phase 
 
Listing - 
Other 
104 
Safety- 
Continuation 
Phase 
Same shell as 
week 48, 
Listing 53 
Listing of eC-SSRS Suicidal Ideation and 
Behaviour Data– Continuation Phase 
 
Listing - 
Other 
105 
Safety- 
Continuation  
Phase 
Same shell as 
week 48, 
Listing 54 
Listing of eC-SSRS False Positive Alerts 
with Corresponding Reasons – Continuation 
Phase 
 
Listing - 
Other 
106 
Safety- 
Continuation  
Phase 
Same shell as 
week 48, 
Listing 55 
Listing of all eC-SSRS True Positive Alerts 
with AE/SAE status – Continuation Phase 
 
Listing - 
Other 
107 
Safety- 
Continuation  
Phase 
Same shell as 
week 48, 
Listing 64 
Listing of Subjects with an Adverse Event of 
Suspected, Probable, Confirmed for 
COVID-19 Infection – Continuation Phase 
 
Listing - 
Other 
108 
Safety 
AE8 
Listing of Non-Serious AEs of Subjects at 
Mexico sites  
 
New Output; 
Mexican Safety 
Report 
requirement 
Listing - 
Other 
109 
Safety 
AE8 
Listing of SAEs of Subjects at Mexico sites 
 
New Output; 
Mexican Safety 
Report 
requirement 
Listing - 
Other 
110 
Safety- 
Continuation  
Phase 
AE8 
Listing of SAEs of Subjects - Continuation  
Phase 
New Output 
 
 


 
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Virology 
Type 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming 
Notes 
Table 
4.9 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.7 
Summary of Subject Accountability: 
Genotypes Available Continuation Phase 
 
Table 
4.10 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.8 
Summary of Subject Accountability: 
Phenotypes Available- Continuation 
Phase   
 
Table 
4.11 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.1 
Summary of INI Mutations at Baseline and 
Time of CVW- Continuation Phase   
 
Table 
4.12 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.2 
Summary of Major Mutations of NRTI, 
NNRTI and PI Classes by region at 
Baseline and Time of CVW- Continuation 
Phase   
 
Table 
4.13 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.3 
Summary of Genotype at Baseline and 
Time of CVW by Genotypic Cut-Off- 
Continuation Phase   
 
Table 
4.14 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.4 
Summary of Phenotype at Time of CVW 
by Phenotypic Cut-off- Continuation 
Phase   
 
Table 
4.15 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.5 
Summary of Phenotype at Time of CVW 
by Number of Drugs to Which Subject are 
Resistant- Continuation Phase   
 
Table 
4.16 
CVW- 
Continuation 
Phase   
Same shell as 
week 48, 
Table 4.6 
Summary of Fold Change to DTG, 3TC at 
Time of CVW- Continuation Phase   
 
Listing- 
Other 
111 
ITT-E- 
Continuation 
Phase 
See Section 
15.17.16  
Listing of All Genotypic Data – CVWs- 
Continuation Phase   
 
Listing- 
Other 
112 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of All Genotypic Data – pPVWs- 
Continuation Phase   
 
Listing- 
Other 
113 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Genotype by Genotypic Cut-Off 
– CVWs- Continuation Phase    
 
Listing- 
Other 
114 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Genotype by Genotypic Cut-Off 
– pPVWs- Continuation Phase    
 
Listing- 
Other 
115 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of All Phenotypic Data - CVWs- 
Continuation Phase     
 


 
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Virology 
Listing- 
Other 
116 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of All Phenotypic Data - pPVWs- 
Continuation Phase     
 
Listing- 
Other 
117 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Replication Capacity - CVWs- 
Continuation Phase     
 
Listing- 
Other 
118 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Replication Capacity - pPVWs-  
Continuation Phase     
 
Listing- 
Other 
119 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Net Assessment Score - CVWs- 
Continuation Phase     
 
Listing- 
Other 
120 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Net Assessment Score - 
pPVWs- Continuation Phase     
 
Listing- 
Other 
121 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Genotypic and Phenotypic Data 
for Subjects with Confirmed Virologic 
Withdrawal Criteria- Continuation Phase    
 
 
Listing- 
Other 
122 
CVW- 
Continuation 
Phase   
See Section 
15.17.16  
Listing of Genotypic and Phenotypic Data 
for Subjects with Potential Precautionary 
Virologic Withdrawal Criteria- 
Continuation Phase     
 
 
 
 
Other analyses (Health Outcomes) 
Type 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming 
Notes 
Table  
6.14 
ITT-E -
Continuation 
Phase 
Same shell as 
week 48, Table 
6.8 
Summary of SDM bother score Change 
from Baseline by Visit- Continuation 
Phase 
 


 
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15.17. 
Appendix 17: List of Data Displays 
15.17.1. Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.01 to 1.n 
1.01 to 1.n 
Efficacy 
2.01 to 2.n 
2.01 to 2.n 
Safety 
3.01 to 3.n 
3.01 to 3.n 
Virology 
4.01 to 4.n 
4.01 to 4.n 
Pharmacokinetic 
5.01 to 5.n 
5.01 to 5.n 
Health Outcomes 
6.01 to 6.n 
6.01 to 6.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
y to z 
 
15.17.2. Mock Example Shell Referencing 
 
Non- GSK Statistical Display Standard specifications will be referenced as indicated and 
if required example mock-up displays provided in Appendix 18: 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 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Population Pharmacokinetic (PopPK) 
POPPK_Fn 
POPPK_Tn 
POPPK_Ln 
Pharmacodynamic and / or Biomarker 
PD_Fn 
PD_Tn 
PD_Ln 
Pharmacokinetic / Pharmacodynamic 
PKPD_Fn 
PKPD_Tn 
PK/PD_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘GSK Statistical Display Standard/  Example Shell’ or ‘Programming 
Notes’ column as ‘[Non-Standard] + Reference.’ 
 
15.17.3. Deliverables 
Delivery [Priority] [1] 
Description 
DS [X] 
During Study 
IA SAC [X] 
Interim Analysis Statistical Analysis Complete 
SAC [X] 
Final Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 


 
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15.17.4. Study Population Tables 
 
Note that where the Deliverable column states ‘All’, this refers to all reporting efforts i.e. Weeks 24 and 48. 
Study Population Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
ITT-E 
ES1  
 
Summary of Subject Status and Subject Disposition by 
Relationship to COVID-19 Pandemic 
ICH E3, FDAAA, EudraCT 
Present by “Not Related to COVID-19” 
and “ Related to COVID-19” and Overall  
All 
1.2. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
Journal Requirements 
 
All 
1.3. 
Screened 
NS1 
Summary of Number of Subjects Enrolled by Country and 
Site ID 
EudraCT/Clinical Operations 
Repeat by ITT-E population for 
Disclosure purpose. Add Table 1.3.1 
All 
1.4. 
ITT-E 
POP_T1 
Summary of Reasons for Withdrawal by Visit 
ICH E3 
All 
1.5. 
ITT-E 
POP_T13 
Summary of Misrandomized Strata or Treatment 
 
All 
1.6. 
ITT-E 
POP_T9 
Summary of Number of Subjects Attending Nominal and 
Actual Analysis Visits 
 
All 


 
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Study Population Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviation 
1.7. 
ITT-E 
DV1 
Summary of Important Protocol Deviations by Relationship 
to COVID-19 
ICH E3  
Present by “Not Related to COVID-19” 
and “ Related to COVID-19” and Overall 
All 
1.8. 
ITT-E 
DV1 
Summary of Protocol Deviations Leading to Exclusion from 
the Per-Protocol Population 
GSK Statistical Display Standard 
All 
1.9. 
 
 
 
Will be combined with Table 1.7 
 
Population Analysed 
1.10. 
Screened 
SP1 
Summary of Study Populations  
GSK Statistical Display Standard 
All 
Demographic and Baseline Characteristics 
1.11. 
ITT-E 
DM1  
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
All 
1.12. 
Screened 
DM11 
Summary of Age Ranges 
EudraCT 
All 
1.13. 
 
 
 
No longer  required as it is part of 1.14 
 
1.14. 
ITT-E 
DM6 
Summary of Race and Racial Combinations Details 
ICH E3, FDA, FDAAA, EudraCT 
All 
1.15. 
ITT-E 
BASELINE3 
Summary of Hepatitis Status at Entry 
 
All 
1.16. 
ITT-E 
CDC1 
Summary of CDC Classification of HIV Infection at 
Baseline 
 
All 
1.17. 
ITT-E 
RF1 
Summary of HIV Risk Factors 
 
All 


 
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Study Population Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.18. 
ITT-E 
BASELINE4 
Summary of Screening and Baseline Cardiovascular Risk 
Assessments 
GSK Statistical Display Standard 
All 
1.19. 
ITT-E 
BASELINE2 
Summary of Distribution of CD4+ Cell Count (cells/mm^3) 
Results at Screening and Baseline 
 
All 
1.20. 
ITT-E 
BASELINE1 
Summary of Distribution of Quantitative Plasma HIV-1 RNA 
Results at Baseline 
 
All 
Prior and Concomitant Medications, Medical Conditions 
1.21. 
ITT-E 
MH1 
Summary of Current Medical Conditions 
ICH E3 
All 
1.22. 
ITT-E 
MH1 
Summary of Past Medical Conditions 
ICH E3 
All 
1.23. 
ITT-E 
CM1 
Summary of Concomitant Medications by Ingredient ATC 
Level 1 
ICH E3 
All 
1.24. 
ITT-E 
CA1 
Summary of Antiretroviral Therapy Stopped Prior to 
Screening 
 
All 
1.25. 
ITT-E 
CA1 
Summary of Antiretroviral Therapy Received at Screening 
 
All 
1.26. 
 
 
 
Covered in 1.25 
 
1.27. 
ITT-E 
CA1 
Summary of On-Treatment Antiretroviral Therapy Starting 
after Day 1 
 
All 
1.28. 
ITT-E 
CA1 
Summary of Antiretroviral Therapy Starting after Treatment 
Discontinuation 
 
All 


 
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Study Population Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.29. 
 
 
 
Covered in 1.28 
 
1.30. 
ITT-E 
CA2 
Summary of Baseline Third Agent Class 
 
All 
1.31. 
ITT-E 
POP_T12 
Summary of Time since First Antiretroviral Therapy until 
Day 1 
 
All 
1.32. 
ITT-E 
POP_T7 
Summary of History of Depression and Anxiety at Baseline 
 
All 
Impact of COVID-19 Pandemic 
1.33. 
ITT-E 
PAN4 
Summary of Visits impacted by COVID-19 Pandemic 
 
All 
1.34. 
ITT-E 
SD4 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment by Relationship to COVID-19 Pandemic 
Summarise by: 
• 
Related to COVID-19 
Not related to COVID-19 
All 
1.35. 
Screened 
NS1 
Summary of Recruitment by Country and Site Before & After 
Implementation of Pandemic Measures 
The dates when implementation of 
pandemic measures began will be 
available in HARP dataset and 
should be used to define before & 
after implementation of pandemic 
measures 
All 
 


 
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15.17.5. Study Population Figures 
Impact of COVID-19 Pandemic : Figures 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
TST ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Visits impacted by COVID-19 Pandemic 
1.1.  
ITT-E 
PAN8 
Visits impacted by COVID-19 Pandemic 
 
All 
15.17.6. Efficacy Tables 
Efficacy: Tables 
No. 
Populati
on 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Primary Efficacy Analysis 
2.1. 
ITT-E 
EFF_T1 
Summary of Analysis for Percent of Subjects with Plasma 
HIV-1 RNA  50 c/mL at Week X – Snapshot Analysis 
 
All 
2.2. 
Per-
Protocol 
EFF_T1 
Summary of Analysis for Percent of Subjects with Plasma 
HIV-1 RNA  50 c/mL at Week X – Snapshot Analysis 
 
All 
2.3. 
ITT 
EFF_T1 
Summary of Analysis for Percent of Subjects with Plasma 
HIV-1 RNA  50 c/mL at Week X – Snapshot Analysis 
 
All 
2.4. 
ITT-E 
EFF_T1 
Summary of Analysis for Percent of Subjects with Plasma 
HIV-1 RNA  50 c/mL at Week X – Snapshot Analysis 
 
All 


 
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Efficacy: Tables 
No. 
Populati
on 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
(Sparse Data Sensitivity Analysis) 
Secondary Efficacy Analyses 
2.5. 
ITT-E 
EFF_T1 
Summary of Analysis for Percent of Subjects with Plasma 
HIV-1 RNA <50 c/mL at Week X – Snapshot Analysis 
 
All 
2.6. 
ITT-E 
EFF_T2 
Summary of Study Outcomes (Plasma HIV-1 RNA  / < 50 
c/mL) at Week X – Snapshot Analysis 
 
All 
2.7. 
Per-
Protocol 
EFF_T2 
Summary of Study Outcomes (Plasma HIV-1 RNA  / < 50 
c/mL) at Week X – Snapshot Analysis 
 
All 
2.8. 
ITT 
EFF_T2 
Summary of Study Outcomes (Plasma HIV-1 RNA  / < 50 
c/mL) at Week X – Snapshot Analysis 
 
All 
2.9. 
ITT-E 
EFF_T2a 
Summary of Study Outcomes (Plasma HIV-1 RNA  / < 50 
c/mL) at Week X – Modified Snapshot Analysis 
 
All 
2.10. 
 
ITT-E 
EFF_T5 
Summary of Percent of Subjects with Plasma HIV-1 RNA 
50 c/mL by Visit – Snapshot Analysis 
 
All 
2.11. 
 
ITT-E 
EFF_T5 
Summary of Percent of Subjects with Plasma HIV-1 RNA 
<50 c/mL by Visit – Snapshot Analysis  
 
All 
2.12. 
 
ITT-E 
EFF_T6 
Summary of Percent of Subjects with Plasma HIV-1 RNA 
<50 c/mL at Week X by Subgroup – Snapshot Analysis  
 
All 
2.13. 
 
ITT-E 
EFF_T3 
Summary of Study Outcomes (Plasma HIV-1 RNA  / < 50 
c/mL) at Week X by Subgroup - Snapshot Analysis  
 
All 
2.14. 
 
ITT-E 
EFF_T8 
Summary of Change from Baseline in Plasma HIV-1 RNA 
(log10 c/mL) by Visit  
 
All 


 
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Efficacy: Tables 
No. 
Populati
on 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.15. 
 
ITT-E 
EFF_T9 
Summary of Change from Baseline in in CD4+ count 
(cells/mm3) by Visit 
 
All 
2.16. 
 
ITT-E 
EFF_T9 
Summary of Change from Baseline in in CD4+/CD8+ count 
ratio (cells/mm3) by Visit 
 
All 
2.17. 
 
ITT-E 
EFF_T14 
Summary of Change from Baseline in CD4+/CD8+ Count 
Ratio (cells/mm3) at Week X by Subgroup 
 
All 
2.18. 
 
ITT-E 
EFF_T10 
Summary of Post-Baseline HIV-1 Associated Conditions 
Including Recurrences 
 
All 
2.19. 
 
ITT-E 
EFF_T10 
Summary of Post-Baseline HIV-1 Associated Conditions 
Excluding Recurrences 
 
All 
2.20. 
 
ITT-E 
EFF_T11 
Summary of Post-Baseline HIV-1 Disease Progressions 
 
All 
2.21. 
 
ITT-E 
EFF_T12 
Cumulative Proportion of Subjects Meeting Confirmed 
Virologic Withdrawal Criteria by Visit  
 
All 
2.22. 
 
ITT-E 
EFF_T13 
Distribution of Quantitative Plasma HIV-1 RNA Results at 
Suspected and Confirmed Virologic Withdrawal 
 
All 
2.23. 
 
ITT-E 
EFF_T14 
Summary of Change from Baseline in in CD4+ count 
(cells/mm3) at Week X by Subgroup 
 
All 
2.24. 
 
ITT-E 
EFF_T15 
Summary of Kaplan-Meier Estimates of Proportion of 
Subjects Without Confirmed Virologic Withdrawal at Week 
X - Treatment Related Discontinuation = Failure  
 
All 
2.25. 
 
ITT-E 
EFF_T15 
Summary of Kaplan-Meier Estimates of Proportion of 
Subjects Without Confirmed Virologic Withdrawal at Week 
X - Efficacy Related Discontinuation = Failure  
 
All 


 
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Efficacy: Tables 
No. 
Populati
on 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.26. 
 
ITT-E 
EFF_T1 
Summary of Analysis for percent of Subjects with Plasma 
HIV-1 RNA <40 c/mL at Week X – Snapshot Analysis 
 
All 
2.27. 
 
ITT-E 
EFF_T1 
 Summary of Analysis for Percent of Subjects with Plasma 
HIV-1 RNA <40 c/mL and Target Not Detected Status at 
Week X - Snapshot Analysis - ITT-E 
 
 All 
2.28. 
 
ITT-E 
EFF_T5 
Summary of Percent of Subjects with Plasma HIV-1 RNA 
<40 c/mL by Visit - Snapshot Analysis   
 
All 
2.29. 
 
ITT-E 
EFF_T5 
Summary of Percent of Subjects with Plasma HIV-1 RNA 
<40 c/mL and Target Not Detected Status by Visit - 
Snapshot Analysis 
 
All 
2.30. 
 
ITT-E 
EFF_T2 
Summary of Study Outcomes (<40 c/mL and Target Not 
Detected Status) at Week X - Snapshot 
 
All 
2.31. 
 
ITT-E 
EFF_T6 
Summary of Percent of Subjects with Plasma HIV-1 RNA 
<40 c/mL and Target Not Detected Status at Week X by 
Baseline Third Agent Class -Snapshot Analysis - ITT-E  
 
All 
2.32. 
 
ITT-E 
EFF_T2 
Summary of Study Outcomes (<40 c/mL) at Week X - 
Snapshot 
 
 
 
 
 


 
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15.17.7. Efficacy Figures 
 
Efficacy: Figures 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Secondary Efficacy Analyses 
2.1. 
ITT-E 
EFF_F2 
Unadjusted Treatment Difference in Percent (95% CI) of 
Subjects with HIV-1 RNA <50 c/mL at Week X by 
Subgroup – Snapshot Analysis 
 
All 
2.2. 
ITT-E 
EFF_F3 
Individual Plasma HIV-1 RNA and CD4+ Profiles by Visit 
for subjects with at least one viral load ≥50 c/mL 
 
All 
2.3. 
ITT-E 
EFF_F4 
Kaplan-Meier Plot of Time to Failure - Treatment Related 
Discontinuation = Failure (TRDF)  
 
All 
2.4. 
ITT-E 
EFF_F4 
Kaplan-Meier Plot of Time to Failure - Efficacy Related 
Discontinuation = Failure (ERDF)  
 
All 
 
 
 
 
 


 
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15.17.8. Safety Tables 
 
Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Exposure 
3.1. 
Safety 
SAFE_T1 
Summary of Extent of Exposure Study Treatment- Randomized Phase  
 
ICH E3 
 
All 
Adverse Events 
3.2. 
Safety 
AE1  
 
Summary of All Adverse Events by System Organ Class and Preferred Term 
 
ICH E3 
 
All 
3.3. 
Safety 
AE5B 
Summary of Adverse Events by System Organ Class, Maximum Toxicity and 
Subgroups 
 
All 
3.4. 
Safety 
AE5A 
Summary of All Adverse Events by Maximum Grade  
ICH E3 
All 
3.5. 
Safety 
AE3 
Summary of Common (>=2%) Adverse Events by Overall Frequency 
ICH E3 
All 
3.6. 
Safety 
AE3 
Summary of Common (>=2%) Grade 2-5 Adverse Events by Overall 
Frequency 
ICH E3 
All 
3.7. 
Safety 
AE1  
 
Summary of All Drug-Related Adverse Events by System Organ Class and 
Preferred Term 
 
ICH E3 
All 


 
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Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
3.8. 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade 
ICH E3 
All 
3.9. 
Safety 
AE15 
Summary of Common (>=2%) Non-serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subject and Occurrences) 
FDAAA, EudraCT 
 
All 
3.10. 
Safety 
AE3 
Summary of Common (>=0.5%) Drug-Related Grade 2-5 Adverse Events by 
Overall Frequency 
ICH E3 
All 
3.11. 
Safety 
SAFE_T16 
Summary of Subjects with Any Adverse Events by Visit 
 
All 
3.12. 
Safety 
AE20 
Summary of Serious Fatal and Non-Fatal Drug-Related Adverse Events by 
Overall Frequency 
Plain 
Language 
Summary 
requirements 
All 
Serious and Other Significant Adverse Events 
3.13. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences) 
FDAAA, EudraCT 
 
All 
3.14. 
Safety 
AE1  
Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment or Withdrawal from Study by System Organ Class and Preferred 
Term /by Overall Frequency 
GSK Statistical 
Display Standard 
 
All 
3.15. 
Safety 
AE5A 
Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment or Withdrawal from Study by Maximum Grade 
 
All 


 
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Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
3.16. 
Safety 
AE1 
Summary of Serious Drug-Related Adverse Events by System Organ Class 
Plain 
Language 
Summary 
requirements. 
All 
3.17. 
Safety 
SAFE_T2 
Summary of Cumulative Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by Visit 
 
All 
Impact of Covid-19 on Assessment of Safety Based on COVID-19 eCRF 
3.18. 
Safety 
PAN1 
Number of Subjects with an Adverse Event of Suspected, Probable, 
Confirmed for COVID-19 Infection 
GSK Statistical 
Display Standard 
 
All 
3.19. 
 
 
 
Covered in 3.18 
 
 
Laboratory: Chemistry  
3.20. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline by Visit 
ICH E3 
All 
3.21. 
Safety 
SAFE_T17 
Summary of Chemistry by Visit 
ICH E3 
All 
3.22. 
Safety 
SAFE_T13 
Summary of AST, ALT and Total Bilirubin Maximum Post-Baseline Emergent 
Toxicity by Baseline Hepatitis C Status 
ICH E3 
All 
3.23. 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
GSK Statistical 
Display Standard 
 


 
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Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Laboratory: Lipids 
3.24. 
Safety 
LB1 
Summary of Fasting Lipids by Visit  
display both 
mmol/L and 
mg/DL 
All 
3.25. 
Safety 
LB1 
Summary of Change from Baseline in Fasting Lipids by Visit 
display both 
mmol/L and 
mg/DL 
All 
3.26. 
Safety 
SAFE_T5 
Summary of Changes in NCEP Lipid Baseline Category to Week X Category-
Shift Table  
display both 
mmol/L and 
mg/DL 
All 
3.27. 
Safety 
SAFE_T7b 
Statistical Analysis of Change from Baseline in Fasting Lipids at Week X -
Multiple Imputed Loge Transformed Data - MAR 
display both 
mmol/L and 
mg/DL 
All 
3.28. 
Safety 
SAFE_T7b 
Statistical Analysis of Change from Baseline in Fasting Lipids at Week X - 
Loge Transformed Data – MMRM/ANCOVA 
display both 
mmol/L and 
mg/DL 
ANCOVA-
Week 24 
MMRM-Week 
48 
All 
Laboratory: Hematology 


 
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Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
3.29. 
Safety 
LB1 
Summary of Hematology Changes from Baseline by Visit 
ICH E3 
All 
3.30. 
Safety 
SAFE_T17 
Summary of Hematology by Visit 
 
All 
Laboratory: Urinalysis 
3.31. 
Safety 
LB1 
Summary of Urinalysis Changes from Baseline by Visit 
ICH E3 
All 
3.32. 
Safety 
SAFE_T17 
Summary of Urinalysis by Visit 
 
All 
Laboratory: Hepatobiliary (Liver) 
3.33. 
Safety 
LIVER10 
Summary of Subjects Meeting Hepatobiliary Abnormality Criteria – All Post-
Baseline Abnormalities 
GSK Statistical 
Display Standard 
All 
Biomarkers (Bone, Renal and Inflammatory) 
3.34. 
Safety 
LB1 
Summary of Change from Baseline in Bone Biomarkers by Visit 
 
All 
3.35. 
Safety 
LB1 
Summary of Change from Baseline in Renal Biomarkers by Visit 
 
All 
3.36. 
Safety 
LB1 
Summary of Change from Baseline in Renal Biomarkers by Visit- Loge 
Transformed Data  
 
All 
3.37. 
Safety 
LB1 
Summary of Change from Baseline in Inflammatory 
Biomarkers - Loge Transformed Data 
 
All 
3.38. 
Safety 
SAFE_T7b 
Statistical Analysis of Change from Baseline Bone Biomarkers at Week X –  
MMRM/ANCOVA 
ANCOVA-
Week 24 
MMRM-Week 
48 
All 


 
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Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
3.39. 
Safety 
SAFE_T7a 
Statistical Analysis of Change from Baseline in Renal Biomarkers at Week X 
– MMRM/ANCOVA 
ANCOVA-
Week 24 
MMRM-Week 
48 
All 
3.40. 
Safety 
SAFE_T7b 
Statistical Analysis of Change from Baseline in Renal Biomarkers at Week X 
- Loge Transformed Data - MMRM /ANCOVA 
ANCOVA-
Week 24 
MMRM-Week 
48 
All 
3.41. 
Safety 
SAFE_T7b 
Statistical Analysis of Change from Baseline in Inflammatory Biomarkers at 
Week X  - Loge Transformed Data – MMRM/ANOCVA 
ANCOVA-
Week 24 
MMRM-Week 
48 
All 
Weight, BMI, HOMA-IR and HbA1c 
3.42. 
Safety 
SAFE_T17 
Summary of Weight (kg) by Visit 
 
All 
3.43. 
Safety 
LB1 
Summary of Change from Baseline in Weight (kg) by Visit 
 
All 
3.44. 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in Weight (kg)  by Visit- MMRM 
 
All 
3.45. 
Safety 
SAFE_T18 
Summary of Proportion of Subjects with Change from Baseline in Weight 
(>=3% and >=10%) at Week X 
 
All 
3.46. 
Safety 
SAFE_T17 
Summary of BMI (kg/m2) by Visit 
 
All 


 
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Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
3.47. 
Safety 
LB1 
Summary of Change from Baseline in BMI (kg/m2) by Visit 
 
All 
3.48. 
Safety 
SAFE_T5 
Summary of Changes in BMI (kg/m2) from Baseline to Week X -Shift Table 
 
All 
3.49. 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in BMI (kg/m2) by Visit- MMRM 
 
All 
3.50. 
Safety 
SAFE_T17 
Summary of HOMA-IR by Visit 
 
All 
3.51. 
Safety 
LB1 
Summary of Change from Baseline in HOMA-IR by Visit - Loge Transformed 
Data 
 
All 
3.52. 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in HOMA-IR  by Visit- Loge 
Transformed Data - MMRM 
 
All 
3.53. 
Safety 
SAFE_T19  
Statistical Analysis of Variables Associated with ≥2 
HOMA-IR at Week X – Logistic Regression 
 
All 
3.54. 
Safety 
SAFE_T19  
Statistical Analysis of Variables Associated with ≥3 
HOMA-IR at Week X – Logistic Regression 
 
All 
3.55. 
Safety 
SAFE_T19  
Statistical Analysis of Variables Associated with ≥4 
HOMA-IR at Week X – Logistic Regression 
 
All 
3.56. 
Safety 
SAFE_T17 
Summary of HbA1c by Visit 
 
All 
3.57. 
Safety 
LB1 
Summary of Change from Baseline in HbA1c by Visit 
 
All 
3.58. 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in HbA1c by Visit - MMRM 
 
All 


 
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Safety: Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Other Safety Analyses 
3.59. 
Safety 
SAFE_T8 
Summary of True Positive Suicidal Indication Alerts Based on eCSSRS by 
Visit 
 
All 
3.60. 
Safety 
SAFE_T9 
Summary of Subjects with eCSSRS Suicidal Ideation or Behaviour at 
Baseline 
 
All 
3.61. 
Safety 
SAFE_T9 
Summary of Subjects with Post Baseline eCSSRS Suicidal Ideation or 
Behaviour  
 
All 
3.62. 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Adverse Events of Special 
Interest 
Present each 
AESI in a 
separate table. 
Table 
numbering 
should be from 
3.621 to 3.628  
All 


 
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15.17.9. Safety Figures 
Safety: Figures 
No. Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1. 
Safety 
AE10 
Plot of Common (>=2%) Adverse Events and Relative Risk 
 
All 
Laboratory: Biomarkers 
3.2. 
Safety 
LIPID7 
Heatmap Plot of NCEP Categories in Lipids Over Time 
 
All 
3.3. 
Safety 
SAFE_F2 
Line Plot of Adjusted Mean (95% CI) Change from Baseline in Renal Biomarkers 
Over Time — MMRM  
 
All 
3.4. 
Safety 
SAFE_F3 
Line Plot of Ratio of Geometric Means (95% CI) in Renal Biomarkers Over Time - 
Loge Transformed Data - MMRM  
 
All 
3.5. 
Safety 
SAFE_F2 
Line Plot of Adjusted Mean (95% CI) of Change from Baseline in Bone 
Biomarkers Over Time — MMRM 
 
All 
3.6. 
Safety 
SAFE_F2 
Line Plot of Ratio of Geometric Means (95% of CI) in Inflammatory Biomarkers 
Over Time - Loge Transformed - MMRM 
 
All 
3.7. 
Safety 
SAFE_F5 
Line Plot of Adjusted Mean (95% CI) of Change from Baseline in Weight (kg) Over 
Time — MMRM 
 
All 
3.8. 
Safety 
SAFE_F5 
Line Plot of Adjusted Mean (95% CI) of Change from Baseline in BMI (kg/m2) 
Over Time — MMRM 
 
All 


 
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Safety: Figures 
No. Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
3.9. 
Safety 
SAFE_F2 
Line Plot of Ratio of Geometric Means (95% of CI) in HOMA-IR Over Time - Loge 
Transformed Data – 
MMRM 
 
All 
3.10. 
Safety 
SAFE_F5 
Line Plot of Adjusted Mean (95% CI) of Change from Baseline in HbA1c Over 
Time — MMRM 
 
All 
Other Safety 
3.11. 
Safety 
LIPID7 
Heatmap Plot of BMI (kg/m2) Categories Over Time 
 
All 
3.12. 
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
 
All 


 
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15.17.10. Virology Tables  
Virology: Tables 
No. Population 
GSK 
Statistical 
Display 
Standard/ 
TST ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
4.1. 
CVW 
VIR_T1 
Summary of INI Mutations at Baseline and Time of CVW at or prior to Week X 
 
All 
4.2. 
CVW 
VIR_T2 
Summary of Major Mutations of NRTI, NNRTI and PI Classes by region at 
Baseline and Time of CVW at or prior to Week X 
 
All 
4.3. 
CVW 
VIR_T3 
Summary of Genotype at Baseline and Time of CVW by Genotypic Cut-Off at 
or prior Week X 
 
All 
4.4. 
CVW 
VIR_T4 
Summary of Phenotype at Time of CVW by Phenotypic Cut-off at or prior 
Week X 
 
All 
4.5. 
CVW 
VIR_T5 
Summary of Phenotype at time of CVW by Number of Drugs to Which Subject 
are Resistant at or prior Week X 
 
All 
4.6. 
CVW 
VIR_T6 
Summary of Fold Change to DTG, 3TC at - Time of CVW at or prior to Week X 
 
 
All 
4.7. 
CVW 
VIR_T7  
Summary of Subject Accountability: Genotypes Available at or prior to Week X 
 
All 
4.8. 
CVW 
VIR_T8  
Summary of Subject Accountability: Phenotypes Available at or prior to Week 
X 
 
All 


 
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153 
15.17.11. Pharmacokinetic Tables 
 
There is no pharmacokinetic analysis planned in this study. 
15.17.12. Pharmacokinetic Figures 
 
There is no pharmacokinetic analysis planned in this study. 
15.17.13. Health Outcomes Tables  
Health Outcomes : Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
TST ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Treatment Satisfaction (HIVTSQ) 
6.1. 
ITT-E 
THO1 
Summary of HIVTSQ Individual Item Scores by Visit  
 
All 
6.2. 
ITT-E 
THO2 
Summary of HIVTSQ Total Score, Lifestyle/Ease and General 
Satisfaction/Clinical Sub-score by Visit  
 
All 
6.3. 
ITT-E 
THO2 
Summary of Change from Baseline in HIVTSQ Total Score, 
Lifestyle/Ease and General Satisfaction/Clinical Sub-score by Visit  
 
All 
6.4. 
ITT-E 
THO3 
Statistical Analysis of HIVTSQ Total Score, Lifestyle/Ease and General 
Satisfaction/Clinical Sub-score Change from Baseline - MMRM 
 
All 
6.5. 
ITT-E 
THO3 
Statistical Analysis of HIVTSQ Total Score, Lifestyle/Ease and General 
Satisfaction/Clinical Sub-score Change from Baseline by Subgroups - 
MMRM 
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
154 
Health Outcomes : Tables 
No. 
Population 
GSK 
Statistical 
Display 
Standard/ 
TST ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Symptom Distress Module 
6.6. 
ITT-E 
THO4 
Summary of SDM Symptom Count by Visit  
 
All 
6.7. 
ITT-E 
THO4 
Summary of SDM Symptom Bother Score by Visit  
 
All 
6.8. 
ITT-E 
THO4 
Summary of SDM Symptom Bother Score Change from Baseline by 
Visit  
 
All 
6.9. 
ITT-E 
THO5 
Percentage of Subjects with Each Type of Symptom as per the SDM 
by Visit  
 
All 
6.10. ITT-E 
THO6 
Percentage of Subjects in SDM Symptom Bother Score Categories  by 
Visit  
 
All 
6.11. ITT-E 
THO3 
Statistical Analysis of Change from Baseline in SDM Symptom Bother 
Score at Week X– MMRM 
 
All 
6.12. ITT-E 
THO3 
Statistical Analysis of Change from Baseline in SDM Symptom Bother 
Score  by Subgroups at Week X– MMRM 
 
All 
Willingness to switch 
6.13. ITT-E 
THO8 
Summary of Reasons for Willingness to Switch  
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
155 
15.17.14. Health Outcomes Figures 
Health Outcomes : Figures 
No. Population 
GSK 
Statistical 
Display 
Standard/ 
TST ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Treatment Satisfaction (HIVTSQ) 
6.1. 
ITT-E 
FHO1 
Line Plot of Adjusted Mean (95% CI) Change from Baseline in HIVTSQ 
Total Treatment Satisfaction Score, Lifestyle/Ease and General 
Satisfaction/Clinical Sub-score Over Time 
 
All 
Symptom Distress Module 
6.2. ITT-E 
FHO1 
Line Plot of Adjusted Mean (95% CI) Change from Baseline in SDM 
Symptom Bother Score Over Time  
 
All 
 


 
CONFIDENTIAL 
 
 
 
208090 
156 
15.17.15. ICH Listings 
ICH: Listings 
No. Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable [Priority] 
Subject Disposition 
1.  
ITT-E 
ES2  
Listing of Reasons for Study Withdrawal 
ICH E3 
All 
2.  
ITT-E 
SD2 
Listing of Reasons for Study Treatment 
Discontinuation 
ICH E3 
All 
Protocol Deviation 
3.  
ITT-E 
DV2 
Listing of Important Protocol Deviations  
ICH E3. Listing to be 
run regardless of 
relationship to 
COVID-19 
All 
4.  
ITT-E 
IE4 
Listing of Subjects with Inclusion/Exclusion 
Criteria Deviations 
ICH E3 
All 
Populations Analysed 
5.  
ITT-E 
SP3a 
Listing of Protocol Deviations Leading to 
Exclusion from the Per Protocol Population 
ICH E3 
All 
6.  
ITT-E 
DV2 
Listing of Protocol Deviations Related to 
COVID-19 
ICH E3 
Include a column 
to flag Important 
PDs 
All 
Demographic and Baseline Characteristics 


 
CONFIDENTIAL 
 
 
 
208090 
157 
ICH: Listings 
No. Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable [Priority] 
7.  
ITT-E 
DM2 
Listing of Demographic Characteristics 
ICH E3 
All 
8.  
ITT-E 
DM10 
Listing of Race 
ICH E3 
All 
Efficacy  
9.  
ITT-E 
EFF_L1 
Listing of Study Outcome ( / < 50 c/mL) at 
Week 48 – Snapshot Analysis 
 
All 
10.  
ITT-E 
EFF_L2 
Listing of Quantitative and Qualitative Plasma 
HIV-1 RNA Data 
 
All 
11.  
ITT-E 
EFF_L1 
Listing of Study Outcome ( / < 50 c/mL) at 
Week 48 – Modified Snapshot Analysis 
 
All 
Exposure and Treatment Compliance 
12.  
Safety 
EX3  
Listing of Exposure Data 
ICH E3 
All 
Adverse Events 
13.  
Safety 
AE8  
Listing of All Adverse Events 
ICH E3 
All 
14.  
Safety 
AE14 
Listing of Reasons for Considering as a 
Serious Adverse Event 
ICH E3 
All 
15.  
Safety 
AE8 
Listing of Adverse Events Leading to 
Withdrawal from Study / Permanent 
Discontinuation of Study Treatment 
ICH E3 
All 


 
CONFIDENTIAL 
 
 
 
208090 
158 
ICH: Listings 
No. Population 
GSK 
Statistical 
Display 
Standard/ 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable [Priority] 
16.  
Safety 
PSRAE1 
Listing of Possible Suicidality-Related Adverse 
Event Data: Event and Description (Section 1- 
Section 2) 
ICH E3 
All 
17.  
Safety 
PSRAE3 
Listing of Possible Suicidality-Related Adverse 
Event Data: Possible Cause(s) (Section 3) 
 
All 
18.  
Safety 
PSRAE4 
Listing of Possible Suicidality-Related Adverse 
Event Data (Section 4) 
 
All 
19.  
Safety 
PSRAE5 
Listing of Possible Suicidality-Related Adverse 
Event Data (Section 5- Section 8) 
 
All 
All Laboratory 
20.  
Safety 
LB5  
Listing of All Laboratory Data for Subjects with 
Any Value of Potential Clinical Importance 
Include 
Chemistry, 
Hematology and 
Lipids. 
ICH E3 
All 
21.  
Safety 
LB5 
Listing of Urinalysis Data for Subjects with 
Any Value of Potential Clinical Importance 
 
All 
Vital Signs 
22.  
Safety 
VS4 
Listing of Vital Signs 
ICH E3 
All 


 
CONFIDENTIAL 
 
 
 
208090 
159 
15.17.16. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
GSK Statistical Display 
Standard/ Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Study Population 
23.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
GSK Statistical Display 
Standard 
All 
24.  
ITT 
TA1  
Listing of Planned Randomized and Actual Strata 
and Treatment Assignments 
 
All 
25.  
ITT 
POP_L1 
Listing of Subjects Randomized but not Treated 
 
All 
26.  
Screened 
POP_L2 
 
 
Listing of Subjects Enrolled by Country and Site 
ID 
 
All 
27.  
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
 
All 
28.  
ITT-E 
POP_L3 
 
Listing of Visit Dates 
 
All 
29.  
Screened 
POP_L4 
 
Listing of Study Populations 
 
All 
30.  
ITT-E 
BASELINE6 
 
Listing of Hepatitis Test Results at Entry 
 
All 
31.  
ITT-E 
CDC3 
Listing of CDC Classification of HIV Infection at 
Baseline 
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
160 
Non-ICH: Listings 
No. 
Population 
GSK Statistical Display 
Standard/ Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
32.  
ITT-E 
RF2 
Listing of HIV Risk Factors 
 
All 
33.  
ITT-E 
BASELINE7 
 
Listing of Screening Cardiovascular Risk 
Assessment Data 
 
All 
34.  
ITT-E 
MH2 
Listing of Current and Past Medical Conditions at 
Baseline 
 
All 
35.  
ITT-E 
POP_L7 
 
Listing of Relationship Between Concomitant ATC 
Level 1, Ingredient and Verbatim Text  
 
All 
36.  
ITT-E 
CM2 
Listing of Concomitant Medications 
GSK Statistical Display 
Standard 
All 
37.  
ITT-E 
CM2 
Listing of Antiretroviral Therapy Stopped Prior to 
Screening 
 
All 
38.  
ITT-E 
CM2 
Listing of Antiretroviral Therapy Received at 
Screening 
 
All 
39.  
ITT-E 
CM2 
Listing of On-Treatment Antiretroviral Therapy 
Starting after Day 1 
 
All 
40.  
ITT-E 
CM2 
Listing of Antiretroviral Therapy Starting after 
Treatment Discontinuation 
 
All 
41.  
ITT-E 
POP_L8 
 
Listing of Relationship Between Concomitant ATC 
Level 4, Ingredient and Verbatim Text  
 
All 
42.  
ITT-E 
POP_L12 
 
Listing of Menopause History 
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
161 
Non-ICH: Listings 
No. 
Population 
GSK Statistical Display 
Standard/ Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Efficacy 
43.  
ITT-E 
VF4 
Listing of Plasma HIV-1 RNA data and CD4+ cell 
count data for subjects with Confirmed Virologic 
Withdrawal  
 
All 
44.  
ITT-E 
EFF_L4 
Listing of CD4+ Cell Count Data 
 
All 
45.  
ITT-E 
EFF_L5 
Listing of CD8+ and CD4+/CD8+ Cell Count Ratio 
Data 
 
All 
46.  
ITT-E 
HIV4 
Listing of Stage 3 HIV-1 Associated Conditions 
 
All 
47.  
ITT-E 
EFF_L6 
Listing of Subjects Treatment-related 
discontinuation = Failure (TRDF)  
 
All 
48.  
ITT-E 
EFF_L6 
Listing of Subjects Efficacy-related 
discontinuation = Failure (ERDF) 
 
All 
Safety 
49.  
Safety 
EG3  
Listing of ECG Findings 
 
All 
50.  
Safety 
SAFE_L1 
Listing of Post Baseline Maximum ALT and 
Maximum Bilirubin  
 
All 
51.  
Safety 
SAFE_L2 
Listing of Subjects Meeting Hepatobiliary 
Abnormality Criteria – All Post-Baseline 
Abnormalities 
 
All 
52.  
Safety 
SAFE_L3 
Listing of eCSSRS Suicidal Ideation and 
Behaviour Data Alerts (4-9) 
 
All 
53.  
Safety 
SAFE_L4 
Listing of eCSSRS Suicidal Ideation and 
Behaviour Data  
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
162 
Non-ICH: Listings 
No. 
Population 
GSK Statistical Display 
Standard/ Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
54.  
Safety 
SAFE_L5 
Listing of eCSSRS False Positive Alerts with 
Corresponding Reasons 
 
All 
55.  
Safety 
SAFE_L5 
Listing of all eCSSRS True Positives, with 
Corresponding Reasons and AE or SAE status 
 
All 
56.  
Safety 
SAFE_L6 
Listing of Subjects Who Became Pregnant During 
the Study 
 
All 
57.  
Safety 
SAFE_L7 
Patient Profiles for Subjects Meeting Protocol 
Defined Liver Stopping Criteria 
 
All 
58.  
Safety 
SAFE_L7 
Patient Profiles for Subjects Meeting Confirmed 
Virologic Withdrawal Criteria 
 
All 
59.  
Safety 
SAFE_L7 
Patient Profiles for Subject Excluded from Safety 
Population Due to Non-Study Treatment Ongoing 
at Randomisation 
 
All 
60.  
Safety 
SAFE_L8 
Listing of Cardiovascular Events  
 
All 
61.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse 
Events  
 
All 
62.  
Safety 
AE2 
Listing of Relationship Between Adverse Event 
System Organ Classes, Preferred Terms, and 
Verbatim Text  
 
All 
63.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
 
All 
64.  
Safety 
PAN12 
Listing of Subjects with an Adverse Event of 
Suspected, Probable, Confirmed for COVID-19 
Infection 
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
163 
Non-ICH: Listings 
No. 
Population 
GSK Statistical Display 
Standard/ Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
65.  
 
 
 
Covered in 64 
 
Hepatobiliary (Liver) 
66.  
Safety 
MH2 
Listing of Medical Conditions for Subjects with 
Liver Stopping Events 
 
All 
67.  
Safety 
SU2 
Listing of Substance Use for Subjects with Liver 
Stopping Events 
 
All 
68.  
Safety 
PK07 
Listing of Plasma DTG Pharmacokinetic for 
Subjects with Liver Stopping Events 
 
All 
Virology 
69.  
CVW 
VIR_L1 
Listing of All Genotypic Data – CVWs 
 
All 
70.  
pPVW  
VIR_L1 
Listing of All Genotypic Data – pPVWs  
 
All 
71.  
CVW 
VIR_L2 
Listing of Genotype by Genotypic Cut-Off – 
CVWs 
 
All 
72.  
pPVW  
VIR_L2 
Listing of Genotype by Genotypic Cut-Off – 
pPVWs 
 
All 
73.  
CVW 
VIR_L3 
Listing of All Phenotypic Data – CVWs 
 
 
All 
74.  
pPVW  
VIR_L3 
Listing of All Phenotypic Data – pPVWs 
 
 
All 
75.  
CVW 
VIR_L4 
Listing of Replication Capacity – CVWs 
 
 
All 
76.  
pPVW  
VIR_L4 
Listing of Replication Capacity – pPVWs 
 
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
164 
Non-ICH: Listings 
No. 
Population 
GSK Statistical Display 
Standard/ Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
77.  
CVW 
VIR_L5 
Listing of Net Assessment Score – CVWs 
 
 
All 
78.  
pPVW  
VIR_L5 
Listing of Net Assessment Score – pPVWs 
 
 
All 
79.  
CVW 
VIR_L7 
Listing of Genotypic and Phenotypic Data for 
Subjects with Confirmed Virologic Withdrawal 
Criteria 
 
All 
80.  
pPVW  
 
VIR_L7 
Listing of Genotypic and Phenotypic Data for 
Subjects with Potential Precautionary Virologic 
Withdrawal Criteria 
 
All 
80.1 
 
 
 
ITT-E 
 
 
 
VIR_L7 
Listing of Genotypic and Phenotypic Data for 
Subjects Last on Study HIV-1 RNA >400 c/mL 
with Resistance  Testing 
 
Week 48 
81.  
pPVW 
VF4 
Listing of Plasma HIV-1 RNA data and CD4+ cell 
count data for subjects with Potential 
Precautionary Virologic Withdrawal Criteria 
 
All 
Health Outcomes 
82.  
ITT-E 
LHO1 
Listing of HIV Treatment Satisfaction Questionnaire 
Scores (HIVTSQ) 
 
All 
83.  
ITT-E 
LHO2 
Listing of Symptom Distress Module Outcome 
 
All 
84.  
ITT-E 
LHO3 
Listing of Willingness to Switch 
 
All 


 
CONFIDENTIAL 
 
 
 
208090 
165 
Non-ICH: Listings 
No. 
Population 
GSK Statistical Display 
Standard/ Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Impact of COVID-19 Pandemic 
85.  
ITT-E 
PAN7 
Listing of All Subjects with Visits and Assessments 
Impacted by COVID-19 Pandemic 
 
 
86.  
Screened 
PAN5 
Listing of Country Level Start Dates of COVID-19 
Pandemic Measures 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
208090 
166 
15.18. 
Appendix 18: Example Mock Shells for Data Displays 
Available Upon Request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Signature Page for  208090 TMF-15022019 v1.0
Signature Page for TMF-15022019 v1.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 29-Sep-2022 16:35:55 GMT+0000
PPD

Prot_000.pdf: 
2 0 1 7 N 3 3 1 0 0 8 _ 0 6
C O N FI D E N TI A L
Vii V H e alt h c ar e gr o u p of c o m p a ni e s
2 0 8 0 9 0
1
TI T L E P A G E
Pr ot oc ol Title: A P hase III, ra n d o mize d, m ultice nter, o pe n-la bel, n o n-i nferi orit y st u d y 
e val uati n g t he efficac y, safety a n d t olera bilit y o f s witc hi n g t o d ol ute gra vir/la mi v u di ne 
fi xe d d ose c o m bi nati o n i n HI V- 1 i nfecte d a d ults w h o are vir ol o gicall y s u p presse d
Pr ot oc ol N u m ber : 2 0 8 0 9 0 A me n d me nt 0 4
C o m p o u n d N u m ber: G S K 1 3 4 9 5 7 2 + G R 1 0 9 7 1 4 ( G S K 3 5 1 5 8 6 4)
S h ort Title : A P hase III, ra n d o mize d, m ultice nter, o pe n -la bel, n o n-i nferi orit y st u d y 
e val uati n g t he efficac y, safety a n d t olera bilit y of s witc hi n g t o d ol ute gra vir/la mi v u di ne 
fi xe d d ose c o m bi nati o n i n HI V-1 i nfecte d a d ults w h o are vir ol o gicall y  s u p presse d
A ut h ors:
 
 
S p o ns or N a me a n d Le g al Re gistere d A d dress (e xcl u di n g U S): 
Vii V Healt hcare U K L i mite d
9 8 0 Great West R oa d
Bre ntf or d
Mi d dlese x, T W 8 9 G S
U K
U S I N D S p o ns or N a me a n d Le g al Re gistere d A d dress :
Vii V Healt hcare C o m pa n y
Fi ve M o ore Dri ve
P. O. 1 3 3 9 8
Researc h Tria n gle Par k, N C 2 7 7 0 9 -3 3 9 8, U S A
Tele p h o ne: 
A p pr o v al D ate: 0 5- M A Y -2 0 2 0
P P D
C o p y ri g ht 2 02 0 Vii V Healt hcare gr o u p of c o m pa nies.  All ri g hts reser ve d.  U na ut h orise d 
c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.
P P D


2017N331008_06
CONFIDENTIAL
ViiV Healthcare group of companies
208090
2
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 and PPD are supporting 
ViiV Healthcare in the conduct of this study.  
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): US IND: 127475/ EudraCT: 2018-000177-
72


1
Fr o m:
S e nt:
W e d n es d a y, M a y 6, 2 0 2 0 1 2: 2 2 A M
T o:
S u bj e ct:
F W: Pr ot- A m e n d 4- 2 0 8 0 9 0-s p o nsi g n
H ell o, 
Pl e as e fi n d s p o ns or a p pr o v al b el o w f or 2 0 8 0 9 0 a m e n d m e nt 0 4. 
 
Ki n d r e g ar ds, 
 
Fr o m:  S h er e n e Mi n 
 
S e nt:  T u es d a y, M a y 0 5, 2 0 2 0 1: 3 8 P M 
T o:
S u bj ect:  R E: Pr ot- A m e n d 4- 2 0 8 0 9 0-s p o nsi g n 
 
D e ar  
, 
 
I a p pr o v e t h e pr ot oc ol a m e n d m e nt. 
Ki n d r e g ar ds, 
S h er e n e 
 
S h er e n e S h a ki b Mi n, M D, M P H 
V P, H e a d of Cli nic al D e v el o p m e nt 
 
Vii V H e alt hc ar e 
Fi v e M o or e Dri v e 
P P D
R T P, N C. 2 7 7 0 9 
 
M:
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


2
 
 
Fr o m:  
  
S e nt:  M o n d a y, M a y 0 4, 2 0 2 0 1: 3 1 P M 
T o:  S h er e n e Mi n
S u bj ect:  Pr ot- A m e n d 4- 2 0 8 0 9 0-s p o nsi g n 
 
De ar S p o ns or, 
T o a p pr o ve t he cli nical pr ot oc ol i n dicate d bel o w, re pl y t o t his e mail a n d state y o ur a p pr o val. 
P R O T O C O L N U M B E R: 2 0 8 0 9 0  
D O C U M E N T I D E N TI FI E R:  2 0 1 7 N 3 3 1 0 0 8 _ 0 6  
A M E N D M E N T N U M B E R:  0 4 P R O T O C O L TI T L E: A P hase II I, ra n d o mize d, m ultice nter, o pe n-la bel, n o n-
i nferi orit y st u d y e val uati n g t he efficacy, safet y a n d t olera bilit y of s witc hi n g t o d ol ute gra vir/la mi v u di ne fi xe d 
d ose c o m bi nati o n i n HI V- 1 i nfecte d a d ults w h o are vir ol o gicall y s u p presse d 
Na me of S p o ns or Si g nat or y: 
S here ne S ha ki b Mi n, M D, M P H 
Title of S p o ns or Si g nat or y: 
 
Vice Presi de nt a n d Hea d of Cli nical  De vel o p me nt, Vii V Healt hcare 
 
P P D
P P D


2017N331008_06
CONFIDENTIAL
208090
4
PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
DNG Number
Protocol Amendment 04
05-MAY-2020
2017N331008_06
Protocol Amendment 03/SWE-
DEN-1
29-JUL-2019 
2017N331008_05
Protocol Amendment 03/CHI-1 
31 -MAY-2019 
2017N331008_04
Protocol Amendment 03
25-MAR-2019
2017N331008_03
Protocol Amendment 02
14-NOV-2018
2017N331008_02
Protocol Amendment 01
26-MAR-2018
2017N331008_01
Original
25-JAN-2018
2017N331008_00
Amendment 04, 05-MAY-2020
Overall Rationale for the Amendment: A global amendment, applicable to all 
participating countries (updates from global protocol amendment 04 will be incorporated 
into a country specific amendment for China, called 208090 Amendment 04/CHI-1). This 
amendment describes possible changes in patient management related to the impact of 
COVID-19, COVID-19 case definition guidance, ending recruitment due to COVID-19 
before the original sample size was achieved and sample size considerations and 
statistical analyses updates.  Additionally, the list of prohibited medications was updated 
to add fampridine to align with the Investigator Brochure version 13 and other 
administrative updates were made to provide updated information, correct errors and
improve accuracy and consistency.
Section # and Name
Description of Change
Brief Rationale
Title Page
Updated authors
To reflect authors 
of current 
amendment
Sponsor Signatory
Updated Sponsor signatory 
name and title
To align with ViiV 
organizational 
updates
Section1.1, Synopsis
Added text to clarify that the 
study will limit the enrolment 
of participants with current 
or prior exposure to DTG to 
approximately 20%.
To add clarity in 
the Synopsis in 
order to align with 
protocol section 
4.2
Section 1.1, Synopsis
Section 1.2, Schema
Section 1.3, Schedule of Activities
Section 4.1, Overall Design
Added text that continuation 
phase is not applicable for 
Sweden and Denmark
To clarify country 
specific 
requirements for 
Sweden and 
Denmark in the 
body of the 


2017N331008_06
CONFIDENTIAL
208090
5
Section # and Name
Description of Change
Brief Rationale
Section 4.3, Participant and Study Completion
Section 6.8, Treatment after the end of the Study
protocol to align 
with Appendix 13
Section 1.1, Synopsis
Section 4.1, Overall Design
Section 4.2, Number of Participants
Section 4.4, Scientific Rationale for Study Design
Section 9, Statistical Considerations
Updated statistical 
hypotheses and sample size 
determination.
The COVID-19 
pandemic of 
2019/2020 
occurred during 
screening 
resulting in 
planned 
enrolment being 
terminated when 
approximately 
445 participants 
were randomized 
and 53 were in 
screening
Section 1.3, Schedule of Activities 
Section 8, Study Assessments and Procedures
Updated table and footnote
To clarify when 
menopause 
history data will 
be collected 
Section 1.3, Schedule of Activities
Section 11.7, Appendix 7: Clinical Laboratory Tests
Added creatine 
phosphokinase to the list of 
labs collected as part of 
clinical chemistry in 
Appendix 7, footnote 
included in Schedule of 
Activities to refer to 
Appendix 7 and other 
footnote letters adjusted 
accordingly
To allow for 
collection of this 
lab in addition to 
the other liver 
chemistry tests 
already collected
Section 2, Introduction
Summary of TANGO Week 
48 data added
To provide data 
that has become 
available since 
the prior 
amendment 
version
Section 2.3.1, Risk Assessment
Added text to describe 
fampridine risk and updated 
results from the Botswana 
birth outcome surveillance 
study for DTG and neural 
tube defects
To provide new 
information from 
the updated 
Investigator 
Brochure version 
13
Section 4.3, Participant and Study Completion 
Added text
To aid clarity
Section 6.5, 
Added reference to COVID-
19 appendix 14
To link appendix 
14 to the main 


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Section # and Name
Description of Change
Brief Rationale
Preparation/Handling/Storage/Accountability
Section 7.1.1.1, Participants Meeting Virologic 
Management Criteria
Section 8, Study Assessments and Procedures 
Section 8.2.4, Clinical Safety Laboratory Assessments
Section 8.3, Adverse events (AE) and serious adverse 
events (SAEs)
Section 11.7, Appendix 7: Clinical Laboratory Tests
body of the 
protocol
Section 6.8, Treatment after the end of the study
Removed text, Added text
To correct an 
administrative 
error and to aid 
clarity
Section 10, References
Added references
To reflect new
text added to the 
amendment
Section 11.6, Appendix 6, Prohibited Medications
Added fampridine and 
related text and clarifications
To align with 
current 
Investigator 
Brochure version 
13 and aid clarity
Section 11.9.1, Liver Chemistry Stopping Criteria: 
Required Actions and Follow up Assessments
Added laboratory 
assessments
To align with 
updated 
guidance
Section 11.13, Appendix 13: Country-specific 
Requirements
Added new sections to 
describe previous country 
specific amendments for 
Sweden/Denmark and 
China. Sweden/Denmark will 
now be incorporated into this 
global amendment. 
To consolidate 
Sweden/Denmark 
into the global 
amendment and 
provide clarity on 
past country 
specific protocol 
amendments
Section 11.14, Appendix 14: 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


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES.................................................4
1.
PROTOCOL SUMMARY........................................................................................11
1.1.
Synopsis.....................................................................................................11
1.2.
Schema ......................................................................................................15
1.3.
Schedule of Activities (SoA)........................................................................16
2.
INTRODUCTION....................................................................................................21
2.1.
Study Rationale ..........................................................................................22
2.2.
Background ................................................................................................23
2.3.
Benefit/Risk Assessment ............................................................................25
2.3.1.
Risk Assessment .........................................................................26
2.3.2.
Benefit Assessment.....................................................................30
2.3.3.
Overall Benefit: Risk Conclusion..................................................30
3.
OBJECTIVES AND ENDPOINTS...........................................................................31
4.
STUDY DESIGN ....................................................................................................33
4.1.
Overall Design ............................................................................................33
4.2.
Number of Participants ...............................................................................34
4.3.
Participant and Study Completion...............................................................34
4.4.
Scientific Rationale for Study Design ..........................................................35
4.5.
Justification for Dose ..................................................................................36
5.
STUDY POPULATION...........................................................................................38
5.1.
Inclusion Criteria.........................................................................................38
5.2.
Exclusion Criteria........................................................................................40
5.3.
Lifestyle Restrictions...................................................................................43
5.4.
Screen Failures...........................................................................................43
6.
STUDY INTERVENTION........................................................................................43
6.1.
Study Interventions Administered ...............................................................45
6.2.
Dose Modification .......................................................................................45
6.3.
Method of Treatment Assignment ...............................................................45
6.4.
Blinding.......................................................................................................46
6.5.
Preparation/Handling/Storage/Accountability..............................................46
6.6.
Treatment Compliance................................................................................47
6.7.
Concomitant Therapy..................................................................................47
6.7.1.
Permitted Medications and Non-Drug Therapies..........................47
6.8.
Treatment after the End of the Study ..........................................................48
7.
DISCONTINUATION CRITERIA.............................................................................49
7.1.
Discontinuation of Study Intervention..........................................................49
7.1.1.
Virologic Criteria for Participant Management and Viral 
Resistance Testing ......................................................................49
7.1.1.1.
Participants Meeting Virologic Management 
Criteria........................................................................49


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7.1.1.2.
Managing Participants Meeting Precautionary 
Virologic Withdrawal (PVW) or Confirmed 
Virologic Withdrawal (CVW) Criteria...........................50
7.1.2.
Liver Chemistry Stopping Criteria ................................................54
7.1.3.
Temporary Discontinuation ..........................................................54
7.1.4.
Restart.........................................................................................54
7.2.
Withdrawal from the Study..........................................................................54
7.3.
Lost to Follow Up........................................................................................56
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................57
8.1.
Efficacy Assessments.................................................................................59
8.1.1.
Primary Efficacy Endpoint............................................................59
8.1.2.
Secondary Efficacy Endpoints .....................................................60
8.2.
Safety Assessments ...................................................................................60
8.2.1.
Physical Examinations.................................................................60
8.2.2.
Vital Signs....................................................................................60
8.2.3.
Electrocardiograms......................................................................60
8.2.4.
Clinical Safety Laboratory Assessments ......................................60
8.2.5.
Suicidal Risk Monitoring...............................................................61
8.2.6.
Pregnancy ...................................................................................62
8.3.
Adverse Events (AE) and Serious Adverse Events (SAEs).........................63
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................63
8.3.2.
Method of Detecting AEs and SAEs.............................................64
8.3.3.
Follow-up of AEs and SAEs.........................................................64
8.3.4.
Regulatory Reporting Requirements for SAEs .............................64
8.3.5.
Cardiovascular and Death Events................................................64
8.3.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................65
8.4.
Treatment of Overdose...............................................................................65
8.5.
Pharmacokinetics .......................................................................................66
8.6.
Pharmacodynamics ....................................................................................66
8.7.
Genetics .....................................................................................................66
8.8.
Biomarkers .................................................................................................66
8.9.
Health Economics and Outcomes Research...............................................67
8.10.
HIV-1 Polymerase Viral Genotyping and Phenotyping ................................68
8.10.1.
HIV-1 Exploratory Analysis ..........................................................68
9.
STATISTICAL CONSIDERATIONS........................................................................69
9.1.
Statistical Hypotheses.................................................................................69
9.2.
Sample Size Determination ........................................................................69
9.2.1.
Sample Size Assumptions ...........................................................69
9.2.1.1.
Response and virologic failure rate 
assumptions ...............................................................70
9.2.2.
Sample Size Sensitivity................................................................73
9.2.3.
Sample Size Re-estimation or Adjustment...................................73
9.3.
Populations for Analyses ............................................................................73
9.4.
Statistical Analyses.....................................................................................74
9.4.1.
Efficacy Analyses.........................................................................74
9.4.2.
Safety Analyses...........................................................................76
9.4.3.
Other Analyses ............................................................................77
9.5.
Interim Analyses .........................................................................................77


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9.5.1.
Independent Data Monitoring Committee (IDMC) ........................77
9.5.2.
Analysis Datasets ........................................................................78
9.5.3.
Treatment Comparisons ..............................................................78
9.5.3.1.
Primary Comparison of Interest ..................................78
9.5.3.2.
Other Comparisons of Interest....................................79
10. REFERENCES.......................................................................................................80
11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................86
11.1.
Appendix 1: Abbreviations and Trademarks................................................86
11.2.
Appendix 2: A Sub-study of Virologic Response to Subsequent ART 
after Discontinuation from 208090 for Meeting CVW or PVW Criteria.........90
11.2.1.
Rationale for CVW and PVW Sub-study ......................................90
11.2.2.
Sub-study Objectives and Endpoints ...........................................90
11.2.3.
Sub-study Design ........................................................................90
11.2.4.
Sub-study data Collection............................................................92
11.2.5.
Statistical Considerations and Data Analysis ...............................92
11.3.
Appendix 3: Toxicity Management ..............................................................93
11.3.1.
Specific Toxicities/Adverse Event Management...........................94
11.3.1.1.
Liver Chemistry Stopping and Follow-up 
Criteria........................................................................94
11.3.1.2.
Restarting Study Intervention .....................................95
11.3.1.3.
Decline in Renal Function...........................................95
11.3.1.4.
Proteinuria..................................................................95
11.3.1.5.
Allergic reaction..........................................................95
11.3.1.6.
Rash...........................................................................96
11.3.1.7.
Hypertriglyceridemia/Hypercholesterolemia................97
11.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................98
11.4.1.
Definitions....................................................................................98
11.4.2.
Contraception Guidance ..............................................................98
11.4.3.
Collection of Pregnancy Information ..........................................100
11.5.
Appendix 5:  Child-Pugh Classification .....................................................101
11.6.
Appendix 6:  Prohibited Medications.........................................................102
11.7.
Appendix 7: Clinical Laboratory Tests.......................................................104
11.8.
Appendix 8: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................106
11.8.1.
Definition of AE..........................................................................106
11.8.2.
Definition of SAE........................................................................107
11.8.3.
Definition of Cardiovascular Events ...........................................108
11.8.4.
Recording AE and SAE..............................................................109
11.8.5.
Reporting of SAE and other events to ViiV/GSK/PPD................111
11.9.
Appendix 9: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart Guidelines..........................112
11.9.1.
Liver Chemistry Stopping Criteria:  Required Actions and 
Follow up Assessments .............................................................112
11.9.2.
Study Intervention Restart after Stopping for Liver Criteria ........115
11.10. Appendix 10: Regulatory, Ethical and Study Oversight 
Considerations..........................................................................................119
11.10.1. Regulatory and Ethical Considerations ......................................119
11.10.2. Financial Disclosure...................................................................119


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11.10.3. Informed Consent Process ........................................................119
11.10.4. Data Protection..........................................................................120
11.10.5. Committees Structure ................................................................120
11.10.6. Publication Policy.......................................................................120
11.10.7. Dissemination of Clinical Study Data .........................................121
11.10.8. Data Quality Assurance .............................................................121
11.10.9. Source Documents ....................................................................122
11.10.10.Study and Site Closure ..............................................................122
11.11. Appendix 11:  Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events Version 2.1, March 2017...................123
11.12. Appendix 12:  CDC Classification for HIV-1 Infection (2014).....................153
11.13. Appendix 13: Country-specific requirements.............................................155
11.14. Appendix 14: COVID-19 Pandemic and Clinical Trial Continuity...............157
11.14.1. Changes to Study Visits and Study Procedures.........................157
11.14.2. Changes to Informed Consent ...................................................158
11.14.3. Direct-To-Patient (DTP) Shipment of Study IP...........................159
11.14.4. COVID-19 Experimental Agents ................................................160
11.14.5. COVID-19 Specific Data Capture...............................................160
11.14.5.1. Capturing COVID-19 Specific Protocol 
Deviations ................................................................160
11.14.5.2. Capturing COVID-19 Specific AEs and SAEs...........161
11.15. Appendix 15: Protocol Amendment History...............................................164


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Phase III, randomized, multicenter, open-label, non-inferiority study 
evaluating the efficacy, safety and tolerability of switching to dolutegravir/lamivudine 
fixed dose combination in HIV-1 infected adults who are virologically suppressed
Short Title: A Phase III, randomized, multicenter, open-label, non-inferiority study 
evaluating the efficacy, safety and tolerability of switching to dolutegravir/lamivudine 
fixed dose combination in HIV-1 infected adults who are virologically suppressed
Rationale: This study is being conducted to establish if adults living with human 
immunodeficiency virus type 1 (HIV-1) with virologic suppression on a ≥3 drug current 
antiretroviral regimen (CAR) remain suppressed upon switching to 
dolutegravir/lamivudine (DTG/3TC) fixed-dose combination (FDC).  This study will also 
provide important information regarding the safety and health related quality of life with 
this two-drug regimen.  This trial is designed to demonstrate the non-inferior antiviral 
activity of switching to DTG/3TC FDC once daily compared to continuation of CAR 
over 48 weeks.  


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Objectives and Endpoints:
Objectives
Endpoints
Primary
To demonstrate the non-inferior antiviral activity 
of switching to DTG/3TC FDC once daily 
compared to continuation of CAR over 48 
weeks in virologically suppressed adults living 
with HIV-1
Virologic failure endpoint as per Food and Drug 
Administration (FDA) snapshot category at 
Week 48
Secondary
To demonstrate the antiviral activity of switching 
to DTG/3TC FDC once daily compared to 
continuation of CAR over 48 weeks
Proportion of participants with plasma HIV-1 
RNA <50 c/mL at Week 48 using the Snapshot 
algorithm for the intent-to-treat exposed (ITT-E)
population 
To evaluate the antiviral activity of switching to 
DTG/3TC FDC once daily compared to 
continuation of CAR over 24 weeks 

Virologic failure endpoint as per FDA 
snapshot category at Week 24

Proportion of participants with plasma HIV-1 
RNA <50 c/mL at Week 24 using the 
Snapshot algorithm for the ITT-E population
To evaluate the immune effects of DTG/3TC 
FDC once daily compared to continuation of 
CAR

Change from Baseline in CD4+ cell count 
and in CD4+/CD8+ cell counts ratio at 
Weeks 24 and 48

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS], and 
death) through Weeks 24 and 48
To evaluate the safety and tolerability of 
DTG/3TC FDC once daily compared to CAR 
over time 

Incidence and severity of adverse events 
(AEs) and laboratory abnormalities 

Proportion of participants who discontinue 
treatment due to AEs 
To evaluate the safety and tolerability of 
DTG/3TC FDC once daily in those with 
creatinine clearance of between 
30-49 mL/min/1.73m2 compared to those with a 
creatinine clearance of 50 mL/min/1.73m2

Incidence and severity of AEs and 
laboratory abnormalities 

Proportion of participants who discontinue 
treatment due to AEs 
To evaluate the effects of DTG/3TC FDC once 
daily on fasting lipids over time compared to 
CAR
Change from Baseline in fasting lipids at Weeks 
24 and 48
To assess viral resistance in participants 
meeting Confirmed Virologic Withdrawal (CVW) 
Criteria
Incidence of observed genotypic and 
phenotypic resistance to antiretrovirals (ARVs)
for participants meeting CVW Criteria 


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Objectives
Endpoints
To assess health related quality of life for 
participants treated with DTG/3TC FDC 
compared to CAR
Change from Baseline in health status using 
HIV treatment satisfaction questionnaire (HIV 
TSQ) at Weeks 24 and 48 (or Withdrawal from 
the study) and symptom distress module (SDM)
at Weeks 24, 48 and every 24 weeks during the 
continuation phase (or Withdrawal from the 
study)
Overall Design:
This is a 52-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of switching 
from CAR to DTG/3TC FDC in adults living with HIV who are virologically suppressed 
and stable on CAR.  The study will include a Screening Phase (up to 28 days), a 
Randomized Phase up to Week 52, and a Continuation Phase (post Week 52) (Section 
1.2).  The Continuation Phase is not applicable for participants in Sweden and Denmark. 
Approximately 490 adults living with HIV who are on a stable CAR will be randomized 
1:1 to switch to DTG/3TC FDC once daily for up to 52 weeks, or to continue their CAR 
for 52 weeks.  To control for treatment related factors that may impact study outcomes, 
randomization will be stratified by baseline third agent class (protease inhibitor [PI], 
integrase inhibitor [INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]). For 
participants randomized to CAR, provisions will be in place, as needed and after 
discussion with the study team, to assist participants in obtaining CAR during the study.
The primary endpoint for the study is the virologic failure endpoint as per FDA Snapshot 
category at Week 48 using the Intent-to-Treat Exposed (ITT-E) population.  The Week 
48 primary analysis will take place after the last participant has had their Week 48 viral 
load assessed, including any retests. Participants randomized to DTG/3TC FDC will 
receive DTG/3TC FDC up to Week 52. 
All participants in the DTG/3TC FDC arm who successfully complete up to 52 weeks of 
treatment will have the opportunity to continue receiving DTG/3TC FDC once daily in a 
Continuation Phase (See Section 4.3).  The Continuation Phase is not applicable for 
participants in Sweden and Denmark.
CVW Sub-study:  A sub-study of Virologic Response to Subsequent ART after 
Discontinuation from 208090 for Meeting CVW or Precautionary Virologic Withdrawal 
(PVW) Criteria will be conducted.  Details are provided in Section 11.2.
Disclosure Statement: This is a parallel-group treatment study with two arms that is 
open-label.
Number of Participants: Assuming 20% screen failure rate, approximately 622 adult 
participants living with HIV will be screened to achieve approximately 490 randomized 


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participants for a total of 245 evaluable participants per treatment group (See Section 
9.3).  
A goal of this study is to enroll populations who are underrepresented in clinical studies 
including 20% women and approximately 20% of participants who are ≥50 years of age. 
Another goal is to enroll approximately 20% of participants taking 
efavirenz/emtricitabine/tenofovir disoproxil fumarate. The study will limit the enrolment 
of participants with current or prior exposure to DTG to approximately 20%.
Intervention Groups and Duration: The study will include a Screening Phase (up to 28 
days), a Randomized Phase up to Week 52, and a Continuation Phase (post Week 52) 
(Section 1.2). The Continuation phase is not applicable for participants in Sweden and 
Denmark. Participants will be randomized 1:1 to switch to DTG/3TC FDC once daily for 
up to 52 weeks, or to continue their CAR for 52 weeks.  To control for treatment related 
factors that may impact study outcomes, randomization will be stratified by baseline third 
agent class (protease inhibitor [PI], integrase inhibitor [INI], or non-nucleoside reverse 
transcriptase inhibitor [NNRTI]).
All participants in the DTG/3TC FDC arm who successfully complete up to 52 weeks of 
treatment will have the opportunity to continue receiving DTG/3TC FDC once daily in a 
Continuation Phase (See Section 4.3).  Participants in the CAR arm will complete the 
study at Week 52.  The Continuation Phase is not applicable for participants in Sweden 
and Denmark.
No dose reductions, modifications, or changes in the frequency of any components of
each regimen will be allowed during this study with the exception of a switch from a PI 
boosted with ritonavir to the same PI boosted with cobicistat and vice versa. A switch 
from lamivudine to emtricitabine and vice versa is also permitted. Protocol waivers or 
exemptions are not allowed. Adherence to the study design requirements, including those 
specified in the Schedule of Activities (Section 1.3), are essential and required for study 
conduct. If deviations are required for the management of immediate safety concerns, 
these should be communicated promptly to the study medical monitor.
Independent Data Monitoring Committee (IDMC): An IDMC will be instituted to 
ensure external objective medical and/or statistical review of efficacy to protect the 
ethical interests and well-being of participants and to protect the scientific validity of this 
study.


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1.2.
Schema
Figure 1
Study Schematic
Note: The Continuation Phase is not applicable for participants in Sweden and Denmark.


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1.3.
Schedule of Activities (SoA)
Procedures
Screening Visita
Randomized Phase
Continuation
Phasec
Withdrawal
Follow-upd
Baseline/
Day 1
4
12
24
36
48b
52
Every 12
Weeks
After 
Week 52
Clinical and Other Assessments
Written informed consent
X
Inclusion/Exclusion criteriae
X
X
Demography
X
Prior ART history
X
Medical historyf
X
Menopause historyg
X
X
X
X
Current medical conditions
X
Cardiovascular risk assessment including 
vital signsh
X
Body Weight (BMI will be calculated within 
the eCRF)i
X
X
X
X
X
X
X
X
X
X
X
HIV risk factors and mode of transmission
X
CDC HIV-1 classification
X
X
HIV associated conditionsj
X
X
X
X
X
X
X
X
X
Columbia Suicidality Severity Rating Scale
Xk
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
Symptom Directed Physical Examl
X
X
X
X
X
X
X
X
X
X
12-lead ECGm
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Serious adverse events
Xn
X
X
X
X
X
X
X
X
X
X


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Procedures
Screening Visita
Randomized Phase
Continuation
Phasec
Withdrawal
Follow-upd
Baseline/
Day 1
4
12
24
36
48b
52
Every 12
Weeks
After 
Week 52
Willingness to Switcho
Xo
HIV TSQp
X
X
X
X
X
Symptom Distress Modulep
X
X
X
X
X (every 24 weeks)
X
Laboratory Assessments
Quantitative plasma HIV-1 RNAq
X
X
X
X
X
X
X
X
X
Lymphocyte subsetr
X
X
X
X
X
X
X
X
Plasma for storages
X
X
X
X
X
X
X
X
X
Clinical chemistryt
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
PT/INR (for Child-Pugh)
X
Fasting lipids and glucoseu
X
X
X
Xv
Urinalysis and spot urine for protein 
analysisw
X
X
X
X
X
Pregnancy testx, y
S
U/Sz
S
S
S
S
S
S
S
S
HBsAg, anti-HBc, Anti-HBs, and HBV 
DNAaa
X
HCV antibody
X
RPR
X
Renal, bone and inflammatory marker 
analytes (blood/urine) and HbA1c, insulin 
and glucosebb
X
X
X
X
Whole Blood (Virology)cc
X
X
X
Whole Blood (Telomere Length)dd
X
X
Xee


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Procedures
Screening Visita
Randomized Phase
Continuation
Phasec
Withdrawal
Follow-upd
Baseline/
Day 1
4
12
24
36
48b
52
Every 12
Weeks
After 
Week 52
PBMCsff
X
X
X
Xgg
Study Treatment
IVRS/IWRShh
X
X
X
X
X
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
X
X
X
IP accountability (pill counts)
X
X
X
X
X
X
X
ART - antiretroviral therapy, BMI - body mass index, CDC - centers for disease control and prevention, DNA - deoxyribonucleic acid, ECG – electrocardiogram, eCRF - electronic case 
report form, HBV – hepatitis B virus, HCV – hepatitis C virus, INR - international normalized ratio, IP - investigational product
a.
As soon as all Screening results are available, randomization may occur.
b.
Participants with plasma HIV-1 RNA 50 c/mL at Week 48 (primary endpoint) must have HIV-1 RNA level re-assessed by a second measurement performed 2-4 weeks later, 
occurring prior to Week 52.  
c.
All participants on the DTG/3TC FDC arm who complete through Week 52 will have the opportunity to enter the Continuation Phase.  The Continuation Phase is not applicable for 
participants in Sweden and Denmark. For participants who will not continue past Week 52, do not dispense study intervention. Participants completing the Continuation Phase 
must return to the clinic for an End of Continuation Phase visit when transitioning to commercial supplies or to an alternate ART regimen, if appropriate. At this visit, conduct study 
assessments as specified for all Continuation Phase visits except for dispensing study intervention. 
d.
An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study intervention for participants with the following conditions at the last on-study visit:  ongoing AEs, 
serious adverse events (SAEs) regardless of attributability, and any laboratory abnormalities that are considered to be AEs or potentially harmful to the participant. However, the 
investigator, in consultation with the medical monitor, should follow-up with the participant until the event is resolved, stabilized, otherwise explained, or the participant is lost to 
follow-up
e.
Inclusion/exclusion criteria will be assessed fully at the Screening visit. Changes between the Screening visit and the Day 1 visit should be considered to ensure eligibility, 
including review of additional assessments performed at Day 1. Genotypic resistance testing results if available MUST be provided to ViiV after screening and before 
randomization.  
f.
Full medical history will be conducted prior to randomization and include assessments of cardiovascular, metabolic (e.g., Type I or II diabetes mellitus), psychiatric (e.g., 
depression), renal (e.g., nephrolithiasis, nephropathy, renal failure), and bone disorders. 
g.
Menopause history will include date of last menstrual period (collected at Day 1, Week 52 or withdrawal) and menopausal status (collected at Screening, Week 52 or withdrawal)
based on the criteria in Section 11.4.1.  A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.   


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h.
Assessment for cardiovascular risk 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. BMI will be calculated within the eCRF.
i.
The same scale should be used to measure body weight at each visit. 
j.
Based on the participant’s current CDC status in the past 6 months.
k.
On Day 1, the electronic Columbia Suicidality Severity Rating Scale (eC-SSRS), participant completed questionnaire is to be administered prior to the first dose.
l.
Limited physical examination to include blood pressure at Day 1 (recorded in eCRF) for Framingham score assessment.  Blood pressure to be measured after resting in a semi-
supine position for at least 5 minutes. 
m.
A 12-lead ECG will be performed in a semi-supine position after resting for at least 5 minutes.
n.
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and administration of study 
intervention at Day 1. 
o.
Willingness to Switch Survey must be done prior to randomization.
p.
Questionnaire/Surveys are recommended to be administered at the beginning of the visit before any other assessments are conducted.  Only conduct questionnaires/surveys at 
Withdrawal if occurring prior to Week 48, except the Symptom Distress Module which should also be collected if Withdrawal occurs during the Continuation Phase.
q.
See Virologic Withdrawal and Stopping Criteria Section of protocol (Section 7.1.1).
r.
Lymphocyte subset will include collection of CD4 and CD8 for calculation of Cd4:CD8 ratio.  CD8 will also be reported to sponsor.
s.
Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  These 
samples will be used when needed such as when samples are lost, arrive at the laboratory unevaluable, or for genotypic and/or phenotypic analyses when participants meet 
Suspected and Confirmed Virologic Withdrawal criteria. 
t.
See Appendix 7 for a list of clinical chemistry labs.
u.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
v.
Collect fasting lipids and glucose if the Withdrawal visit occurs at Weeks 24 or 48.
w.
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
x.
Women of childbearing potential only. S=serum, U=urine. Pregnancy events will be captured starting at Day 1 following exposure to study intervention.
y.
Remind females of reproductive potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements.
z.
Local Pregnancy result must be available prior to randomization on Day 1.  Local serum pregnancy test on Day 1 is allowed if it can be done, and results obtained, within 
24 hours prior to randomization.
aa. HBV DNA testing will be performed for participants with positive anti-HBc and negative HBsAg and negative anti-HBs (past and/or current evidence).  Participants must return to 
the clinic to provide a sample for HBV DNA testing prior to randomisation.
bb. Blood sample for HbA1c, insulin, glucose, renal, bone and inflammation biomarker assessments: Renal: Cystatin C, Beta-2-Microglobulin (urine), Retinol Binding Protein (RBP;
urine), urine   B2M/creatinine ratio, urine RPB/creatinine ratio, urine albumin/creatinine ratio, urine protein/creatinine ratio, urine phosphate, serum creatinine; Bone: bone specific 
alkaline phosphatase, procollagen type 1-N-propeptide, type 1 collagen cross-linked C-telopeptide, osteocalcin; Inflammation: Interleukin-6 (IL-6), High-sensitivity C reactive 
protein (hs-CRP), D-dimer, Soluble CD14 (sCD14), Soluble CD163 (sCD163); insulin and glucose for HOMA-IR calculation
cc. Where local country or laboratory practices allow, whole blood (Virology) may be used for virologic analyses as described in the protocol.  
dd. Where local country or laboratory practices allow, whole blood will be used for telomere length evaluation.
ee. Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 48.
ff.
Where local country or laboratory practices allow, PBMC collection samples may be used for virologic analyses as described in Section 8.10.1.
gg. Collect sample only if Withdrawal visit occurs at Weeks 24 or 48.


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hh. At Screening, a subject number will be generated.


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2.
INTRODUCTION
Current human immunodeficiency virus (HIV) treatment guidelines recommend 
antiretroviral therapy (ART) regimens consisting of two nucleoside/nucleotide analogue 
reverse transcriptase inhibitors (NRTIs) as a “backbone” combined with a third agent 
from the integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase 
inhibitor (NNRTI), or protease inhibitor (ritonavir-boosted) (PI/RTV) classes [BHIVA, 
2016; DHHS, 2018; EACS, 2017; Gunthard, 2016].  These regimens are highly 
efficacious, generally well tolerated, and have led to remarkable declines in morbidity 
and mortality in people living with HIV.  However, since these regimens will need to be 
taken life-long, there is growing concern about their long-term toxicities and cost.  
Lifelong ART has been associated with higher rates of non-acquired immune-deficiency 
syndrome (AIDS)-defining events (NADEs) such as cardiovascular disease, liver disease 
and cancer.  In addition, as people living with HIV live longer, aging-associated 
co-morbidities are being seen with greater frequency, and this multi-morbidity often 
requires concomitant use of other medications. As the potential for toxicities and cost are 
directly related to the number of antiretrovirals (ARVs) used, there is great interest from 
people living with HIV and clinicians in regimens that minimize ARV-related long-term 
toxicities and drug-drug interactions (DDIs) without sacrificing long-term antiviral 
efficacy.  
Improvements in the clinical efficacy and safety profiles of new ARV drugs have enabled 
the consideration of two-drug regimens as replacements for ≥3-drug ART regimens to 
streamline therapy and potentially minimize ARV-related long-term toxicities from 
cumulative drug exposures and DDIs. Improvements in tolerability may have a big 
impact on adherence to life-long treatment regimens. Additionally, the preservation of 
future ARV options and the lower cost associated with taking one less drug for the 
lifetime of a person living with HIV may have substantial individual and societal cost 
benefits.
The 2-drug regimen, dolutegravir/lamivudine (DTG/3TC) fixed dose combination (FDC), 
has a robust antiviral activity, safety profile, high barrier to resistance, low potential for 
DDIs, and can be administered as a once-daily single tablet regimen (STR). Emerging 
data supports DTG/3TC FDC as a viable option for both ART-experienced and naive 
people living with HIV-1. 
LAMIDOL, a single-arm open-label study (n=110), evaluated a switch from suppressive 
first-line ART to DTG/3TC FDC [Joly, 2017]. Participants initially switched the third 
agent in their regimen to DTG (50 mg once daily) for 8 weeks, then (if HIV RNA 
remained <50 copies/millilitre (c/mL)) switched from 2 NRTIs to 3TC. 97% of 
participants who switched to 2-drug therapy maintained viral suppression after 40 weeks. 
Three participants had HIV RNA >50 c/mL; none of these had INSTI mutations, one had 
an NRTI mutation.
ASPIRE, an open-label, randomized, multicentre pilot study (n=89), evaluated a switch 
from 3 drug regimens (cART) to DTG + 3TC.  In the primary analysis at week 24, 
treatment failure occurred in 3 of 44 (6.8%) receiving DTG/3TC and 3 of 45 (6.7%) 
receiving cART (0.15% difference; 90% CI, −9.8 to 10.2), demonstrating noninferiority 


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of DTG/3TC.  The only participant with virologic failure (VF) (DTG/3TC arm at week 
24) had no emergent RT or integrase resistance mutations, and this participant remained 
viremic after switching to darunavir-cobicistat plus abacavir-3TC.  Using the FDA 
snapshot algorithm, VL was <50 copies/mL at week 24 in 41 of 44 participants in the 
DTG/3TC arm (93.2%) versus 41 of 45 (91.1%) in the cART arm (difference, 2.1%; 95% 
CI, 11.2%–15.3%; P = .71); and at week 48 in 90.9% versus 88.9% (difference 2.0%; 
95% CI, −12.6% to 16.5%; P = .76) [Taiwo, 2018].
An investigator-initiated 48-week pilot study, the PADDLE trial (NCT02211482), has 
provided data on the efficacy of a once-daily DTG/3TC FDC 2-drug regimen for 20 HIV 
treatment-naïve participants with no genotypic resistance to 3TC and a viral load of 
<100,000 c/mL at Screening. In this study, participants were enrolled in two separate 
groups of 10, allowing close evaluation of response while employing a set of stopping 
rules with intensive follow-up in each cohort.  By Week 8, all 20 participants, including 4 
participants with a Baseline HIV-1 RNA of >100,000 c/mL, had reached a viral load <50 
c/mL [Figueroa, 2015]. At Week 48, 18 participants (90%) reached the primary endpoint 
of a plasma viral load <50 c/mL [Cahn, 2017]. The regimen was well tolerated and no 
toxicity issues were observed.  All 18 participants who completed 48 weeks were 
included in an extension phase up to Week 96.  At Week 96, all 18 participants
maintained plasma viral load <50 c/mL [Figueroa, 2017].
Data from larger studies is available from two ongoing Phase III trials (GEMINI-1 and -
2) in naive participants. 714 and 719 adults were randomised and treated in GEMINI-
1&2, respectively. Based on a 10% non-inferiority margin, DTG+3TC was non-inferior 
to DTG+TDF/FTC at Week 48 in both GEMINI-1&2 and in the pooled analysis. 
Response rates in participants with baseline HIV-1 RNA >100,000 c/mL were high and 
similar between arms. Across both studies, 6 participants on DTG+3TC and 4 on 
DTG+TDF/FTC met protocol-defined virologic withdrawal criteria through Week 48; 
none had treatment-emergent primary integrase-strand transfer inhibitor or NRTI 
resistance mutations. Overall rates of AEs were similar between arms, with low rates of 
withdrawals due to AEs for both DTG+3TC and DTG+TDF/FTC. More drug related AEs 
were reported with DTG+TDF/FTC [Cahn, 2018]. Data is also available from a third 
ongoing Phase III trial (TANGO) in ART-experienced participants.  743 adults were 
enrolled and 741 received ≥1 dose of study drug (DTG/3TC, N=369; TAF-based 
regimen, N=372). At Week 48, proportion of participants with HIV-1 RNA ≥50 
copies/mL treated with DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based 
regimen (adjusted treatment difference [95% CI], −0.3 [−1.2, 0.7]), meeting non-
inferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based 
regimen met confirmed virologic withdrawal criteria, with no emergent resistance at time 
of failure. Drug-related grade ≥2 adverse events and adverse events leading to study 
withdrawal were reported in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 
(0.8%) and 2 (0.5%) with a TAF-based regimen, respectively.
2.1.
Study Rationale
This study is being conducted to establish if adults living with HIV-1 with virologic 
suppression on a ≥3 drug current antiretroviral regimen (CAR) remain suppressed upon 
switching to DTG/3TC FDC.  This study will also provide important information 
regarding the safety and health related quality of life with this two-drug regimen.  This 


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trial is designed to demonstrate the non-inferior antiviral activity of switching to 
DTG/3TC FDC once daily compared to continuation of CAR over 48 weeks.  
DTG/3TC FDC may provide an effective and well-tolerated two-drug regimen for 
ART-experienced people living with HIV, limiting the risk of many common adverse 
reactions associated with other ARV drugs.  This regimen could be particularly valuable 
for people with co-morbid conditions such as bone or cardiovascular disease, and in 
resource-limited settings due to DTG’s known efficacy advantages and both drugs’ 
tolerability and long-term safety profiles, as well as ease of use (once daily dosing, no 
food dosing effects/requirements, and limited potential for DDIs). The expected efficacy 
and safety of DTG/3TC FDC will make it suitable for both treatment-naïve individuals 
and as a replacement treatment for ≥3-drug ART in virologically suppressed (“switch”) 
participants. 
By limiting the number of ARV’s to which a participant is chronically exposed, 2-drug 
therapy has the potential benefit of preserving future treatment options, minimizing 
potential long-term toxicity and decreasing the likelihood of DDIs. These benefits could 
have a large impact on tolerability and adherence and thus prevent drug resistance.
2.2.
Background
FDCs and STRs have greatly simplified the treatment of people living with HIV, and 
may be of greater importance in people with lifestyles or care commitments that may 
impair adherence to dosing schedules, including some women and those in underserved 
populations.  In a study by Paterson et. al. [Paterson, 1999], a linear relationship between 
levels of adherence and viral load suppression was observed. Adherence to therapy is 
essential to achieve viral suppression and prevent emergence of resistance mutations. 
Among regimens of comparable efficacy, physicians and people living with HIV-1 who 
receive ART rate total pill burden, dosing frequency, and safety concerns among the 
greatest obstacles to achieving adherence. Drug resistant virus eventually emerges in 
most people who struggle with consistent adherence. To achieve successful long-term 
treatment, the prevention of drug resistance has become the most significant challenge.
DTG is a potent dual cation binding INSTI, exhibiting rapid reduction in viral load, best 
in class efficacy, and a high barrier to resistance.  These properties and its safety profile 
make it an optimal core agent for 2-drug regimens. In addition, due to its mechanism of 
metabolism, DTG lacks many of the frequent DDIs associated with other medications 
commonly taken by people living with HIV.  To date, the efficacy, pharmacokinetics 
(PK), safety and drug interaction potential of DTG has been evaluated in an extensive 
program of Phase I to IIIB clinical trials [TIVICAY Package Insert, 2017; 
GlaxoSmithKline Document Number RM2007/00683/11; GlaxoSmithKline Document 
Number 2017N352880_00; GlaxoSmithKline Document Number 2017N352880_01]. 
3TC is a potent cytidine nucleoside analogue without major side effects and has a well 
proven safety profile.  Available since 1995 as a single agent (EPIVIR) [EPIVIR Package 
Insert, 2017], it is also available as part of three FDC products (zidovudine (ZDV)/3TC, 
COMBIVIR, abacavir (ABC)/3TC, EPZICOM/KIVEXA, ABC/3TC/DTG, TRIUMEQ).  
3TC monotherapy is known to select for resistance due to a single point mutation that 


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reduces antiviral activity.  However, it is predicted that 3TC, when combined with DTG 
with its high barrier to resistance and ability to confer a very rapid decline in HIV-1 
RNA, may be less likely to select for resistance consistent with clinical studies combining 
DTG, 3TC and ABC [Walmsley, 2013; Walmsley, 2015; Cahn 2018].  
Chronic exposure to NRTIs may lead to telomerase and mitochondrial dysfunction, 
processes that may lead to accelerated aging, lipodystrophy, steatohepatitis and other 
aging-related morbidities [Solomon, 2014].  NRTIs have been linked to reduced 
telomerase activity in peripheral blood mononuclear cells (PBMCs) from people living 
with HIV [Leeansyah, 2013]. Of a multitude of NRTIs studied in vitro, tenofovir at 
therapeutic concentrations produced the most significant inhibition of telomerase leading 
to accelerated shortening of telomere length in activated PBMCs [Leeansyah, 2013; 
Stella-Ascariz, 2017]. It is of note that current tenofovir alafenamide (TAF)-regimens 
deliver four-fold higher intracellular levels of tenofovir-diphosphate (the active entity for 
both HIV- reverse transcriptase (RT) and human telomerase) than TDF-regimens and 
thus pose a greater concern for its effects on telomerase and normal cell proliferation. In 
addition, many of the current TAF-based single tablet regimens incorporate a boosting 
agent, cobicistat, while PI-containing regimens require boosting with ritonavir. The use 
of cobicistat- and ritonavir-containing regimens further increase the risk of potential 
DDIs from polypharmacy. 
One of the potential risks of a two-drug regimen, such as DTG/3TC FDC, is the increase 
in virologic failure associated with the emergence of resistance.  DTG, with its higher 
barrier to resistance, may reduce treatment-emergent resistance in participants taking a 
two-drug regimen.  The overall efficacy data from the pivotal Phase III studies of DTG in 
ART-naïve participants are extensive, with no resistance mutations being identified 
through 144 weeks of treatment (SINGLE, ING114467) [Walmsley, 2015].  The absence 
of treatment-emergent mutations to DTG or background agents in ART-naïve 
individuals, rapid virologic response demonstrated for DTG-based regimens, and the in 
vitro potency and well-tolerated safety profile of both DTG and 3TC all provide a strong 
rationale for the development of a DTG/3TC STR as a treatment option for people living 
with HIV.
Several studies have demonstrated the tolerability and durability of the virologic response 
of a 2-drug ARV regimen as replacement for a ≥3-drug ARV regimen in individuals who 
were previously suppressed on triple drug therapy.  
One such study was the Only Lopinavir and Epivir (OLE) study which was an open-label 
study in 250 virologically suppressed individuals living with HIV (HIV-1 
RNA <50 c/mL) receiving a lopinavir (LPV)/r plus 3TC or emtricitabine (FTC) 
containing 3-drug regimen who were randomized to continue their current triple based 
regimen or have their therapy simplified to a 2-drug regimen of LPV/r + 3TC [Arribas, 
2015].  The primary endpoint was the proportion of participants free of therapeutic failure 
at 48 weeks. In a modified Intent to Treat (m-ITT) analysis, 2-drug therapy with LPV/r + 
3TC demonstrated non-inferior efficacy and comparable safety to LPV/r + 2 NRTIs, as 
maintenance therapy in virologically suppressed participants (91.5% vs. 90.9% 
respectively; 95% Confidence Interval (CI): -0.6% to 8.1%).


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The Simplification to Atazanavir/Ritonavir+Lamivudine as Maintenance Therapy
(SALT) study [Perez-Molina, 2015] was a 96-week multicenter, randomized, open-label, 
clinical trial that compared atazanavir/ritonavir (ATV/r) + 3TC with ATV/r + 2NRTIs 
(selected at the discretion of the investigator) in 286 people living with HIV on a stable 3-
drug regimen who switch therapy because of toxicity, intolerance, or simplification.  The 
primary endpoint was to evaluate the non-inferior efficacy of maintenance therapy with 
ATV/r + 3TC compared to ATV/r + 2 NRTIs at 48 weeks (noninferiority margin, –12%) 
using the time to loss of virologic response (TLOVR) algorithm. At 48 weeks, 78.4% of 
participants receiving triple therapy vs. 83.6% of participants switched to 2-drug therapy 
had maintained HIV-RNA levels <50 c/mL thus establishing non-inferiority between 
these two treatment arms (difference between the arms 5.2; -4.8 to 15.2).  Treatment 
discontinuations (2%) were less frequent in the 2-drug therapy group (vs 7% in the triple 
therapy group).
An INSTI-containing oral 2-drug regimen, cabotegravir (CAB) + rilpivirine (RPV), was 
evaluated as a maintenance therapy in people living with HIV who had virologic 
suppression after 24 weeks of 3-drug ART [Margolis, 2015]. The CAB + RPV arms 
showed comparative antiviral efficacy as the efavirenz (EFV) + 2 NRTIs arm. Following 
72 weeks of two-drug maintenance therapy (Week 96), in the ITT maintenance = exposed 
population, 86% of CAB + RPV participants and 83% of EFV + 2 NRTIs participants 
remained virologically suppressed. Virologic failure was seen in 4% of the CAB arm and 
2% of the EFV+2 NRTI arm.
The SWORD-1 and SWORD-2 studies [Llibre, 2017] are ongoing 148-week open-label, 
multicenter Phase III, non-inferiority studies evaluating the efficacy and safety of 
switching from a 3 or 4-drug current antiretroviral regimen (CAR) to DTG + RPV in 
1024 participants. The primary endpoint was the proportion of participants with plasma 
HIV-RNA levels <50 c/mL at Week 48. Switching to DTG + RPV was found to be non-
inferior to continuing CAR in pooled analysis of both the intent-to-treat exposed (ITT-E)
population [95% vs. 95%; difference: -0.2% (95% CI: -3.0%, 2.5%)] and the per-protocol 
population [96% vs. 96%; difference: -0.7% (95% CI: -3.3%, 1.8%)]. For the pooled 
studies, 23% and 21% of participants were female in the DTG +RPV and CAR arms, 
respectively.  Efficacy remained high in the female subgroup (93% vs. 91%).  At Week 
100 in the Early Switch group, 456 (89%) had VL < 50c/mL; low rate of snapshot 
virologic non-response was observed (3%); 6 (1.2%) participants met Confirmed 
Virologic Withdrawal (CVW) criterion.  One participant with RPV resistance at CVW 
(Early Switch group, Wk100) had pre-existing NNRTI mutations at baseline. No 
participants developed INSTI resistance [Aboud, 2018].
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of DTG or 3TC may be found in the most recent 
version of the Investigator’s Brochure (IB) and any IB supplements and the product 
labels.
The following section outlines the risk assessment and mitigation strategy for DTG and 
3TC in this protocol.  For CAR, the approved country product labels for the respective 
drugs should be referenced.


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2.3.1.
Risk Assessment
The following table outlines the risk assessment and mitigation strategy for this protocol.
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG and 3TC]
Refer to Investigator Brochures (IBs) for additional information
DTG: Hypersensitivity 
reaction (HSR) and 
rash
DTG: HSR has been observed uncommonly with DTG.  Rash was 
commonly reported in DTG Phase IIb/III clinical trials; episodes 
were generally mild to moderate in intensity; no episodes of severe 
rash, such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal 
Necrolysis (TEN) and erythema multiforme were reported. 
Participants with history of allergy/sensitivity to any of the study 
interventions are excluded.
Specific/detailed toxicity management guidance is provided for rash 
(Section 11.3.1.6).
The participant informed consent form (ICF) includes information on 
this risk and the actions participants should take in the event of a 
HSR or associated signs and symptoms
DTG: Drug induced 
liver injury (DILI) and 
other clinically 
significant liver 
chemistry elevations
3TC: Use in HBV co-
infected participants 
and emergence of HBV 
variants resistant to
3TC
DTG: Non-clinical data suggested a possible, albeit low, risk for 
hepatobiliary toxicity with DTG.  Drug-related hepatitis is considered 
an uncommon risk for ART containing DTG regardless of dose or 
treatment population.  For participants with hepatitis B virus (HBV) 
and/or hepatitis C virus (HCV) co-infection, improvements in 
immunosuppression as a result of HIV virologic and immunologic 
responses to DTG- containing ART, along with inadequate therapy 
for HBV co-infected participants, likely contributed to significant 
elevations in liver chemistries. A review of postmarketing data 
found that the number of cases reporting particularly severe liver 
dysfunction was found to be very low in the context of exposure to 
DTG and DTG/ABC/3TC. The reported cases of severe liver 
dysfunction (including acute hepatic failure) are complex with 
potential confounding factors but in a very small number of cases, 
drug-induced liver injury is likely and the role of DTG containing 
regimens cannot be ruled out particularly in those involving DTG 
Participants meeting any of the following criteria during the 
screening period are excluded from participating.

Alanine aminotransferase (ALT) 5 times the upper limit of 
normal (ULN) or ALT 3xULN and bilirubin 1.5x ULN (with 
>35% direct bilirubin)

Participants positive for Hepatitis B surface antigen (+HBsAg)

Participants negative for HBsAg and anti-HBsAg and positive for 
anti-HBc and HBV DNA

Anticipated need for any hepatitis C virus (HCV) therapy during 
the randomized phase of the study, or anticipated need for HCV 
therapy with a potential for adverse drug-drug interactions with 
DTG or 3TC
Specific/detailed liver stopping criteria and toxicity management 
guidance is provided for suspected DILI or other clinically significant 
liver chemistry elevations (Section 11.9).


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG and 3TC]
Refer to Investigator Brochures (IBs) for additional information
with ABC/3TC or DTG/ABC/3TC.
3TC:  Current treatment guidelines [DHHS, 2018; EACS, 2017] do 
not recommend monotherapy with 3TC for participants with HBV 
infection, which is what participants randomised to DTG/3TC FDC, 
would effectively be receiving.  Emergence of HBV variants 
associated with resistance to 3TC has been reported in HIV-1-
infected participants who have received 3TC-containing 
antiretroviral regimens in the presence of concurrent infection with 
HBV.  Additionally, discontinuation of 3TC in HBV co-infected 
participants can result in severe exacerbations of hepatitis B.
DTG: Psychiatric 
disorders
DTG: Psychiatric disorders including suicidal ideation and 
behaviours are common in people living with HIV. Events of suicidal 
ideation, attempt, behaviour and completion were observed in 
clinical studies of DTG, primarily in participants with a pre-existing 
history of depression or other psychiatric illness. The psychiatric 
profile for DTG (including suicidality, depression, bipolar and 
hypomania, anxiety and abnormal dreams) was similar to RAL- or 
favourable compared with EFV- based regimens. 
The reporting rate for insomnia was statistically higher for blinded 
DTG+ abacavir/lamivudine (ABC/3TC) compared to EFV/TDF/FTC 
in ING114467; however, this was not duplicated in any other Phase 
IIb/III study conducted with DTG.  
Participants who in the investigator’s judgment, pose a significant 
suicidality risk, are excluded from participating.
Because of the elevated risk in the population of people living with 
HIV, treatment emergent assessment of suicidality will be monitored 
during this study through the end of the continuation phase.  
Investigators are advised to consider mental health consultation or 
referral for participants who experience signs of suicidal ideation or 
behaviour (See Section 8.2.5).
The participant informed consent form includes information on the 
risk of depression and suicidal ideation and behaviour.    
DTG: Increased rates 
of virologic failure/ 
Virologically suppressed participants switching from stable ART to 
DTG/3TC FDC may experience virologic failure/breakthrough and 
Participants with any switch to a second line regimen due to 
previous virologic failure and participants with evidence of 


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG and 3TC]
Refer to Investigator Brochures (IBs) for additional information
Observed Resistance
development of resistance.
DTG: Week 96 and Week 144 analyses for the Phase III/IIIb clinical 
studies supported the efficacy findings from earlier analyses, and 
demonstrated robust maintenance of viral suppression with no 
finding of HIV-1 resistance in treatment-naïve participants.
3TC:  M184V is the common single mutation that leads to full 
resistance to 3TC.  
pre-existing viral resistance mutation (including M184I/V) are 
excluded from this study.   
Genotypic resistance testing results be reviewed by ViiV Virology
to ensure participants with exclusionary mutations are not 
randomized. 
Participants will have HIV-1 RNA measured at routine study visits. 
An independent data monitoring committee (IDMC) will be instituted 
to ensure external objective medical and/or statistical review of 
efficacy.
DTG: Theoretical 
serious drug interaction 
with dofetilide, 
pilsicainide and 
fampridine
Co-administration of DTG may increase dofetilide/pilsicainide and 
fampridine plasma concentration via inhibition of organic cation 
transporter (OCT-2), resulting in potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide, pilsicainide or 
fampridine is prohibited in the study (Section 11.6).
DTG and 3TC: Renal 
function
DTG:  Mild elevations of creatinine have been observed with DTG 
which are related to a likely benign effect on creatinine secretion 
with inhibition of OCT-2.  DTG has been shown to have no 
significant effect on glomerular filtration rate (GFR) or effective renal 
plasma flow.
3TC:  3TC is eliminated by renal excretion and exposures increase 
in participants with renal dysfunction.  3TC is not recommended to 
treat participants with a creatinine clearance <50 mL/min.
Specific/detailed toxicity management guidance is provided for 
participants who develop a decline in renal function (Section
11.3.1.3).
Creatinine clearance is calculated in all participants prior to initiating 
therapy and renal function (creatinine clearance and serum 
phosphate) will be monitored at all subsequent study visits.
Participants with creatinine clearance <30 mL/min are excluded from 
participation in this study. Safety events, including laboratory 
toxicities will be monitored closely in participants with creatinine 
clearance between 30-49 mL/min, as outlined in the Schedule of 
Activities table.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG and 3TC]
Refer to Investigator Brochures (IBs) for additional information
DTG: Neural tube 
defects
In one ongoing birth outcome surveillance study in Botswana, 
updated results from an interim analysis show that 5/1683 (0.3%) of 
women who were taking DTG when they became pregnant had 
babies with neural tube defects compared to a background rate of 
0.1%.
1. A female participant is eligible to participate if she is not 
pregnant, not lactating, and, if she is a female of reproductive 
potential, agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) (see 
Appendix 4, Section 11.4.2) from 30 days prior to the first dose 
of study medication and for at least 2 weeks after the last dose 
of study medication.
2. Women who are breastfeeding or plan to become pregnant or 
breastfeed during the study are excluded.
3. Women who become pregnant, or who desire to be pregnant 
while in the study, or who state they no longer are willing to 
comply with the approved pregnancy avoidance methods, will 
have study treatment discontinued and will be withdrawn from 
the study.
4. Females of reproductive potential are reminded re: pregnancy 
avoidance and adherence to contraception requirements at 
every study visit.
5. Pregnancy status is monitored at every study visit
a.
Careful monitoring of events will be conducted using serious adverse event (SAE) reports and alerts for Grade 3/4 laboratory toxicities (per Division of Acquired 
Immune Deficiency Syndrome [DAIDS] toxicity gradings for HIV-infected participants). Serious/severe events will be managed appropriately including, but not 
limited to, withdrawal of study intervention, and will be followed to resolution as per Sponsor’s standard medical monitoring practices.  
b.
Clinical Safety Data will be routinely reviewed in GlaxoSmithKline (GSK)/ViiV Safety Review Team meetings. This will include in-stream review of data from this 
clinical trial on a routine basis, review of aggregate data on a protocol and program basis when available, and review of competitor data from the literature.


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2.3.2.
Benefit Assessment
Individually, DTG and 3TC are conveniently dosed once daily without regard to meals, 
without need for a PK booster, and with limited safety implications resulting from 
theoretical or actual DDIs compared to other ART agents (including EFV and those 
requiring a PK booster).  In addition, the high barrier to resistance observed with DTG 
should help protect against the development of resistance to both components of the 
DTG/3TC FDC regimen.  Individually, DTG and 3TC in combination with other ARVs 
have demonstrated durable virologic and immunologic response. 
In general, switching participants to a DTG/3TC FDC regimen from a dual NRTI-based
3-drug regimen may increase tolerability, reduce the frequency of adverse events
associated with NRTI-based regimens and/or DDIs.  Study participants also may benefit 
from the medical tests and screening procedures performed as part of this study.
2.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with DTG/3TC FDC are justified 
by the anticipated benefits that may be afforded to study participants switching to this 2-
drug regimen.


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To demonstrate the non-inferior antiviral activity 
of switching to DTG/3TC FDC once daily 
compared to continuation of CAR over 48 
weeks in virologically suppressed adults living 
with HIV-1
Virologic failure endpoint as per FDA snapshot 
category at Week 48
Secondary
To demonstrate the antiviral activity of switching 
to DTG/3TC FDC once daily compared to 
continuation of CAR over 48 weeks
Proportion of participants with plasma HIV-1 
RNA <50 c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population 
To evaluate the antiviral activity of switching to 
DTG/3TC FDC once daily compared to 
continuation of CAR over 24 weeks 

Virologic failure endpoint as per FDA 
snapshot category at Week 24

Proportion of participants with plasma HIV-1 
RNA <50 c/mL at Week 24 using the 
Snapshot algorithm for the ITT-E population
To evaluate the immune effects of DTG/3TC 
FDC once daily compared to continuation of 
CAR

Change from Baseline in CD4+ cell count
and in CD4+/CD8+ cell counts ratio at 
Weeks 24 and 48

Incidence of disease progression (HIV-
associated conditions, AIDS, and death) 
through Weeks 24 and 48
To evaluate the safety and tolerability of 
DTG/3TC FDC once daily compared to CAR 
over time

Incidence and severity of adverse events 
(AEs) and laboratory abnormalities 

Proportion of participants who discontinue 
treatment due to AEs 
To evaluate the safety and tolerability of 
DTG/3TC FDC once daily in those with 
creatinine clearance of between 
30-49 mL/min/1.73m2 compared to those with a 
creatinine clearance of 50 mL/min/1.73m2

Incidence and severity of AEs and 
laboratory abnormalities 

Proportion of participants who discontinue 
treatment due to AEs 


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Objectives
Endpoints
To evaluate the effects of DTG/3TC FDC once 
daily on fasting lipids over time compared to 
CAR
Change from Baseline in fasting lipids at Weeks 
24 and 48
To assess viral resistance in participants 
meeting Confirmed Virologic Withdrawal (CVW)
Criteria
Incidence of observed genotypic and 
phenotypic resistance to ARVs for participants 
meeting CVW Criteria 
To assess health related quality of life for 
participants treated with DTG/3TC FDC
compared to CAR
Change from Baseline in health status using 
HIV TSQ at Weeks 24 and 48 (or Withdrawal 
from the study) and SDM at Weeks 24, 48 and
every 24 weeks during the continuation phase 
(or Withdrawal from the study)
Exploratory
To assess willingness to switch for participants 
treated with DTG/3TC FDC compared to CAR
Reasons for Willingness to Switch at Day 1
To evaluate renal (in urine and blood), bone (in 
blood), inflammatory (in blood) biomarkers and 
insulin resistance in participants treated with 
DTG/3TC FDC compared to CAR
Change from Baseline in renal, bone and 
inflammatory biomarkers and homeostasis 
model of assessment-insulin resistance (HOMA-
IR) at Weeks 24 and 48
To evaluate biomarkers of telomerase function 
in participants treated with DTG/3TC FDC
compared to CAR.
Change from baseline in biomarkers of 
telomerase function at Week 48 


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4.
STUDY DESIGN
4.1.
Overall Design
This is a 52-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of switching 
from CAR to DTG/3TC FDC in adults living with HIV who are virologically suppressed 
and stable on CAR.  The study will include a Screening Phase (up to 28 days), a 
Randomized Phase up to Week 52, and a Continuation Phase (post Week 52) (Section 
1.2).  The Continuation Phase is not applicable for participants in Sweden and Denmark.  
Approximately 490 adults living with HIV who are on a stable CAR will be randomized 
1:1 to switch to DTG/3TC FDC once daily for up to 52 weeks, or to continue their CAR 
for 52 weeks. To control for treatment related factors that may impact study outcomes, 
randomization will be stratified by baseline third agent class (protease inhibitor [PI], 
integrase inhibitor [INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]). For 
participants randomized to CAR, provisions will be in place, as needed and after 
discussion with the study team, to assist participants in obtaining CAR during the study.
The primary endpoint for the study is the virologic failure endpoint as per FDA Snapshot 
category at Week 48 using the Intent-to-Treat Exposed (ITT-E) population.  The Week 
48 primary analysis will take place after the last participant has had their Week 48 viral 
load assessed, including any retests. Participants randomized to DTG/3TC FDC will 
receive DTG/3TC FDC up to Week 52. 
All participants in the DTG/3TC FDC arm who successfully complete up to 52 weeks of 
treatment will have the opportunity to continue receiving DTG/3TC FDC once daily in a 
Continuation Phase (See Section 4.3).  Participants in the CAR arm will complete the 
study at Week 52.  The Continuation Phase is not applicable for participants in Sweden 
and Denmark.
No dose reductions, modifications, or changes in the frequency of any components of
each regimen will be allowed during this study with the exception of a switch from a PI 
boosted with ritonavir to the same PI boosted with cobicistat and vice versa. A switch 
from lamivudine to emtricitabine and vice versa is also permitted. Protocol waivers or 
exemptions are not allowed. Adherence to the study design requirements, including those 
specified in the Schedule of Activities (Section 1.3), are essential and required for study 
conduct. If deviations are required for the management of immediate safety concerns, 
these should be communicated promptly to the study medical monitor.
An Independent Data Monitoring Committee (IDMC) will be instituted to ensure external
objective medical and/or statistical review of efficacy to protect the ethical interests and 
well-being of participants and to protect the scientific validity of this study.
A sub-study of Virologic Response to Subsequent ART after Discontinuation from 
208090 for Meeting CVW or PVW Criteria will be conducted.  Details are provided in 
Section 11.2.


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4.2.
Number of Participants
Assuming 20% screen failure rate, approximately 622 adult participants living with HIV 
will be screened to achieve approximately 490 randomized participants for a total of 245
evaluable participants per treatment group (See Section 9.3).
A goal of this study is to enrol populations who are underrepresented in clinical studies 
including at least 20% women and approximately 20% of participants who are ≥50 years 
of age.  To provide sufficient data to determine whether women respond differently than 
male participants and whether participants who are ≥50 years of age respond differently 
than those < 50 years of age, sites are expected to consider women and participants ≥50 
years of age in their screening strategies.  Another goal of the study is to enrol 
approximately 20% of participants taking efavirenz/emtricitabine/tenofovir disoproxil 
fumarate to reflect on its continued use as first line ARV of choice in many countries.
Enrolment may be allowed to continue at select sites to attempt to reach targets in these
key study populations.  
The study will limit the enrolment of participants with current or prior exposure to DTG 
to approximately 20%.
4.3.
Participant and Study Completion
Participants are considered to have completed the study if they satisfy one of the 
following: 

Randomly assigned to either treatment group, completed the Randomized Phase 
including the Week 52 visit, and did not enter the Continuation Phase;

Randomly assigned to DTG/3TC FDC, completed the Randomized Phase including 
the Week 52 visit, entered and completed the Continuation Phase, defined as 
remaining on study until:

DTG and 3TC are each locally approved for use as part of a 2-drug regimen, and 
each of the single entities of DTG and 3TC are available through public health 
services or through the participant’s usual health insurance payer, or

the actual DTG/3TC FDC tablet, if required by local regulations, is available, or

the participant no longer derives clinical benefit, or 

the participant meets a protocol-defined reason for discontinuation, or 

development of the DTG plus 3TC 2-drug regimen is terminated
The Continuation Phase is not applicable for participants in Sweden and Denmark.
An in-clinic Follow-Up visit will be conducted approximately 4 weeks after the last dose 
of study medication for participants with ongoing AEs, serious adverse events (SAEs) 
regardless of attributability, and any laboratory abnormalities that are considered to be 
AEs or potentially harmful to the participant, at the last on-study visit. Assessments at the 
Follow-up visit should reflect any ongoing complaints (e.g., blood draws to follow a 


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laboratory abnormality).  The Follow-Up visit is not required for successful completion 
of the study.
4.4.
Scientific Rationale for Study Design
The design of this study (1:1 randomized, open-label, active-controlled, multicenter, 
parallel group, non-inferiority study) is well established for confirming the 
non-inferiority of an investigational agent compared with an active ART standard-of-care 
regimen and generally is accepted by regulatory authorities as rigorous proof of antiviral 
activity. The primary endpoint, proportion of participants defined as virologic failures by 
the FDA Snapshot algorithm, is recommended in the FDA’s 2015 guidance document for 
assessing efficacy in Switch Trials [CDER, 2015].  The key secondary endpoint, 
proportion of participants at Week 48 with plasma HIV-1 RNA<50 c/mL, is also a well-
established surrogate endpoint for prognosis of HIV-1 infection and disease progression 
[CDER, 2015].
Several studies have demonstrated the value/feasibility of a switch study design, an 
approach that has been shown to generate valuable data supporting ARV combinations 
that allow dosing flexibility, reduced toxicity and/or drug interactions or a reduction in 
pill burden. A simplified ARV regimen may also contribute to increased medication 
adherence and reduced HIV transmission.  A potential disadvantage of a switch study 
design is that effective, well-tolerated ART is discontinued at the time of switching to the 
simplified regimen [Carr, 2012].
Previous studies have shown the non-inferiority of a 2-drug regimen in maintaining 
virologic suppression when participants who were virologically suppressed on a 3-drug 
regimen were switched to a 2-drug regimen (See Section 2.2). 
In this study, participants will be randomized 1:1 to switch to DTG/3TC FDC from CAR 
at Day 1 or stay on their CAR for up to 52 weeks.  The primary endpoint will be 
evaluated at Week 48 using a 5% non-inferiority (NI) margin.  The rationale for this 
decision is provided in Section 9.2.1. This study is evaluating the rate of Snapshot 
algorithm measured virologic failure in already suppressed participants to test the 
hypothesis that maintenance of the suppression of HIV-1 replication by DTG/3TC FDC
will be non-inferior to that observed in the CAR arm of the study through Week 48.  
This study will also evaluate the safety and tolerability of this 2-drug regimen in persons 
with a creatinine clearance of between 30 – 49 mL/min/1.73m2. The DTG 50mg dose is 
approved for persons with a creatinine clearance of as low as 30 mL/min/1.73m2. 3TC 
plasma concentrations area under the curve (AUC) are increased in participants with 
moderate to severe renal impairment due to decreased clearance, and the current label 
recommends a dose of 150 mg once a day for a creatinine clearance of between 
30-49 mL/min/1.73m2. However, several randomized controlled studies that have 
compared  a total 3TC daily dose of 600 mg/day to 300 mg/day showed only small, 
statistically non-significant differences between the treatment arms in the frequency of 
AEs, drug-related AEs, SAEs, Grade 3/4 clinical and laboratory toxicities and 
withdrawals due to AEs [Eron, 1995; GlaxoWellcome Document Number UCR/95/003, 
1995; GlaxoWellcome Document Number GIO/94/005, 1995].  Our study will allow 


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inclusion of participants with creatinine clearance of ≥30 mL/min/1.73m2 to confirm 
these earlier observations.  The protocol includes extensive serum and urine renal 
function laboratory tests collected at each study visit, and has management procedures for 
specified change (decrease) in renal function.
This study will aim to enrol 20% females to provide safety and efficacy data to help 
inform clinicians about use of this ART regimen in women.  While women comprise 
approximately 50% of people living with HIV globally, the number of women in most 
HIV clinical trials remains low, and recruiting and retaining women into antiretroviral 
clinical studies remains a challenge.  The reasons are multiple, but may reflect 
differences in lifestyle, care commitments, behaviour and socioeconomics between 
women and men living with HIV.  Additionally, women may metabolize and respond to 
antiretroviral agents differently than men; women may have higher drug exposure, be at 
greater risk for some adverse events (i.e., lactic acidosis, hepatotoxicity/rash, and 
osteoporosis), and have an added potential for drug-drug interactions (i.e., oral hormonal 
contraceptives/or estrogen).  
The open-label design best suits the objectives of this study.  A double-dummy design 
could not be undertaken given the increase in pill burden that would result from blinding, 
the differing requirements for dosing a variety of CAR with food, and wide variety of 
potential DDIs.  An increase in pill burden could hinder compliance substantially and 
discourage participant enrolment.  The use of the FDA snapshot algorithm for assessing 
the proportion of participants with virologic failure as an objective primary endpoint will 
help reduce biases inherent to an open-label study design.
4.5.
Justification for Dose
To date, the efficacy, PK, safety, and drug interaction potential of DTG and 3TC as 
individual agents have been evaluated in two extensive clinical development programs of 
Phase I to III clinical trials.  As individual agents, DTG and 3TC are both approved and 
marketed as TIVICAY 50 mg once daily and EPIVIR 300 mg once daily, respectively.  
These doses will be used in the current study.  
Comprehensive clinical studies have been conducted with the individual DTG and 3TC 
products, including clinical pharmacology studies evaluating potential DDIs between 
each of these active ingredients and other agents.  There are no known clinically relevant 
PK interactions between DTG and 3TC with concomitant dosing. 
A summary of the overall clinical development for both products is available in the most 
recent version of the IBs and or Product Insert(s) for the respective products [see DTG 
IB: GlaxoSmithKline Document Number RM2007/00683/11; GlaxoSmithKline 
Document Number 2017N352880_00; GlaxoSmithKline Document Number 
2017N352880_01; Dolutegravir (TIVICAY) Product Insert; 2017; EPIVIR Product 
Insert, 2017].
Based on the preliminary results of the pivotal bioequivalence study (204994), a bilayer 
tablet formulation with a core which utilizes the same formulation in the respective layers 
as the single entity tablets was selected.  When administered in the fasted state, the 
bilayer tablet demonstrated bioequivalence to the single entity tablets for dolutegravir 
area under the curve zero to infinity (AUC(0-∞)) & maximum concentration (Cmax) and 


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lamivudine AUC(0-).  However, the bilayer tablet showed a modest increase in 
lamivudine Cmax compared to the single entity tablet, which is not considered to be 
clinically significant.


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5.
STUDY POPULATION
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational product or other study interventions 
that may impact participant eligibility is provided in the Product Insert(s) for DTG, 3TC 
or CAR.
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. Prospective approval of protocol deviations to recruitment and enrolment
criteria, also known as protocol waivers or exemptions, is not permitted.
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).
Laboratory results provided from central laboratory services will be used to assess 
eligibility. In exceptional circumstances only, if a central lab result cannot be generated, 
local labs can be reviewed and approved by the Medical Monitor, for consideration of 
participant eligibility, except for plasma HIV-1 RNA.
5.1.
Inclusion Criteria
Eligible participants must:

be able to understand and comply with protocol requirements, instructions, and 
restrictions;

be likely to complete the study as planned;

be considered appropriate candidates for participation in an investigative clinical 
trial with oral medication (e.g. no active problematic substance abuse, acute major 
organ disease, or potential long-term work assignments out of the country).  
Participants are eligible to be included in the study only if all of the following 
criteria apply:
Age
1. Aged 18 years or older (or older, if required by local regulatory agencies), at the 
time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Adults living with HIV


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3. Documented evidence of at least two plasma HIV-1 RNA measurements 
<50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month 
window, and one within 6 months prior to Screening.
4. Plasma HIV-1 RNA <50 c/mL at Screening.
5. Must be on uninterrupted current regimen (either the initial or second cART 
regimen) for at least 3 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 and/or safety concerns or 
access to medications, or convenience/simplification and must NOT have been 
done for suspected or established treatment failure. The following switches, if 
they are the only switches, would not be considered a change in regimen:
a.
A switch from a PI boosted with RTV to the same PI boosted with cobicistat 
is allowed (and vice versa).
b. A switch from lamivudine (3TC) to emtricitabine (FTC) (and vice versa)
c.
A switch from tenofovir disoproxil fumarate (TDF) to tenofovir 
alafenamide (TAF) (and vice versa)”
Acceptable stable cART 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) (either the initial or second PI-based 
cART regimen)
NOTE: Combination triple ART 10 days with any antiretroviral agent following a 
diagnosis of HIV-1 infection is not considered a prior cART regimen. 
Sex
6. Male and Female
a. Female participants: 
A female participant is eligible to participate if she is not pregnant [as confirmed by 
a negative serum human chorionic gonadotrophin (hCG) test at screen and a negative 
urine hCG test at Randomization (a local serum hCG test at Randomization is 
allowed if it can be done, and results obtained, within 24 hours prior to 
randomization)], not breastfeeding, and at least one of the following conditions 
applies:

Not a woman of childbearing potential (WOCBP) as defined in
Section 11.4.1
OR
A WOCBP who agrees to follow the contraceptive guidance in Section 11.4.2
during the treatment period from 28 days prior to the first dose of study 


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medication and for at least 2 weeks after the last dose of study medication.
The investigator should evaluate the effectiveness of the contraceptive method 
in relationship to the first dose of study intervention.
The investigator is responsible for ensuring that participants understand how to properly 
use these methods of contraception.
All participants in the study should be counselled on safer sexual practices including the 
use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of 
HIV transmission to an uninfected partner.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 10 which
includes compliance with the requirements and restrictions listed in the informed 
consent form and in this protocol.
Other
8. Participants enrolled in France must be affiliated to, or a beneficiary of, a social 
security category.  
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Concurrent Conditions/Medical History
1. Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed 
during the study
2. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3
disease [CDC, 2014], EXCEPT cutaneous Kaposi’s sarcoma not requiring systemic 
therapy.  Historical or current CD4 cell counts less than 200 cells/mm3 are NOT
exclusionary.
3. Participants with severe hepatic impairment (Class C) as determined by Child-Pugh 
classification (see Section 11.5).
4. Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's 
syndrome or asymptomatic gallstones).  
5. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at 
Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-
HBc), Hepatitis B surface antigen antibody (anti-HBs) and HBV DNA as follows:

Participants positive for HBsAg are excluded.

Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg 
status) and positive for HBV DNA are excluded.  


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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.  
Anti-HBc must be either total anti-HBc or anti-HBc immunoglobulin G (IgG), and 
NOT anti-HBc IgM.  Participants with a documented history of chronic HBV and 
current undetectable HBV DNA while on a TAF/TDF regimen are excluded.
6. Anticipated need for any hepatitis C virus (HCV) therapy during the randomized 
phase of the study, or anticipated need for HCV therapy with a potential for adverse 
drug-drug interactions with DTG or 3TC. 
7. Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without 
clear documentation of treatment).  Participants who are at least 7 days post 
completed treatment are eligible.
8. History or presence of allergy or intolerance to the study interventions or their 
components or drugs of their class.
9. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile 
intraepithelial neoplasia.
10. Participants who in the investigator’s judgment, poses a significant suicidality risk
11. Any pre-existing physical or mental condition which, in the opinion of the 
Investigator, may interfere with the participant’s ability to comply with the dosing 
schedule and/or protocol evaluations or which may compromise the safety of the 
participant.
12. Any condition which, in the opinion of the Investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the study interventions or render 
the participant unable to take oral medication.
Exclusionary Treatments Prior to Screening or Day 1
13. Use of any regimen consisting of single or dual ART (peri-partum treatment with 
single dose nevirapine is allowed). 
14. Current use of stavudine, didanosine, or nelfinavir
15. Participants receiving any prohibited medication listed in Section 11.6 and who are 
unwilling or unable to switch to an alternate medication
16. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
17. Treatment with any of the following agents within 28 days of Screening

radiation therapy

cytotoxic chemotherapeutic agents

any systemic immune suppressant
18. 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 the first dose of IP.


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Laboratory Values or Clinical Assessments at Screening
19. Any evidence of major NRTI mutation or presence of any DTG resistance-associated 
mutation [Wensing, 2017] in any available prior resistance genotype assay test result, 
if known.  Refer to the most recent version of IAS Guidelines [Wensing, 2017], SRM, 
and Section 8 (Screening Assessments) for more information.  All resistance reports 
with HIV-1 reverse transcriptase or integrase genotypic data must be provided to 
ViiV after screening and before randomization for review by ViiV virology.
20. Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during 
the Screening period to verify a result.
21. Alanine aminotransferase (ALT) 5 times the upper limit of normal (ULN) or
ALT 3xULN and bilirubin 1.5xULN (with >35% direct bilirubin).
22. Creatinine clearance of <30 mL/min/1.73m2 via CKD-EPI method. Participants with 
creatinine clearance between 30 – 49 mL/min/1.73m2 are eligible after the medical 
monitor has provided approval after reviewing participant’s current ART regimen.
23. Any acute laboratory abnormality at Screening, which, in the opinion of the 
investigator, would preclude the participant’s participation in the study of an 
investigational compound.
Exclusionary Criteria Prior to Screening or Day 1
24. Within the 12 month window prior to Screening and after confirmed suppression to 
<50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL. 
25. Within the 12 month window prior to Screening and after confirmed suppression to 
<50 c/mL, 2 or more consecutive plasma HIV-1 RNA measurements 50 c/mL. A 
single plasma HIV-1 RNA measurement >50 c/mL but less than 200 c/mL, with 
confirmation of return to <50 c/mL is allowed.
26. Any drug holiday during the 6 months prior to Screening, except for brief periods 
(less than 1 month) where all ART was stopped due to tolerability and/or safety 
concerns.
27. Any history of switch to another regimen, defined as change of a single drug or 
multiple drugs simultaneously, due to virologic failure to therapy (defined as a 
confirmed plasma HIV-1 RNA 400 c/mL.
28. Participants who are currently participating in or anticipate to be selected for any 
other interventional study after randomization (NOTE:  participants who are already 
enrolled into another interventional study at time of screening may be eligible after 
consultation with the ViiV Healthcare/GSK study team prior to randomization. 
Considerations include participant’s ability to attend all visits on schedule, and 
possible drug and study procedure compatibility).  See SRM for further details.
Country Specific Requirements
29. Participants enrolled in France (or in other countries as required by local regulations 
or Ethics Committee/Institutional Review Board [IRB]) who:


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participated in any study using an investigational drug or vaccine during the 
previous 60 days or 5 half-lives, or twice the duration of the biological effect of 
the experimental drug or vaccine, whichever is longer, prior to screening for the 
study, or 
participate simultaneously in another clinical study.
Notwithstanding these minimum inclusion and exclusion criteria, Investigators must 
also follow country specific guidelines where they exist when making decisions about 
participants who are eligible for study participation.
5.3.
Lifestyle Restrictions
This section is not applicable to this study.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. 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).
Participants are allowed to re-screen for this study one time (except where screen HIV-1 
plasma RNA 50 c/mL or where exclusionary HIV-1 resistance was present).  
Re-screening will require a new subject number.  
A single repeat test (re-test) per analyte or assessment is allowed during the screening 
period to determine eligibility. However, a repeat HIV-1 RNA, if HIV-1 RNA was 
≥50 c/mL is not allowed.  
Laboratory results provided from central laboratory services will be used to assess 
eligibility. In exceptional circumstances only, if a central lab result cannot be generated, 
local labs can be reviewed and approved by the Medical Monitor, for consideration of 
participant eligibility, except for plasma HIV-1 RNA.
Source documentation to verify entry criteria must be reviewed by the Principal 
Investigator or designee prior to randomization.  Source documents from other medical 
facilities must be located/retrieved during the screening period.  Under no circumstances 
may a participant be randomized in the absence of source documentation including prior 
qualifying viral load data (as outlined in the Inclusion Criteria).
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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Study intervention may refer to the individual study interventions or the combination of 
those study interventions.  All study interventions will be administered at the approved 
dosages.
The investigational study intervention DTG/3TC FDC will be supplied by ViiV 
Healthcare/GSK as the fixed dose combination tablet. Participants randomly assigned to 
continue CAR for up to 52 weeks will not have drug provided as clinical trial material, 
except where provision of CAR in this specific study setting is required by country and 
local regulations.  The individual components of CAR will be recorded on the 
Concomitant ART Therapy (ConART) eCRF page. For participants randomized to CAR, 
provisions will be in place, as needed and after discussion with the study team, to assist 
participants in obtaining their CAR during the study.
DTG/3TC FDC must be stored in a secure area under the appropriate physical conditions 
for the product.  Access to and dispensing of the DTG/3TC FDC will be limited to the 
investigator and authorized site staff.  Study intervention must be dispensed or 
administered only to participants enrolled in the study and in accordance with the 
protocol.  For further details on storage, access and administration of study interventions, 
refer to the SRM. 


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6.1.
Study Interventions Administered
Table 1
Study Interventions
Intervention Name:
DTG/3TC FDC
CAR
Dosage formulation:
White, oval, film-coated 
tablets
Refer to product label
Unit dose strength(s)/Dosage 
level(s):
50mg/300mg
Refer to product label
Route of Administration 
oral
Refer to product label
Dosing instructions:
Take one tablet daily
Refer to product label
Packaging and Labelling
The tablets are packed in high 
density polyethylene (HDPE) 
bottles with induction seals 
and child-resistant closures.  
Each 60mL bottle contains 30 
tablets and a 2 gram silica 
gel desiccant. Each bottle 
will be labelled as required 
per country requirement. 
Refer to product label
Manufacturer
GSK
Refer to product label
6.2.
Dose Modification
No dose adjustments are permitted in this study for DTG/3TC FDC or for CAR. 
6.3.
Method of Treatment Assignment
Informed consent must be obtained prior to any study procedures, including any 
screening assessment. 
Participants will be assigned to study intervention in accordance with the computer-
generated randomization schedule. The central randomization schedule will be generated 
by Pharmaceutical Product Development (PPD) using a validated SAS developed 
program.


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Randomization and study intervention assignment will be facilitated by the interactive 
voice/web recognition system (IVRS/IWRS). Following confirmation of fulfilment of 
study entry criteria, study site personnel will be required to contact the IVRS/IWRS to 
register participants. Participants will be randomized in a 1:1 ratio to DTG/3TC FDC or 
the CAR arm, in accordance with the computer-generated randomization schedule. To 
control for treatment related factors that may impact study outcomes, randomization will 
be stratified by baseline third agent class (protease inhibitor [PI], integrase inhibitor 
[INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]).  Each participant will 
be assigned a unique identifier (designating the participant’s randomization code) and a 
unique treatment number which matches the randomized treatment assignment. 
Participants who are randomly assigned into the trial and subsequently withdrawn may 
not be rescreened.  Once a randomisation number has been assigned it must not be 
re-assigned.
6.4.
Blinding
This is an open-label study; potential bias will be reduced by the following steps: central 
randomization. No summaries of the study data according to actual randomized treatment 
groups will be available to sponsor staff prior to the planned Week 24 preliminary 
analysis. Public presentation of the Week 24 analysis will not be done until after the last 
participant completes their last visit for the primary Week 48 analysis.
6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study intervention is required.

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.

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).

Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM. 

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.

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 
ViiV/GSK.


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
IP accountability will be evaluated using pill counts of unused DTG/3TC FDC only 
and not CAR.  This assessment will be conducted each time the participant receives a 
new (refill) supply of DTG/3TC FDC through the Withdrawal visit or study 
completion. IP accountability records must be maintained throughout the course of 
the study.  These data will be recorded in the participant’s eCRF but will not be 
summarised for analysis purposes.

Please refer to Appendix 14 in Section 11.14 for study management information 
during the COVID-19 pandemic.
6.6.
Treatment Compliance
When participants self-administer study interventions at home, compliance with
DTG/3TC FDC or CAR will be assessed through querying the participant during the site 
visits and documented in the source documents and eCRF.  A record of the number of 
DTG/3TC FDC tablets dispensed to and taken by each participant must be maintained 
and reconciled with study intervention and compliance records.  Intervention start and 
stop dates, including dates for treatment delays will also be recorded in the case report 
form (eCRF) for both DTG/3TC FDC and CAR.
6.7.
Concomitant Therapy
Refer to Appendix 6 for a full list of prohibited medications. The Medical Monitor should 
be contacted if there are any questions regarding concomitant or prior therapy.
Participants should be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
DDIs between such treatments and the study interventions. The investigator should 
evaluate any potential DDIs at every visit, including reviewing the most current version 
of the U.S. or local prescribing information for DTG, 3TC and CAR, especially if any 
new concomitant medications are reported by participants.  All concomitant medications 
(including oral contraception, implants or oral or topical hormone replacement therapy)
taken during the study will be recorded in the eCRF.  The minimum requirement is that 
the drug name, route, and the dates of administration are to be recorded.
Concomitant medications (prescription and non-prescription) should be prescribed by the 
relevant health care provider/investigator and administered only as medically necessary 
during the Randomized and Continuation phases of the study (except prohibited 
medications described in Section 11.6).  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.
6.7.1.
Permitted Medications and Non-Drug Therapies
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 plasma 
RNA, it is highly recommended that a vaccine, if necessary, be given during or 
immediately after a scheduled visit after all laboratory tests have been drawn and only 


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when scheduled visits are ≥4 weeks apart.  This approach will minimize the risk of non-
specific increases in the level of HIV-1 plasma RNA at the next scheduled assessment.
DTG/3TC FDC should be administered 2 hours before or 6 hours after taking antacid or 
laxative products containing polyvalent cations (e.g. aluminium and magnesium),
sucralfate, or calcium supplements.  Proton pump inhibitors and H2-antagonists may be 
used in place of antacids with no scheduling restrictions.  Concurrent administration with 
multivitamins is acceptable.  Iron supplements can be taken with IP provided that all are 
taken together with a meal. Under fasted conditions, DTG +3TC should be given 2 hours 
prior to OR 6 hours after iron supplements.
Metformin concentrations may be increased by DTG.  A dose adjustment of metformin 
should be considered when starting and stopping co-administration of dolutegravir with 
metformin, to maintain glycaemic control.
Clinical monitoring is recommended for participants taking methadone, as methadone 
maintenance therapy may need to be adjusted in some participants.
Non-protocol defined treatments or medical interventions (e.g., physical therapy, 
radiotherapy, surgical procedures) are permitted during the study for appropriate medical 
management of the participant. 
6.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not ViiV is providing
specific post-study treatment.
All participants on DTG/3TC FDC who successfully complete 52 weeks of treatment will 
have the opportunity to receive DTG/3TC FDC once daily in a Continuation Phase until:
DTG and 3TC are each locally approved for use as part of a 2-drug regimen, and 
each of the single entities of DTG and 3TC are available to participants (e.g., 
through public health services or through their usual health insurance payer), or
the actual DTG/3TC FDC tablet, if required by local regulations, is available, or
the participant no longer derives clinical benefit, or 
the participant meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC 2-drug regimen is terminated.
The Continuation Phase is not applicable for participants in Sweden and Denmark. 
The purpose of the Continuation Phase is to ensure provision of DTG/3TC FDC.  
Assessments during the Continuation Phase are limited and will include some safety 
laboratory assessments.


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7.
DISCONTINUATION CRITERIA
7.1.
Discontinuation of Study Intervention
Participants permanently discontinuing study interventions are considered to be 
withdrawn from the study.  Similarly, participants who enter the Continuation Phase but 
permanently discontinue participation in the Continuation Phase prior to transitioning to 
commercially available DTG + 3TC are considered to be withdrawn from study 
intervention and from the study.  Withdrawn participants will not be replaced.  
7.1.1.
Virologic Criteria for Participant Management and Viral 
Resistance Testing
For the purposes of clinical management in this study, suspected virologic withdrawal
(SVW) and confirmed virologic withdrawal (CVW) criteria are defined here, wherein 
the virologic withdrawal criteria are based on the HIV-1 RNA cut-off of 200 c/mL.  
Clinical management for precautionary virologic withdrawal (PVW) criteria are based 
on consecutive viral loads ≥50 and <200 c/mL.
Suspected Virologic Withdrawal criteria

one assessment with HIV-1 RNA 200 c/mL after Day 1 with an immediately 
prior HIV-1 RNA <50 c/mL
Confirmed Virologic Withdrawal criteria

one assessment with HIV-1 RNA 200 c/mL after Day 1 with an immediately 
prior HIV-1 RNA ≥50 c/mL
Precautionary Virologic Withdrawal criteria

may be met after two consecutive assessments with HIV-1 RNA 50 and 
<200 c/mL without an identifiable, non-virologic cause (immunization, illness, 
non-adherence) and after discussion with Medical Monitor, OR

will be met with three consecutive assessments with HIV-1 RNA 50 and 
<200 c/mL
7.1.1.1.
Participants Meeting Virologic Management Criteria
Participants with HIV-1 RNA plasma levels 50 c/mL at any visit after Day 1 meet 
“virologic management” criterion and must have plasma HIV-1 RNA levels re-assessed 
using the algorithm shown in Figure 2. Plasma HIV-1 RNA values determined by the 
central laboratory only will be used to assess virologic management criteria.  Please refer 
to Appendix 14 in Section 11.14 for study management information during the COVID-
19 pandemic.  Upon notification that a participant’s HIV-1 RNA plasma level qualifies 
him/her as meeting a “virologic management” criterion, the Investigator should query the 
participant regarding intercurrent illness, recent immunisation, or interruption of therapy.  
All cases meeting “virologic management” criterion must be confirmed by a second 
measurement performed at least two weeks but not more than 4 weeks apart from 


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the date of the original sample, unless delay is necessary to meet the requirements of
confirmatory HIV-1 RNA testing as outlined below.  
The following guidelines should be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results:

Confirmatory testing should be scheduled 2 to 4 weeks following resolution of any 
intercurrent illness, during which time the participant should receive full doses of all 
study interventions.

Confirmatory testing should be scheduled 4 weeks following any immunisation, 
during which time the participant should receive full doses of study interventions.

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 doses of study interventions.

The participant should have received full doses of study interventions for at least 
2 weeks at the time confirmatory plasma HIV-1 RNA is done.  Sites should contact 
the Medical Monitor to discuss individual participants, whenever necessary.    
7.1.1.2.
Managing Participants Meeting Precautionary Virologic Withdrawal 
(PVW) or Confirmed Virologic Withdrawal (CVW) Criteria
Once a participant has been confirmed as meeting PVW or CVW criteria, a ‘plasma for 
storage’ sample from the earliest viral load ≥200 c/mL [if such is available for a PVW 
case), or from the SVW visit [if ≥200 c/mL) for a CVW case] will be sent as soon as 
possible for genotypic and phenotypic resistance testing and the result made known to the 
Investigator if and when available. Plasma samples for storage also will be obtained at 
unscheduled visits including the time of CVW criteria (see Figure 2).
Participants may continue to receive study intervention at the discretion of the 
investigator until results of resistance testing are available at which time the participant
must be discontinued from the study, except in cases where participant samples have 
HIV-1 RNA <500 c/mL, as noted below.  A participant who meets a PVW or CVW 
criterion must be discontinued from the study.  Selection of post-study ART regimen 
for participants meeting virologic withdrawal criteria will be recorded in the eCRF. To 
collect additional information on participants who meet CVW or PVW criteria, please see 
details on the Sub-study of Virologic Response to Subsequent ART after Discontinuation 
from 208090 for Meeting CVW or PVW Criteria in Section 11.2.
The protease (PRO)/reverse transcriptase (RT)/integrase assays used in this study are not 
validated for plasma HIV-1 RNA levels <500 c/mL.  Nevertheless, for all participants 
who meet CVW criteria, plasma samples will be analysed in an attempt to obtain 
genotype/phenotype data on samples with HIV-1 RNA ≥200 c/mL, as possible. 
Participants with confirmed HIV-1 RNA levels between 200 c/mL and <500 c/mL should 
be transitioned off study intervention within 30 days even if no resistance testing data 
becomes available, as genotype/phenotype data may not be reliably generated from 
plasma samples collected from these participants.  If the confirmed HIV-1 RNA level is 
≥50 and <200 c/mL, and the decision is taken to withdraw the participant, resistance 


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testing will not be done and the participant should be transitioned off study intervention
as soon as possible.
If a participant is prematurely discontinued from participation in the study, the 
Investigator must make every effort to perform the evaluations outlined in the Schedule 
of Activities.  These data will be recorded, as they comprise an essential evaluation that 
needs to be done before discharging any participant from the study.


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Figure 2
Criteria for Withdrawal or Re-Assessment of Plasma HIV-1 RNA
Any Visit (scheduled or unscheduled) after Day 1
Current plasma HIV-1 RNA <50 c/mL
Current plasma HIV-1 RNA 
50 c/mL but 
<200 c/mL
Current plasma HIV-1 RNA 200 c/mL
Regardless of previous plasma HIV-1 
RNA result, proceed to next scheduled 
visit per Schedule of Activities
If previous plasma HIV-1 RNA 
results were <50 c/mL, perform a 
scheduled or an unscheduled visit in 
approximately 2-4 weeks to 
reassess plasma HIV-1 RNAa.
If previous plasma HIV-1 RNA 
results were 50 c/mL, the site must 
discuss results with the medical 
monitorb,c.
Participant has met criteria for 
additional plasma HIV-1 RNA 
testing or possible withdrawal. 
If the participant is withdrawn 
under above criteria they will have 
met “Precautionary Virologic 
Withdrawal Criterion (PVW)”.
If the 2 previous consecutive 
plasma HIV-1 RNA results are 50 
and <200 c/mL, participant has 
met PVW.
If previous plasma HIV-1 RNA was 
<50 c/mL, perform a scheduled or an 
unscheduled visit in approximately 
2-4 weeks to reassess plasma HIV-1 
RNAa
Participant has met “Suspected 
Virologic Withdrawal Criterion
(SVW)”
If previous plasma HIV-1 RNA 
was 50 c/mL, discontinue 
participant from study once 
resistance test results are 
availableb,d.
Participant has met “Confirmed 
Virologic Withdrawal Criterion
(CVW)”


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a.
Investigators should not schedule reassessment blood draws in the presence of factors that could be associated with virologic blips, such as intercurrent infection, treatment 
interruption due to toxicity management or non-compliance, or vaccination. Participants should have received full doses of study intervention for at least 2 weeks at the time of 
plasma HIV-1 RNA reassessment.
b.
In case of withdrawal, a sample from the initial visit where the HIV-1 RNA plasma level is 50 c/mL will be used for resistance testing only if HIV-1 RNA level is 200 c/mL. If 
resistance testing will not be done, withdrawing participants should be transitioned off study intervention as soon as possible. 
c.
The medical monitor and investigator should consider intercurrent illness, recent immunization, interruption of therapy or other non-virologic reasons associated with transient 
elevated HIV-1 RNA measurements 50 and <200 c/mL. If no non-virologic reasons are identified to explain the lack of virologic suppression, the participant must be withdrawn.  
If the Investigator and the medical monitor agree that the participant is experiencing a slow re-suppression due to one of the above issues, then a retest HIV-1 RNA measurement 
is required in approximately 2-4 weeks. If the HIV-1 RNA remains 50 c/mL on a second retest (the third consecutive HIV-1 RNA assessment), the participant must be withdrawn.
d.
Participants with confirmed HIV-1 RNA results in the range 200 c/mL to <500 c/mL, should be transitioned off study intervention and withdrawn from study within 30 days 
regardless of whether resistance testing has been reported as genotype/phenotype data may not be reliably generated from plasma collected from these participants


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7.1.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Discontinuation of study intervention for abnormal liver tests is required when:

a participant meets one of the conditions outlined in Section 11.9.1

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.
Liver Safety Required Actions and Follow up Assessments can be found in Section 11.9.
7.1.3.
Temporary Discontinuation
Participants may have a temporary interruption to their study intervention for 
management of toxicities.  Such interruption of study intervention does not require 
withdrawal from the study.  However, consultation with the Medical Monitor is required.
7.1.4.
Restart
If participant meets liver chemistry stopping criteria do not restart the participant with 
study intervention unless:

ViiV Healthcare Safety and Labelling Committee (VSLC) approval is granted,

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the participant.

Refer to Section 11.9.2 for full guidance. 
7.2.
Withdrawal from the Study
Participants may be prematurely discontinued from the study for any of the 
following reasons:

Participant or Investigator non-compliance;

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, behavioral, 
compliance or administrative reasons. This is expected to be uncommon;


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
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;

At the request of, 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 the study for any of the following reasons:

Virologic withdrawal criteria as specified in Section 7.1.1 are met

Participant is identified as having been mistakenly screened/randomized with 
exclusionary resistance (see Section 7.1.1)

Participant requires substitution or dose modification of DTG, 3TC or any 
component of CAR. For participants on CAR, a switch from a PI boosted with 
ritonavir to the same PI boosted with cobicistat (and vice versa) and a switch from 
lamivudine to emtricitabine (and vice versa) is permitted per protocol.

Liver toxicity where stopping criteria specified in Section 7.1.2 are met and no 
compelling alternate cause is identified

Allergic reaction or Rash criteria as described in Section 11.3.1.5 and Section 
11.3.1.6 are met and no compelling alternate cause is identified

Renal toxicity as specified in Section 11.3.1.3 are met and no compelling alternate 
cause is identified

Grade 4 clinical or laboratory AE considered causally related to study intervention

Pregnancy (intrauterine), regardless of termination status of pregnancy (Section 
8.2.6).  As a reminder, females of reproductive potential who change their minds and 
desire to be pregnant, or who state they no longer are willing to comply with the 
approved pregnancy avoidance methods, should also be withdrawn from the study.
Refer to the Schedule of Activities (SoA) (Section 1.3) for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed.
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.   An 
in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study 
medication for participants with ongoing AEs, serious adverse events (SAEs) regardless 


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of attributability, and any laboratory abnormalities that are considered to be AEs or 
potentially harmful to the participant, at the last on-study visit.
Participants are not obligated to state the reason for withdrawal.  However, a reason for 
withdrawal 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.
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 with a primary reason of lost to follow-up. 


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8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the Schedule of Activities 
(SoA) (Section 1.3). 

Please refer to Appendix 14 in Section 11.14 for study management information 
during the COVID-19 pandemic.

Protocol waivers or exemptions are not allowed

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA.
Screening Assessments
Written informed consent must be obtained from each potentially eligible participant by 
study site personnel prior to the initiation of any Screening procedures as outlined in this 
protocol.  The consent form must have been approved by the IRB/Independent Ethics 
Committee (IEC).  After signing an informed consent, participants will complete 
Screening assessments to determine participant eligibility. Each participant being 
screened for enrolment evaluation will be assigned a participant number at the Screening 
visit. This number will be given sequentially in chronological order of participant 
presentation according to a numeric roster provided by PPD.
Eligibility criteria must be assessed carefully at the Screening visit.  Physical 
examinations should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF.  Cardiovascular medical history/risk factors, 
including vital signs (as detailed in the eCRF) will be assessed at the Screening visit 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.  Background information to be collected at Screening 
includes demography (year of birth, sex, race and ethnicity), prior ART history, medical 
history and current medical conditions, menopause history, concomitant medications, 
assessment of CDC HIV-1 classification, a 12-lead ECG and laboratory assessments as 
detailed in Section 1.3.
Eligible participants may be randomly assigned immediately as soon as all Screening 
assessments are complete and the results are available and documented.  All participants


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will complete the Screening period up to 28 days prior to Baseline (Day 1) during which 
all clinical and laboratory assessments of eligibility must be performed and reviewed.  
The Screening period of up to 28 days is to accommodate availability of all Screening 
assessment results, completion of source document verification to satisfy the Inclusion 
and Exclusion Criteria including the required previous HIV-1 RNA values, and 
scheduling.  All Screening results must be available prior to randomization. 
All information about the participant’s current and any past regimen must be 
available for review by the Principal Investigator or designee prior to 
randomization.  Source documents from other medical facilities must be 
located/received during the 28-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. A participant may be re-screened if 
the source documentation is obtained after the screening window closes.
Details regarding prior resistance data must be noted in the source documentation.  
Resistance testing reports with genotypic data must be provided to ViiV after screening 
and before randomization for review by ViiV.  Sites must wait for the study virologists to 
confirm the lack of exclusionary resistance mutations, which will be provided to the site 
before the screening window closes. Details for tracking historic resistance report 
availability and sending to ViiV Virology for evaluation are described in the SRM.  
Details regarding baseline or prior resistance data must be noted in the source 
documentation.  If a participant is identified as having been mistakenly 
screened/randomized with exclusionary resistance, they will be withdrawn.
Participants with chronic active hepatitis B virus infection are excluded.  Evidence of 
Hepatitis B virus (HBV) infection is based on the results of testing at Screening for 
Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B 
surface antibody (anti-HBs), and HBV DNA.  HBV DNA testing will only be performed 
for participants with positive anti-HBc and negative HBsAg and negative anti-HBs (past 
and/or current evidence).
All participants will be screened for syphilis at screening. Participants with untreated 
syphilis infection, defined as a positive Rapid Plasma Reagin (RPR) without clear 
documentation of treatment, are excluded unless they complete treatment during the 
28-day screening window and 7 days prior to randomization. Participants who complete 
treatment after the screening window closes may be rescreened.
Participants who meet all entry criteria are randomized and assigned a randomization 
number. Participants not meeting all inclusion and exclusion criteria at initial screen may 
be rescreened and receive a new participant number one time unless they were excluded 
for reason of having exclusionary historic genotypic resistance or for a viral load 
≥50c/mL at time of screening.  Participants who are randomized into the trial and 
subsequently withdrawn from the study for any reason may not be rescreened.


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Baseline Assessments
At Day 1 and prior to randomization, any changes to the eligibility parameters must be 
assessed and any results required prior to randomization (e.g., Day 1 urine pregnancy test 
for women of childbearing potential) must be available and reviewed.
Other baseline information to be collected at Day 1 includes assessment of HIV risk 
factors and mode of transmission, general medical history and current medical 
conditions, and menopause history.  Laboratory and health outcomes assessments will 
also be collected.  Questionnaire/surveys are recommended to be administered at the 
beginning of the visit before any other assessments are conducted.  Refer to Section 1.3
for a summary of all procedures at the Baseline (Day 1) visit.
8.1.
Efficacy Assessments
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Schedule of 
Activities (Section 1.3).  Methods to be used may include but are not limited to the 
Abbott Realtime HIV-1 Assay lower limit of quantitation 40 c/mL. In some cases, (e.g., 
where the plasma HIV-1 RNA is below the lower limit of detection for a given assay) 
additional exploratory methods may be used to further characterize plasma HIV-1 RNA 
levels.
Lymphocyte Subsets
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage, and absolute CD4+ and CD8+ lymphocyte counts, 
CD4+/CD8+ ratio) according to the Schedule of Activities (Section 1.3).
CDC HIV-1 Classification and HIV Associated Conditions
HIV-associated conditions will be recorded as per the Schedule of Activities (Section
1.3).  HIV associated conditions will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection in Adults (see Section 11.12).  When assessing 
CDC stage at Screening/Baseline, consider only the latest available CD4 T-cell count, 
except when the participant had an active Stage 3 event in the 6 months prior to 
Screening. Indicators of clinical disease progression are defined as:
CDC Stage 1 at enrolment → Stage 3 event;
CDC Stage 2 at enrolment → Stage 3 event;
CDC Stage 3 at enrolment → New Stage 3 Event;
CDC Stage 1, 2 or 3 at enrolment → Death.
8.1.1.
Primary Efficacy Endpoint
The primary endpoint will be the proportion of participants with virologic failure 
endpoint as per FDA snapshot category at week 48 for the ITT-E population.  Virologic 


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failure will include the following events; data in window not below 50 c/mL, 
discontinued for lack of efficacy, discontinued for other reason while not below 50 c/mL, 
and change in background therapy.
8.1.2.
Secondary Efficacy Endpoints

Proportion of participants with plasma HIV-1 RNA <50 c/mL at Weeks 24 and 48 
using the Snapshot algorithm for the ITT-E population

Percentage of participants with viral failure endpoint as per FDA snapshot category at 
Weeks 24 

Change from Baseline in CD4+ lymphocyte count and in CD4+/CD8+ cell counts 
ratio at Weeks 24 and 48

Incidence of disease progression (HIV-associated conditions, AIDS and death).
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA) (Section 1.3).
8.2.1.
Physical Examinations
Physical exams should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF.  Abnormalities noted during any exam must be 
recorded in the eCRF (e.g. in the current medical conditions or AE logs).
8.2.2.
Vital Signs

At the Screening visit, vital signs including height, weight and Body Mass Index 
(BMI) will be measured. The systolic and diastolic blood pressure will be measured 
in semi-supine position after 5 minutes rest. Body weight and BMI will also be 
assessed at each visit according to the Schedule of Activities (SoA) (Section 1.3).
8.2.3.
Electrocardiograms

A baseline 12-lead ECG will be conducted at the Screening visit, for possible use as 
a reference during the study (i.e. in evaluation of any pertinent cardiovascular event).
8.2.4.
Clinical Safety Laboratory Assessments
Refer to Appendix 7 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency. All protocol required laboratory 
assessments must be performed by central laboratory services, with the exception of 
exceptional circumstances during screening noted in Section 5.  Please refer to Appendix 
14 in Section 11.14 for study management information during the COVID-19 pandemic.
Laboratory assessments must be conducted in accordance with the Laboratory Manual, 
and SoA (Section 1.3). Laboratory requisition forms must be completed and samples 


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must be clearly labelled with the subject number, protocol number, site/centre number, 
and visit date. Details for the preparation and shipment of samples will be provided by 
Q2 Solutions and are detailed in the laboratory manual.  Reference ranges for all safety 
parameters will be provided to the site by Q2 Solutions.

If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or 
are considered clinically significant by the investigator (e.g. SAE or AE or dose 
modification) the results must be recorded in the eCRF. Please refer to 
Appendix 14 in Section 11.14 for study management information during the 
COVID-19 pandemic.

Labs will be graded automatically by the central lab according to the DAIDS 
toxicity scales (See Section 11.11 “Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events”).

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline or 
are no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

Refer to the SRM for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.

Haematology, clinical chemistry, urinalysis and additional parameters to be 
tested are listed in Section 11.7. 
8.2.5.
Suicidal Risk Monitoring
Participants with HIV infection occasionally may present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour).  In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in people with a 
pre-existing history of depression or psychiatric illness) in some people being treated 
with INIs, including DTG.  Therefore, it is appropriate to monitor participants for 
suicidality before and during treatment. 
Participants should be monitored appropriately and observed closely for suicidal ideation 
and behaviour or any other unusual changes in behaviour. It is recommended that the 


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investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behaviour. Participants presenting with new 
onset/treatment emergent depression should be advised to contact the investigator 
immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop, because medical intervention and discontinuation of the study 
medication may be required.
Assessment of treatment-emergent suicidality will be monitored during this study using 
the electronic version of the Columbia Suicidality Severity Rating Scale (eC-SSRS). The 
definitions of behavioural suicidal events used in this scale are based on those used in the 
Columbia Suicide History Form [Posner, 2007].  Questions are asked on suicidal 
behaviour, suicidal ideation, and intensity of ideation.  Day 1 (Baseline) visit questions 
will be in relation to lifetime experiences and current experiences (within the past 
2 months); all subsequent questioning is in relation to the last assessment. The eC-SSRS 
is to be administered as a participant completed questionnaire specified in the SoA. The 
eC-SSRS will be conducted electronically by telephone or by computer/tablet connected 
to the internet.
Additionally, the investigator will collect information using the Possible Suicidality-
Related AE (PSRAE) eCRF form in addition to the AE (non-serious or SAE) eCRF form 
on any participant that experiences a possible suicidality-related AE 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 behaviour, 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 1 week of the investigator diagnosing a 
possible suicidality-related AE.
8.2.6.
Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
intervention and ending at the final Follow-up visit.  If a pregnancy is reported, the 
investigator should inform ViiV/GSK/PPD within 2 weeks of learning of the pregnancy 
and should follow the procedures outlined in Section 11.4.3.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. 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 SAEs and must be reported.
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 reported promptly to ViiV/GSK (or
designee).
GSK’s central safety department will forward this information to the ART Pregnancy 
Registry.  The international registry is jointly sponsored by manufacturers or licensees of 


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ARV products.  Additional information and a list of participating manufacturers/licensees 
are available from http://www.apregistry.com/.  
8.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 8.
The investigator and any 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 the study (see Section 7). 
Please refer to Appendix 14 in Section 11.14 for study management information during 
the COVID-19 pandemic.
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 1.3).  However, any SAEs assessed 
as related to study participation (e.g., study intervention, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a 
ViiV/GSK product will be recorded from the time a participant consents to 
participate in the study.

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 1.3).

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 (eCRF) 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
Appendix 8. 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 in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in
Appendix 8.


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8.3.2.
Method of Detecting AEs and SAEs
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. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest will be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is given in Appendix 8.
8.3.4.
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.
8.3.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 11.8.3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 


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The Death eCRF 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.
8.3.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(Section 11.12) 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 ViiV/GSK as AEs and SAEs even though such 
event or outcome may meet the definition of an AE or SAE, unless the following 
conditions apply:

The investigator determines that the event or outcome qualifies as an SAE under part 
‘f’ of the SAE definition (see Section 11.8), or

The event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual participant, 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.
8.4.
Treatment of Overdose
For this open-label study, any tablet intake exceeding the randomized daily number of 
tablets for DTG/3TC FDC will be considered an overdose [Dolutegravir (TIVICAY) 
Product Insert, 2017; EPIVIR Product Information, 2017].  ViiV Healthcare does not 
recommend specific treatment for an overdose of DTG/3TC FDC.  As appropriate, the 
Investigator should use clinical judgment and also refer to the prescribing information for 
the individual drugs used for CAR in treating overdose in the CAR arm.
For the purposes of this study, an overdose is not an AE unless it is accompanied by a 
clinical manifestation associated with the overdose.  If the clinical manifestation presents 
with serious criteria, the event is a SAE (see Section 11.8).  If an overdose occurs and is 
associated with an adverse event requiring action, all study medications should be 
temporarily discontinued until the adverse event resolves.
In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities until 
DTG/3TC FDC can no longer be detected systemically (at least 2 days).

Obtain a plasma sample for PK analysis within 60 hours from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-
case basis).


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
Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
8.5.
Pharmacokinetics
Liver Event
As part of the follow-up for any liver stopping event, a blood sample for PK analysis will 
be collected if it can be obtained within 60 hours of the last dose (See Section 11.9.1).  
Overdose
Only if requested by the Medical Monitor, as part of the follow-up for any suspected 
overdose, a blood sample for PK analysis will be collected if it can be obtained within 60 
hours from the date of the last dose of study intervention (See Section 8.4).
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Blood and urine are being collected to perform renal, bone and inflammatory biomarker 
assessments.
Renal biomarkers: 

Cystatin C (blood)

Retinol Binding Protein (RBP, urine),

Beta-2-Microglobulin (B2M, urine)

Urine RBP/creatinine ratio

Urine B2M/creatinine ratio

urine albumin/creatinine ratio, 

urine protein/creatinine ratio, 


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
urine phosphate, and 

serum creatinine.  
Bone biomarkers (blood):

bone-specific alkaline phosphatase, 

procollagen type 1 N-propeptide, 

type 1 collagen cross-linked C-telopeptide, 

osteocalcin
Inflammatory Biomarkers (blood):

Interleukin-6 (IL-6) 

High-sensitivity C reactive protein (hs-CRP)

D-dimer

Soluble CD14 (sCD14)

Soluble CD163 (sCD163)
HbA1c and insulin and glucose for HOMA-IR calculation
Other Biomarkers:

Whole blood will be used for measurement of telomere length.  
Since the intention is to utilize these biomarkers for research purposes and the clinical 
significance of these results is uncertain, the Sponsor will not be reporting real time 
results of these assessments to the investigator except for Cystatin C (Day 1 only) and 
HbA1c.
8.9.
Health Economics and Outcomes Research
Health outcomes assessments will be conducted according to the Schedule of Activities 
(SoA) (Section 1.3). In the event of translations being unavailable, no such assessments 
will be conducted and the responses will be considered as missing in the final analyses. 
Assessments are recommended to be administered at the beginning of the visit prior to 
collection of blood for analysis and other scheduled assessments.  Questionnaires will be 
administered on paper except the willingness to switch survey, which will be a verbal 
question.  
The following health outcomes assessments will be utilized in this study:


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
To assess the reason(s) for their participation and facilitate an understanding of 
participant’s willingness to switch, participants will be asked a single item question 
prior to randomization.

The HIV treatment satisfaction questionnaire (HIV TSQ) (status version) [Woodcock, 
2001; Woodcock, 2006] is a 10-item self-reported scale that measures overall 
satisfaction with treatment and by specific domains e.g., convenience, flexibility.

The Symptom Distress Module (also called the HIV Symptom Index or Symptoms 
Impact Questionnaire) is a 20-item self-reported measure that addresses the presence 
and perceived distress linked to symptoms commonly associated with HIV or its 
treatment [Justice, 2001]. 
8.10.
HIV-1 Polymerase Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each participant to provide plasma 
for storage samples according to the Schedule of Activities (for potential viral genotypic 
and phenotypic analyses).  Participants meeting CVW criteria will have plasma samples
tested for HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype 
and phenotype from samples collected at the time of meeting SVW criteria; these results 
will be reported to the investigator as soon as available to provide guidance for election 
of an alternative regimen
Details concerning the handling, labelling and shipping of these samples will be supplied 
separately.  Genotypic and phenotypic analyses may be carried out by Monogram 
Biosciences using, but not limited to, their Standard PhenoSense and GenoSure testing 
methods for PRO, RT, and integrase assays.
A secondary endpoint of the study will be the incidence of observed genotypic and 
phenotypic resistance to DTG or 3TC and to CAR for participants meeting Virologic 
Withdrawal criteria. The virologic endpoint may also be assessed based on third-agent 
class.
8.10.1.
HIV-1 Exploratory Analysis
HIV-1 exploratory analysis may be carried out for participants meeting virologic failure 
criteria, and for all participants to more broadly assess the contribution of Baseline 
genotypic information on study results.  These tests may be carried out on whole blood 
or stored plasma samples collected at Baseline and/or on stored plasma samples from 
other relevant time points as long as this is feasible per local country and laboratory 
practices.  These exploratory tests and analyses may include but are not limited to 
additional viral genotyping and/or phenotyping, as well as other virologic evaluations 
such as linkage and minority species analyses, low level HIV-1 RNA quantitation, viral 
DNA quantitation and measurement of viral replicative capacity.  HIV-1 PRO and RT 
genotype and phenotype and HIV-1 integrase genotype and phenotype will also be 
determined on the last on-treatment isolates from participants who have HIV-1 RNA 
400 c/mL regardless of confirmatory HIV-1 RNA.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
This study is designed to show that the antiviral effect of switching to a simplified two-
drug regimen of DTG/3TC FDC once-daily is not inferior to continuation of their CAR at 
week 48 in ART-experienced participants living with HIV-1.
Non-inferiority will be concluded if the upper bound of a two-sided 95% confidence 
interval for the difference in virologic failure rates between the two treatment arms is 
smaller than 5%. If rd is the virologic failure rate on DTG/3TC FDC and rf is the virologic 
failure rate on the CAR regimen, then the hypotheses can be written as follows:
H0:  rd – rf ≥5%                   H1: rd – rf <5%
9.2.
Sample Size Determination
9.2.1.
Sample Size Assumptions
The original sample size calculation required approximately 300 participants per arm
(from a target of 857 screened participants) based on a true virologic failure rate of 2.25% 
per arm, a non-inferiority margin of 4%, and a 2.5% one-sided significance level to 
provide approximately 91% power to show non-inferiority for the proportion of 
participants with virologic failure (per FDA’s snapshot algorithm for assessing HIV-1 
RNA 50 c/mL) at Week 48.  
The COVID-19 pandemic of 2019/2020 occurred during screening, and enrolment. 
Because of the COVID-19 pandemic, there is potential impact on participant compliance
with study visits, study drug adherence, and data quality, and then consequently the 
virologic failure rate could be higher than originally expected. With the increase of 
assumed true virologic failure rate, we propose to change non-inferiority margin from 4% 
to 5%. Assuming a virologic failure rate of 3%, a non-inferiority margin of 5%, and a 
2.5% one-sided significance level, a sample size of 245 participants per arm would 
provide approximately 90% power to show non-inferiority for the proportion of 
participants with virologic failure (per FDA’s snapshot algorithm for assessing HIV-1 
RNA 50 c/mL) at Week 48. Based on the sample size recalculation and both statistical 
and practical considerations due to COVID-19 pandemic, a decision was made to 
terminate the study enrolment. At the time of enrolment termination, approximately 445 
participants were randomized and 53 were in screening. Assuming a 20% screen failure 
rate the final number of participants is expected to be approximately 490 (245 per arm). 
Rationale for non-inferiority margin
According to the FDA’s 2015 guidance document (Human Immunodeficiency Virus-1 
Infection: Development of ART Drugs for Treatment, November 2015), the margin for 
switch trials is driven by the largest clinically tolerable virologic failure rate and could be 
from 4% to 6% depending on virologic failure rate. Per the FDA document, typical rates 
of virologic failure seen in switch studies range from 1 to 3 percent and a margin of 4% 


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for virologic failure rate was originally considered tolerable [CDER, 2015]. However due 
to the COVID-19 pandemic, the virologic failure rate could be higher than originally 
expected and hence the increase in the margin to 5%.
9.2.1.1.
Response and virologic failure rate assumptions
Table 2 shows Snapshot response (HIV-1 RNA<50 c/mL) rates and Snapshot virologic 
failure (HIV-1 RNA ≥50 c/mL) rates in previous switch studies in ART-experienced 
participants living with HIV-1. Taken together and without considering the impact of the 
COVID-19 pandemic, these data suggest that a reasonable assumption for the true failure 
rate for the current ART control arm and the switch arm is 2.25%. Taking into 
consideration of the impact of COVID-19, we assume a virologic failure rate of 3% in 
both the CAR control arm and the switch arm.


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Table 2
Snapshot Response and virologic failure rates in previous switch 
studies
Week 48
Study
Treatment Arm
HIV-1 RNA <50
c/mL
Virologic Failure
(HIV-1 RNA 50 
c/mL)
SPIRITa,b
RPV/FTC/TDF
89%
8/317 (2.5%)
STRATEGY-PIc
QUAD
94%
2/290 (<1%)
PI + FTC/TDF
87%
2/139 (1%)
STRATEGY-NNRTId
QUAD
93%
3/290 (1%)
NNRTI + FTC/TDF
88%
1/143 (<1%)
SALTe
ATV/r+3TC
77%
Not availablef
ATV/r+2NRTIs
76%
Not availablef
OLEg
LPV/r+3TC
88%
Not availableh
LPV/r+TDF/FTC or ABC/3TC
87%
Not availableh
GS-292-0109i
E/C/F/TAF
97%
10/959 (1%)
TDF-based regimenj
93%
6/477 (1%)
GS-US-311-1089k
TAF containing regimen
94%
1/333 (<1%)
TDF regimen
93%
5/330 (2%)
SWORD1 & 2l(Overall)
DTG + RPV
95%
3/513(<1%)
CAR
95%
6/511(1%)
SWORD1 & 2l  (Female)
DTG + RPV
93%
1/120 (<1%)
CAR
91%
3/108 (2.8%)
STRIIVINGm
Early Switch DTG + ABC/3TC STR
80%
1/275 (<1%)
Late Switch DTG + ABC/3TC STR
91%
3/244 (1%)
GS-US-380-1844n
BIC/TFC/TAF 
94%
3/282(1.1%)
ABC/DTG/3TC
95%
1/282(<1%)
GS-US-380-1878o
BIC/F/TAF 
92%
5/290(1.7%)
Current Regimen (Boosted ATV or 
DRV plus FTC/TDF or ABC/3TC)
89%
5/287(1.7%)
TANGOp
DTG/3TC
93%
1/369 (<1%)
TAF-based regimen (TBR)
93%
2/372 (<1%)
Week 24
STRIIVINGm
DTG + ABC/3TC STR
85%
3/275 (1%)
Current ART 
88%
4/278 (1%)
BRAAVE2020q
BIC/F/TAF QD
96%
2/328 (<1%)
Stay on baseline regimen (SBR)
95%
3/165 (2%)
E/C/F/TAF - elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide
a.
[Palella, 2014]
b.
Participants in the PI/r +2 NRTIs arm were switched to RPV/FTC/TDF at Week 24; therefore Week 48 response 
data are not available for this treatment group.
c.
[Arribas, 2014]
d.
[Pozniak, 2014]
e.
[Perez-Molina, 2015]
f.
The percentage of snapshot virologic failure is not available; however, 4% in the 2-drug arm and 3% in the cART 
arm had protocol defined virologic failure (PDVF). 
g.
[Arribas, 2015]
h.
The percentage of snapshot virologic failure is not available; however, 2% per arm had PDVF.
i.
[Mills, 2016]
j.
Elvitegravir (EVG)/Cobistat/TDF/FTC, EFV/TDF/FTC, ATV/Cobistat/TDF/FTC, or RTV/ATV/TDF/FTC 
k.
[Gallant, 2016]
l.
[Llibre, 2017]


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m.
[Trottier, 2015]
n.
[Molina, 2018]
o.
[Daar, 2018]
p.
[van Wyk, 2020]
q.
[Hagins, 2020]


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9.2.2.
Sample Size Sensitivity
Figure 3 shows sensitivity of the required sample size to the true response rate for the 
DTG/3TC FDC arm assuming a 3% failure rate in the current ART non-switch arm and a 
5% margin.  
Figure 3
Sample size sensitivity for the Snapshot Virologic Failure
Power=90%, NI margin=5%, control arm failure rate=3%
N=245 per arm, NI margin=5%, 
control arm failure rate=3%
9.2.3.
Sample Size Re-estimation or Adjustment
No further sample size re-estimation will be performed.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined (the analysis population 
for genotypic and phenotypic analyses will be fully described in the reporting and 
analysis plan [RAP]):
Population
Description
Intent-to-Treat Exposed
This population will consist of all randomized participants who 
receive at least one dose of study medication. Participants will be 
assessed according to their randomized treatment, regardless of the 
treatment they receive. Unless stated otherwise, the ITT-E 
Population will be used for efficacy analyses.


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Population
Description
Per Protocol
This population will consist of participants in the ITT-E Population 
with the exception of protocol deviations which could affect the 
assessment of antiviral activity. The PP population will be used for 
sensitivity analyses of the primary efficacy measure. Further details 
will be described in the RAP.
Safety
The Safety Population is defined as all randomized participants who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the treatment they actually received. Unless 
otherwise stated, the Safety Population will be used for safety 
analyses.
9.4.
Statistical Analyses
Additionally, special statistical and data analysis considerations may be warranted in the 
event that the COVID-19 or related epidemics or natural disasters may affect the study 
and data integrity.  To the extent possible, these will be described in the main study RAP; 
alternatively, a separate RAP focusing on modified data handling rules (eg, changes to 
analysis populations, visit windows and endpoints) and analyses (eg, sensitivity analyses 
to assess impact of and account for missing data) may be prepared, taking in to account 
applicable regulatory guidance and industry best practices for handling such situations 
[FDA, 2020; EMA, 2020a; EMA, 2020b].
9.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
For the primary comparison, adjusted estimates of the difference in the
virologic failure rate between the two arms will be presented along with CIs 
based on a stratified analysis using Cochran-Mantel-Haenszel (CMH) 
weights.  All CIs will be two-sided. For the statistical analysis, three strata 
(subgroups) will be formed according to the combinations of levels of the 
following categorical variables:

Baseline third agent: PI

Baseline third agent: INI

Baseline third agent: NNRTI
The CMH estimate of the common difference in rates across strata will be 
calculated as the weighted average of the strata-specific estimates of the 
difference in response rates between the two arms as follows:
If nk is the number of DTG/3TC FDC treated participants, mk is the number 
of INI-, NNTRI-, or PI-based ART treated participants, and Nk = nk + mk is 


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Endpoint
Statistical Analysis Methods
the total number of participants in the kth stratum, then the CMH estimate is 
given by
Where
are CMH weights and 
are estimates of the differences in response rates 
between the two treatment arms, rd – rf, for the kth strata.
The corresponding two-sided 95% CI will be calculated as
using the variance estimator 
given by [Sato, 1989], which is 
consistent in both sparse data and large strata. The full equation for this 
variance estimate is provided in the RAP. Full details will be contained in the 
RAP.
The weighted least squares chi-squared statistic [Fleiss, 1981] will be used 
to test for one-way homogeneity across the levels of each categorical 
variable, with each categorical variable considered separately. Following Lui 
and Kelly [Lui, 2000], ½ will be added to each cell in any strata for which the 
stratum-specific rate estimates of either rd or rf are zero, and tests will be 
one-sided. Any heterogeneity found to be statistically significant will be 
explored and if necessary results will be reported for each level of the 
categorical variable. Investigation of heterogeneity will be confined to the 
primary endpoint using the Week 48 Snapshot analysis. Tests of 
homogeneity will be assessed at the one-sided 10% level of significance.
Further efficacy analyses to assess the sensitivity of the primary endpoint will 
be performed. Details of the sensitivity analyses will be included in the RAP 
and will include the responder endpoint as per FDA snapshot category, ‘time 
to event’ methods which censor participants who discontinue from the study 
with viral load <50 c/mL or for non-efficacy-treatment related reasons. In 
these analyses, participants will be considered to have had an event if they 
have a confirmed viral load ≥50 c/mL or discontinue for efficacy related 
reasons.


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Endpoint
Statistical Analysis Methods
Secondary
Details for secondary efficacy endpoints including the Week 24 interim 
analysis will be discussed in the RAP.
Resistance data will be summarized overall and by baseline third agent 
class.  
The incidence of HIV-1 disease progression (AIDS and death) will be 
presented. The proportion of participants with Snapshot virologic failure will 
be summarized by subgroups (e.g., age, race).
Exploratory
Full details will be described in the RAP
Data gathered after participants withdraw from IP will be listed but will not be included 
in summary tables. Data will be allocated to visit windows using actual visit dates rather 
than nominal visit numbers. Data collected from extra visits within a window will be 
listed and will be included in the derivation of the Snapshot response at analysis visits of 
interest, but summary tables using OC datasets will only use the data captured closest to 
the target visit date. Detailed explanations of the derivation of visit windows will be 
included in the RAP. Any deviations from planned analyses will be detailed in the 
clinical study report.
9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
The observed case dataset will be the primary dataset used for analysis of safety 
endpoints.
Exposure to study medication, measured by the number of weeks on study 
intervention, will be summarized by treatment group.  The proportion of 
participants reporting AEs will be tabulated for each treatment group.  The 
following summaries of AEs will be provided:

Incidence and severity of all AEs

Incidence and severity of treatment related AEs

Incidence and severity of AEs leading to withdrawal

Incidence of SAEs
The incidence and severity of treatment related AEs, SAEs and AEs leading to 
withdrawal will also be assessed by baseline third agent class and in those with 
creatinine clearance of between 30-49 mL/min/1.73m2 compared to those with a 
creatinine clearance of 50 mL/min/1.73m2.


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Further details will be detailed in the RAP.
Laboratory and vital signs data will be summarized by visit and treatment group. 
In addition, the number and percentage of participants with graded laboratory 
toxicities (based on DAIDS categories) will be summarized by treatment group. 
The proportion of participants experiencing changes from Baseline in their 
National Cholesterol Education Program (NCEP) lipid categories will be 
summarized by treatment arm. 
Further details of safety analyses will be described in the RAP.
Exploratory
Full details will be described in the RAP
9.4.3.
Other Analyses
Details of the analyses of Willingness to Switch and change from Baseline in HIV TSQ 
and SDM will be specified in the RAP. 
The incidence of observed genotypic and phenotypic resistance to DTG, 3TC and other 
on-study ART will be summarized by treatment arm for participants meeting confirmed 
virologic withdrawal criteria. Details of the analyses to be performed will be specified in 
the RAP.
9.5.
Interim Analyses
One analysis will be conducted to evaluate the primary objective of the protocol when all 
participants have completed their Week 48 visit.  An interim analysis will be conducted 
when all participants have completed their Week 24 visit.  To minimise bias, the Week 
24 results will not be shared with participants and investigators, or presented externally 
until after the last participant completes their last visit for the primary Week 48 analysis. 
Further data cuts and analyses may be conducted as necessary to support regulatory 
submissions and publications. The Week 48 analysis will be primary. No adjustment for 
multiplicity caused by repeated evaluation of the primary endpoint will be made as the 
Week 24 analyses will be secondary. 
9.5.1.
Independent Data Monitoring Committee (IDMC)
An IDMC will be instituted to ensure external objective medical and/or statistical review 
of efficacy in order to protect the ethical interests and well-being of participants and to 
protect the scientific validity of the study.  An ad-hoc review of data by the IDMC will be 
triggered whenever the number of participants meeting CVW criteria in the DTG/3TC 
FDC arm exceeds thresholds pre-specified in the IDMC charter, to ensure that 
participants are not being sub-optimally treated.  Full details of the methods, timing, 
decision criteria and operating characteristics will be pre-specified in the IDMC Charter.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.


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9.5.2.
Analysis Datasets
The primary analysis set of data is based on virologic failure defined by the FDA 
snapshot algorithm. With the exception below, virologic failure includes participants who 
changed any component of background therapy to a new drug class, changed background 
components that were not permitted per protocol, or changed any background drug in the 
regimen because of lack of efficacy (perceived or documented) before Week 48; 
participants who discontinued study intervention or study before Week 48 for lack or loss 
of efficacy and participants who are equal to or above 50 c/mL in the 48-week window.
A secondary analysis set of data is based on participants’ responses at <50 c/mL 
calculated according to the FDA’s snapshot algorithm. This algorithm treats all 
participants without HIV-1 RNA data at the visit of interest (due to missing data or 
discontinuation of IP prior to visit window) as non-responders, as well as participants 
who switch their concomitant ART prior to the visit of interest, since no switches (with 
the exception below) are allowed in the protocol. 
Note: A switch from a PI boosted with ritonavir to the same PI boosted with cobicistat 
(and vice versa) is permitted per protocol and a switch from lamivudine to emtricitabine 
and vice versa is also permitted and will not be considered as a change in background 
ART hence, will not incur a penalty in the Snapshot algorithm, regardless of reason or 
date of switch, as these agents are expected to have similar boosting effect and no impact 
on overall efficacy of the regimen.
Otherwise, virologic success or failure will be determined by the last available HIV-1 
RNA assessment while the participant is on-treatment within the visit of interest window 
(to be specified in the RAP).  Full details of this snapshot algorithm will be contained in 
the RAP. 
Another secondary set of data will treat participants as censored if they discontinue for 
reasons other than those related to treatment (AEs, tolerability and lack of efficacy). This 
data set will be the Treatment Related Discontinuation = Failure data set.
The observed case (OC) dataset, which uses only data that are available at a particular 
time point with no imputation for missing values, will be the primary dataset for 
assessing safety and will also be used for some analyses of efficacy and health outcomes.
Further details will be provided in the RAP.
9.5.3.
Treatment Comparisons
9.5.3.1.
Primary Comparison of Interest
The primary analysis will be based on the ITT-E population using the Snapshot virologic 
failure dataset.  The primary comparison will be made at a one-sided 2.5% level of 
significance.  Treatment with DTG/3TC FDC will be declared non-inferior to the CAR if 
the upper bound of a two-sided 95% confidence interval for the difference between the 
two groups in virologic failure rates at Week 48 lies below 5%.


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9.5.3.2.
Other Comparisons of Interest
The analysis described above will also be performed using the PP population and the 
results will be compared for consistency with the results from the ITT-E population. If 
both analyses show non-inferiority, then the hypothesis that the antiviral effect of 
treatment with DTG/3TC FDC is superior to the CAR treatment will be tested using the 
same level of significance as for the tests of non-inferiority. Superiority will be declared 
if the upper bound of the confidence internal is below 0%. 
The following key secondary comparison will be tested:

Non-inferiority of switching to DTG/3TC FDC compared to continuation of CAR 
with respect to virologic success endpoint as per FDA snapshot category using a 
-12% non-inferiority margin.
No multiplicity adjustments for statistical testing of secondary endpoints will be 
performed; however, all tests will be pre-specified in the RAP.


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Through Week 48 in a Pilot Randomized Trial.  Clin Infect Dis. 2018 May 
17;66(11):1794-1797.
Trottier B, Lake J, Logue K, et. al.  Switching to Abacavir/Dolutegravir/Lamivudine
Fixed Dose Combination (ABC/DTG/3TC FDC) from a PI, INI or NNRTI Based 
Regimen Maintains HIV Suppression. ICAAC/ICC 2015, San Diego, CA, USA, Sep 17-
21, 2015.  2015-LB-3271-ASM-ICAAC.
U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for Industry: Human 
Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. 
November 2015 Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm355128.pdf.  Accessed February 8, 2017.
U.S. Department of Health and Human Services. Food and Drug Administration (FDA). FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic -
Guidance for Industry, Investigators, and Institutional Review Boards. March 2020. 
Available at: https://www.fda.gov/media/136238/download. Accessed April 6, 2020.
van Wyk J, Ajana F, Bisshop F, De Wit S, et. al. Efficacy and Safety of Switching to 
Dolutegravir/Lamivudine Fixed-Dose Two-Drug Regimen Versus Continuing a 
Tenofovir Alafenamide-Based Three- or Four-Drug Regimen for Maintenance of 
Virologic Suppression in Adults With HIV-1: Phase 3, Randomized, Non-inferiority 
TANGO Study. Clin Infect Dis. 2020 Jan 6. pii: ciz1243. doi: 10.1093/cid/ciz1243


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Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir Plus Abacavir/Lamivudine 
for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 
and Week 144 Results from the SINGLE Randomized Clinical Trial. J Acquir Immune 
Defic Syndr. 2015;70:515–519.
Walmsley SL, Antela A, Clumeck N, et. al.  Dolutegravir plus abacavir-lamivudine for 
the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807-18.
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Resistance Mutations Update. 2017; 24(4):132-41.  December 2016/January 2017.
Woodcock A, Bradley C . Validation of the HIV treatment satisfaction questionnaire 
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Questionnaire status version and new change version. Value Health. 2006;9(5):320-333.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
11.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B Core Antibody
ARV
Antiretroviral
ART
Antiretroviral therapy
ATV
Atazanavir
ATV/r
Atazanavir/ritonavir
AST
Aspartate aminotransferase
AUC
Area under the curve
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
c/mL
Copies/milliliter
CAR
Current ART regimen
cART
Combination ART 
CDC
Centers for Disease Control and Prevention
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum concentration
CMH
Cochran-Mantel Haenszel
CRF
Case Report Form
CI
Confidence interval
ConART
Concomitant ART therapy
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CV
Cardiovascular
CVW
Confirmed Virologic Withdrawal
DAIDS
Division of Acquired Immunodeficiency Syndrome
DDI
Drug-Drug Interaction
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DTG
Dolutegravir, TIVICAY
E/C/F/TAF
Elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide
ECG
Electrocardiogram
eCRF
Electronic case report form
eC-SSRS
Electronic Columbia Suicidality Severity Rating Scale
EFV
Efavirenz


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eGFR
Estimated glomerular filtration rate
EVG
Elvitegravir
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FTC
Emtricitabine
GCP
Good Clinical Practice
GCSP
GSK’s Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
GFR
Glomerular Filtration rate
HAART
Highly active ART therapy
HbA1c
Glycated hemoglobin
HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HDL
High density lipoprotein
HDPE
High density polyethylene
HIV
Human immunodeficiency virus
HIV TSQ
HIV treatment satisfaction questionnaire
HLA
Human leukocyte antigen
HOMA-IR
Homeostasis model of assessment – insulin resistance
HSR
Hypersensitivity reaction
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IDMC
Independent data monitoring committee
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL
Interleukin
INI
Integrase inhibitor
INSTI
Integrase strand transfer inhibitor
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT-E
Intent-to-treat exposed
IUD
Intrauterine device
IVRS/IWRS
Interactive Voice/Web Recognition System
LDL 
Low density lipoprotein
LPV
Lopinavir
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
Mg
Milligram
Mg/dL
Milligram per deciliter
m-ITT
Modified Intent to Treat


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MRHD
maximum recommended human dose
MSDS
Material Safety Data Sheet
NADES
Non-Acquired Immuno-Deficiency Syndrome (AIDS)-Defining 
Events
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed Case
OCT-2
Organic cation transporter
PBMC
Peripheral Blood Mononuclear Cell
PDVF
Protocol defined virologic failure
PI
Protease inhibitor
PK
Pharmacokinetic
PP
Per-protocol
PPD
Pharmaceutical Product Development
PSRAE
Possible suicidality-related adverse event
PVW
Precautionary virologic withdrawal
QTc
Corrected QT interval 
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RBP
Retinol Binding Protein
RNA
Ribonucleic acid
RPR
Rapid plasma reagin
RPV
Rilpivirine, Edurant
RT
Reverse transcriptase
RTV
Ritonavir
SAE
Serious adverse event
SDM
Symptom Distress Module
SJS
Stevens-Johnson syndrome
SRM
Study Reference Manual
STR
Single tablet regimen
SVW
Suspected Virologic Withdrawal
TAF
Tenofovir alafenamide 
TDF/FTC
Tenofovir disoproxil fumarate/Emtricitabine, Truvada
TEN
Toxic epidermal necrolysis
TLOVR
Time To Loss Of Virologic Response
TSQ
Treatment Satisfaction Questionnaire
TRDF
Treatment Related Discontinuation = Failure
ULN
Upper limit of normal
VSLC
ViiV Safety and Labelling Committee
WBC
White blood cell
WOCBP
Women of childbearing potential
ZDV/3TC
Zidovudine/lamivudine, COMBIVIR


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Trademark Information
Trademarks of the ViiV Healthcare group 
of companies
Trademarks not owned by the ViiV 
Healthcare group of companies
COMBIVIR
Abbot Realtime HIV-1
EPIVIR
Edurant
EPZICOM/ KIVEXA
GenoSure
TIVICAY
Genvoya
TRIUMEQ
HIV TSQ
ZIAGEN
Monogram Biosciences
PhenoSense
SAS
SDM
Truvada


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11.2.
Appendix 2: A Sub-study of Virologic Response to 
Subsequent ART after Discontinuation from 208090 for 
Meeting CVW or PVW Criteria
11.2.1.
Rationale for CVW and PVW Sub-study
This sub-study will evaluate and determine the virologic response to subsequent regimens 
of participants who have virologic failure to DTG/3TC FDC. The evaluation period will 
start from the time the participant is discontinued from the 208090 study for confirmed 
virologic withdrawal (CVW) or precautionary virologic withdrawal (PVW) criteria while 
on DTG/3TC FDC, and will last for up to 12 months. The results of this study may 
provide information that will help guide treatment decisions for people living with HIV
who virologically fail a DTG/3TC FDC regimen.
11.2.2.
Sub-study Objectives and Endpoints
Objectives
Endpoints
Exploratory
To determine the drug regimens that are used 
after CVW or PVW with DTG/3TC FDC.
Incidence of drug regimens used as subsequent 
regimens after CVW or PVW with DTG/3TC
FDC.
To determine the proportion of participants with 
CVW or PVW with DTG/3TC FDC who achieve 
virologic suppression with the subsequent 
regimen at the end of 12 months of follow up.

Proportion with plasma HIV-1 RNA <50 
copies/mL, 50-200 copies and >200 
copies/mL through 12 months

Proportion with plasma HIV-1 RNA <50 
copies/mL after switching to subsequent 
regimens
To describe the reasons for discontinuation 
of/switching from subsequent treatment regimen
and reason for virologic failure
Describe reasons for switching from subsequent
regimen and reasons for virologic failure
11.2.3.
Sub-study Design
This is a prospective observational study that will enroll participants in 208090 who 
withdraw from the study for meeting CVW or PVW criteria. All participants who 
withdraw from the 208090 study for meeting CVW or PVW criteria while on DTG/3TC 
FDC and consent to participate will be followed for up to 12 months after withdrawal. 
The medical charts of participants who consent will be abstracted at baseline (time of 
withdrawal), 3, 6 and up to 12 months after withdrawal from the 208090 study. For 
participants who attend a separate clinic for HIV care after withdrawal from the 208090 
study, the PI or designated site staff will be required to contact the clinic physician to 
collect the required information. The following information will be obtained:


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
ART drug regimen(s) that participants started after withdrawal from the main 
study due to meeting CVW or PVW criteria

Plasma HIV-1 RNA levels after regimen switch and up to 12 months after CVW 
or PVW date

Reasons for virologic failure when the subsequent treatment regimen is changed
nonadherence, tolerability, adverse event, etc.

Reasons for switching when the subsequent treatment regimen is changed -
virologic failure, tolerability, safety, adherence, convenience, etc.

Adverse Events, SAEs or Death leading to ARV discontinuation

Adverse Drug Reactions, SAEs or Death related to ViiV Healthcare products

Pregnancy while on ViiV Healthcare products

Concomitant Medications
Schedule of Activities
Procedures
Baseline (after 
regimen switch 
upon withdrawal 
from 208090 main 
study)
3 months
6 months
12 
months
Written Informed Consent
X
Current ART regimen
X
X
X
X
Plasma HIV-1 RNA (if available)
X
X
X
X
Reasons for Virologic Failure
X
X
X
Reasons for Switch (if subsequent 
regimen is changed)
X
X
X
Adverse Events, SAEs, or Death
leading to ARV discontinuation
X
X
X
X
Adverse Drug Reactions, SAEs, or 
Death related to ViiV Healthcare 
products
X
X
X
X
Pregnancy while on ViiV Healthcare 
productsa
X
X
X
X
Concomitant Medications
X
X
X
X
a.
Investigator must collect pregnancy information on the appropriate form and submit to ViiV/GSK/PPD


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Since this sub-study is an observational study of participants who have withdrawn from 
the main study, the protocol-specified withdrawal and stopping criteria are not applicable.
11.2.4.
Sub-study data Collection
For this study, participant data will be entered into eCRFs, transmitted electronically to 
GSK or designee and supplemented with demographic and clinical data provided from 
the 208090 study in a validated data system.
Management of clinical data will be performed in accordance with applicable PPD 
standards and data cleaning procedures to ensure the integrity of the data, e.g. removing 
errors and inconsistencies in the data.
Adverse events, SAEs and concomitant medications terms will be coded using MedDRA 
and an internal validated medication dictionary, GSKDrug.
eCRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent at the end of the study in CD format to GSK to be retained. Each investigator will 
receive a copy of his or her site-specific data in the same format to maintain as the 
investigator copy. Participant initials will not be collected or transmitted to ViiV 
Healthcare/GSK according to ViiV Healthcare/GSK policy.
11.2.5.
Statistical Considerations and Data Analysis
This is a descriptive study. No formal hypothesis will be tested. Where possible, 
frequency tables will be provided.
The endpoint assessing the proportion of participants with plasma HIV-1 RNA <50 
copies/mL, 50-200 copies and >200 copies/mL at the end of 12 months will be based on 
an observed case analysis for this descriptive study. 
Further details will be provided in the RAP.


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11.3.
Appendix 3: Toxicity Management
Adverse events that occur during the trial should be evaluated by the investigator and 
graded according to the DAIDS toxicity scales (see Section 11.11).  Additional 
information regarding detecting, documenting and reporting AEs and SAEs are available 
in Section 11.8.
Study intervention may be interrupted at the discretion of the investigator and according 
to the severity of the AE. If one or more ART medication is held due to toxicity or AEs, 
all ART medications should be held to reduce the risk of development of resistance 
taking into account the length of the planned interruptions and the PK half-life of each 
ART of the regimen, in order to minimize the risk of development of resistance.
No toxicity-related dose reductions of study interventions will be allowed.  Study 
interventions should be restarted as soon as medically appropriate; in general, this should 
be no longer than 4 weeks after interruption (unless Grade 3 or 4 toxicities persist).  
Decisions regarding sequential reintroduction of study interventions or temporary 
interruption of one but not all drugs within the ART regimen should be made with the 
understanding that these changes may result in incomplete viral suppression and selection 
of resistant virus.  Guidance is provided below on participant management and study 
intervention interruptions based on the severity of the AE for specific toxicities.  All 
changes in study intervention must be accurately recorded in the participant’s eCRF.
Grade 1 or Grade 2 Toxicity/Adverse Event
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue study 
intervention at the discretion of the investigator.  Participants who choose to withdraw 
from the study due to a Grade 1 or 2 AE should have study withdrawal and follow-up 
evaluations completed.
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 study intervention, dosing may continue after discussion with the medical 
monitor.
Participants who develop a Grade 3 AE or toxicity that the investigator considers related 
or possibly related to the interventions should have study intervention withheld and be 
rechecked each week until the AE returns to Grade 2.  Once the AE is Grade ≤2, study 
intervention may be restarted. 
Should the same Grade 3 AE recur within 28 days in the same participant, study 
intervention should be permanently discontinued and the participant withdrawn from 
study.  Participants experiencing Grade 3 AEs requiring permanent discontinuation of 
study intervention should be followed weekly until resolution of the AE and have 
withdrawal study evaluations completed.  A Follow-up visit should be performed 
4 weeks after the last dose of study interventions.


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Participants with asymptomatic Grade 3 laboratory abnormalities should be investigated 
for all potential non-drug related causes, and, following discussion with the medical 
monitor, may continue study intervention if the investigator has compelling evidence that 
the toxicity is not related to study intervention.
Exceptions are noted for lipid abnormalities in Section 11.3.1.7 and rash in Section 
11.3.1.6.
Grade 4 Toxicity/Adverse Event
Participants who develop a Grade 4 AE or toxicity should have study intervention 
discontinued.  However, if the investigator has compelling evidence that the AE is not 
causally related to the study interventions, 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 study 
intervention should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal and follow-up study evaluations as noted above.
Participants with asymptomatic Grade 4 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 study intervention.  Exceptions are noted for lipid abnormalities 
in Section 11.3.1.7.  An in-clinic Follow-Up visit will be conducted approximately 
4 weeks after the last dose of study medication for participants with ongoing AEs, serious 
adverse events (SAEs) regardless of attributability, and any laboratory abnormalities that 
are considered to be AEs or potentially harmful to the participant, at the last on-study 
visit.
11.3.1.
Specific Toxicities/Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be 
related or possibly related to study intervention are provided below.
Participants who permanently discontinue study intervention for reasons of toxicity 
should be followed weekly until resolution of the AE and encouraged to complete the 
withdrawal and Follow-up study evaluations (see Section 7.2).
11.3.1.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure participant 
safety and to evaluate liver event aetiology during administration of study intervention 
and the follow-up period. For a complete listing of stopping and follow-up criteria refer 
to Section 11.9.1.


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11.3.1.2.
Restarting Study Intervention
Refer to Section 11.9.2 for details on drug restart following transient resolving liver 
events not related to study intervention.
11.3.1.3.
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, urine albumin/creatinine and 
urine total protein/creatinine ratios, serum cystatin C and an estimated GFR using the 
CKD-EPI (cystatin C) [Inker, 2012] 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 experience progression to an estimated GFR (using the CKD-EPI-
creatinine) of <30 mL/min/1.73m2 must return for a confirmatory assessment within 
2 weeks [Levey, 2009].  A urinalysis, urine albumin/creatinine and urine 
protein/creatinine ratios, serum cystatin C and an estimated GFR using the CKD-EPI 
(cystatin C) [Inker, 2012] should be done at this confirmatory visit.  If an estimated GFR 
of <30 mL/min/1.73m2 is confirmed using the CKD-EPI (cystatin C), then study 
intervention should be discontinued and the participant withdrawn from the study (as 
dose adjustment is needed for NRTIs, which is not possible in a study of a fixed-dose 
combination tablet).
11.3.1.4.
Proteinuria
Participants with an abnormal urine albumin/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 albumin/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.
11.3.1.5.
Allergic reaction
Participants may continue study intervention 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. 


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Participants with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the study intervention should permanently discontinue study 
intervention and the participant should be withdrawn from the study.  Participants should 
be treated as clinically appropriate and followed until resolution of the AE.
11.3.1.6.
Rash
Mild to moderate rash is an expected adverse reaction for DTG-containing ART.  
Episodes generally occur within the first ten weeks of treatment, rarely require 
interruptions or discontinuations of therapy and tend to resolve within two to three weeks.  
No instances of serious skin reaction, including SJS, TEN and erythema multiforme, have 
been reported for DTG in clinical trials.  For further characterisation of HSR and rash 
observed with DTG-containing ART, please see the current version of the IB and any IB 
supplements [GlaxoSmithKline Document Number RM2007/00683/11, GlaxoSmithKline 
Document Number 2017N352880_00, GlaxoSmithKline Document Number
2017N352880_01].
Participants with an isolated Grade 1 rash may continue study intervention 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 intervention for an isolated Grade 2 rash.  However, 
study intervention (and all other concurrent medication(s) suspected in the Investigators 
causality assessment) should be permanently discontinued for any Grade ≥2 rash that is 
associated with an increase in ALT.  The participant should be advised to contact the 
physician immediately if rash fails to resolve (after more than two weeks), if there is any 
worsening of the rash, if any systemic signs or allergic symptoms develop, or if mucosal 
involvement develops.
Participants should permanently discontinue study intervention [and all other concurrent 
medication(s) suspected in the Investigators causality assessment] for an isolated Grade 3 
or 4 rash, except where the aetiology of the rash has been definitively diagnosed as NOT 
attributable to study intervention (see below), and the participant should be withdrawn 
from the study.  Participants should be treated as clinically appropriate and followed until 
resolution of the AE.  Every effort should be made to collect as much information as 
possible about the evolution of the event and any relationship with potentially related 
medical events (e.g., viral infection) or start of concomitant medication.
The rash and any associated symptoms should be reported as adverse events and 
appropriate toxicity ratings should be used to grade the events (based on DAIDS toxicity 
gradings, Section 11.10.
However, if the aetiology of the rash has been definitively diagnosed as being unrelated 
to study intervention and due to a specific medical event or a concomitant infection or a 
concomitant non-study medication, routine management should be performed and 


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documentation of the diagnosis provided. In this situation, the study intervention should 
be continued. 
11.3.1.7.
Hypertriglyceridemia/Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the 
Schedule of Activities (Section 1.3).  Participants who experience asymptomatic 
triglyceride or cholesterol elevations may continue to receive study intervention.
REFERENCE:
Inker LA, Schmid CH, Tighiouart H, et al; Estimating Glomerular Filtration Rate from
Serum Creatinine and Cystatin C. N Engl J Med. 2012;367:20-9.
Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular 
filtration rate.  Ann Int Med. 2009;150:604-12.


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11.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
11.4.1.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
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.
3.
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.
11.4.2.
Contraception Guidance
Female participants
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 3.
The list does not apply to FRP with same sex partners or for participants who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 


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basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
Table 3
List of Highly Effective Contraceptive Methods
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when 
used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner

Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.
Highly Effective Methodsb That Are User Dependent 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

injectable

Progestogen-only hormone contraception associated with inhibition of ovulation
oral

injectable

Sexual abstinence

Note: 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 intervention. 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
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.


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Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction)
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that participants understand how to properly use these methods of contraception.
11.4.3.
Collection of Pregnancy Information
Female Participants who become pregnant

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 
ViiV/GSK/PPD within 2 weeks of learning of a participant's pregnancy. 

Participants will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to ViiV/GSK/PPD. Generally, follow-up will not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date.  GSK’s central safety 
department will forward this information to the Antiretroviral Pregnancy Registry.  
The international registry is jointly sponsored by manufacturers and licensees of 
antiretroviral products.  Additional information and a list of participating 
manufacturers/licensees are available from http://www.apregistry.com/.  

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. 

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and must be reported.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
ViiV/GSK/PPD as described in Appendix 8. While the investigator is not obligated 
to actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn 
from the study.


2 0 1 7 N 3 3 1 0 0 8 _ 0 6
C O N FI D E N TI A L
2 0 8 0 9 0
1 0 1
1 1. 5.
A p p e n di x 5 :  C hil d-P u g h Cl a s sifi c ati o n
A partici pa nt is classifie d wit h mil d he patic i m pair me nt ( Class
) if t heir o verall s u m of 
sc ores is 
 p oi nts, m o derate he patic i m pair me nt ( Class
) if t heir o verall s u m of sc ores 
is 
 p oi nts, a n d se vere he patic i m pair me nt ( Class
) if t heir o verall s u m of sc ores is 
 base d o n t he C hil d-P u g h s ys te m [P u g h , 1 9 7 3] sc ori n g descri be d i n t he f oll o wi n g 
ta ble (Ta ble 4 ).  F or partici pa nts re q uiri n g a ntic oa g ulati o n t hera p y, disc ussi o n wit h t he 
st u d y me dical m o nit or will be re q uire d.
T a bl e 4
C hil d -P u g h S y st e m
Fi n di n g 
P oi nt s S c or e d f or E a c h O b s er v e d Fi n di n g 
[P u g h , 1 9 7 3; L uc ey , 1 9 9 7]
R ef er e n c e s
L uce y  M R, Br o w n K A, E vers o n G T, et al. Mi ni mal criteria f or place me nt of a d ults o n 
t he li ver tra ns pla nt waiti n g list: a re p ort of a nati o nal c o nfere nce or ga nize d b y t he 
A merica n S ociet y of Tra ns pla nt P h y sicia ns a n d t he A merica n Ass ociati o n f or t he St u d y 
of L i ver Diseases. Liver Tr a ns pl S ur g . 1 9 9 7; 3: 6 2 8- 3 7.
P u g h R N H, M urra y -L y o n I M, Da ws o n J L,  Pietr o ni M C, Willia ms R. Tra nsecti o n of t he 
oes o p ha g us f or blee di n g oes o p ha geal varices. Br J S ur g
C CI
. 1 9 7 3; 6 0: 6 4 6- 4 9.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI
C CI
C CI
C CI
C CI
C CI


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11.6.
Appendix 6:  Prohibited Medications
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. 

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited (a list of examples is provided in the SRM).  This includes 
topical agents with substantial systemic exposure and systemic effects.  Use of 
topical imiquimod is permitted.   

For participants with an unanticipated requirement for HCV therapy during 
study, interferon or any other medications that have a potential for adverse drug-
drug interactions with study intervention are prohibited during the conduct of the 
study.  

Acetaminophen (paracetamol) cannot be used in participants with acute viral 
hepatitis [James, 2009].
The following medications or their equivalents may cause decreased concentrations of 
DTG. Therefore, the following medications must not be administered concurrently with 
DTG.

Carbamazepine

Oxcarbamazepine

Phenobarbital

Phenytoin

Rifampicin or rifapentine

St. John’s wort (Hypericum perforatum)
Dofetilide, pilsicainide and fampridine are prohibited as DTG may inhibit their renal 
tubular secretion resulting in increased dofetilide, pilsicainide or fampridine 
concentrations and potential for toxicity.
Any substrate of organic cation transporter 2 (OCT2), with a narrow therapeutic window 
should not be administered concurrently with DTG containing products.
Note:  Any prohibited medication should be discontinued for a minimum of two weeks or 
a minimum of three half-lives (whichever is longer) prior to the first dose.  


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For information on concurrent therapies and interactions suspected to be relevant to 
other antiretroviral therapy in the CAR regimen, please consult the local prescribing 
information.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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11.7.
Appendix 7: Clinical Laboratory Tests

The tests detailed in Table 5 will be performed by central laboratory services, 
with the exception of exceptional circumstances during screening noted in 
Section 5. Please refer to Appendix 14 in Section 11.14 for study management 
information during the COVID-19 pandemic.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 5
Protocol Required Safety Laboratory Assessments
Hematology:
Platelet count
Automated WBC differential:
RBC count
Neutrophils
WBC count (absolute)
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
MCV
Basophils
MCH
Clinical Chemistry:
BUN
Potassium
AST
Total bilirubina
Direct bilirubina
Creatinine
Chloride
ALT
Albumin
Glucoseb
Total CO2
Alkaline phosphatase
GFR/Creatinine clearancec
Sodium
Phosphate
Cystatin-C (Day 1 only)
Calcium
Protein
Creatine Phosphokinase 
Fasting Lipid Paneld
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Urinalysis
specific gravity, pH, glucose, protein, blood and ketones by dipstick (with microscopic examination if blood 
or protein is abnormal), urine albumin/creatinine ratio, urine protein/creatinine ratio, urine phosphate
Other Tests
Plasma HIV-1 RNAe
CD4+ and CD8+ lymphocyte counts, CD4+/CD8+ cell count ratio
Hepatitis B (HBsAg, anti-HBc, anti-HBs, HBV DNA)
Hepatitis C (anti-HCV)
PT/INR 
Pregnancy test for women of childbearing potentialf
Renal biomarkers including Cystatin-C (blood), Retinol Binding Protein (RBP, urine); and 
Beta-2-Microglobulin (B2M, urine), urine RBP/creatinine ratio, urine B2M/creatinine ratiog
Bone biomarkers including: Bone-specific alkaline phosphatase, procollagen type 1 N-propeptide, type 1 
collagen cross-linked C-telopeptide, osteocalcin
Inflammation Biomarkers: Interleukin-6 (IL-6), High-sensitivity C reactive protein (hs-CRP), D-dimer, Soluble 
CD14 (sCD14), Soluble CD163 (sCD163)
HbA1c and insulin and glucose for HOMA-IR calculation


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MCV = mean corpuscular volume, MCH = mean corpuscular haemoglobin, RBC = red blood cells, WBC = white blood 
cells, BUN = Blood urea nitrogen, AST=aspartate aminotransferase, ALT = alanine aminotransferase, CO2 = carbon 
dioxide, HDL = high density lipoprotein, LDL = low density lipoprotein, HbsAg= hepatitis B virus surface antigen,
PT/INR = prothrombin time/international normalized ratio, HbA1c = glycated haemoglobin, HOMA-IR = homeostasis 
model of assessment – insulin resistance, IL-6 = interleukin-6, hs-CRP = high-sensitivity C reactive protein, sCD = 
soluble CD.
a)
Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN.
b)
For fasting glucose assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is 
acceptable for participants with afternoon appointments.
c)
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI-creatinine) [Levey, 2009]. In addition, GFR will be estimated by the central 
laboratory using the CKD-EPI-cystatin C [Inker, 2012] at day 1 and when indicated by renal toxicity criteria.
d)
For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable 
for participants with afternoon appointments.
e)
For participants meeting virologic withdrawal criteria, plasma samples will be analyzed in attempt to obtain 
genotype/phenotype data.
f)
Urine pregnancy test/ serum pregnancy test will be performed according to the Schedule of Activities. 
g)
The intention is to utilize these biomarker data for research purposes; the sponsor will not be reporting real-time 
results of these assessments to the investigator, except for Cystatin C (Day 1 only) and HbA1c.
References
Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular 
filtration rate.  Ann Int Med. 2009;150:604-12.


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11.8.
Appendix 8: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
11.8.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention.

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 study intervention.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease).

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 intervention administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses 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. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE. 


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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
11.8.2.
Definition of SAE
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).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
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 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils 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 


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baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
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 events 
should usually be considered serious.
Examples of such events include 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.
11.8.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization


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11.8.4.
Recording AE and SAE
AE 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) 
related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to ViiV/GSK/PPD in lieu of completion of the AE/SAE eCRF 
page.

There may be instances when copies of medical records for certain cases are 
requested by ViiV/GSK/PPD. In this case, all participant identifiers, with the 
exception of the subject number, will be redacted on the copies of the medical 
records before submission to ViiV/GSK/PPD.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the categories in the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE Grading 
Table”) in Section 11.10:

Grade 1/ Mild

Grade 2/ Moderate

Grade 3/ Severe

Grade 4/ Potentially life threatening

Grade 5/ Death
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/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 underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in 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 in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to ViiV/GSK. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to 
ViiV/GSK/PPD.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by ViiV/GSK/PPD to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. 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 ViiV/GSK with a copy of any 
post-mortem findings including histopathology.


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
New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to ViiV/GSK/PPD within 
24 hours of receipt of the information.
11.8.5.
Reporting of SAE and other events to ViiV/GSK/PPD
Reporting of SAEs and other events to ViiV/GSK/PPD

The primary mechanism for reporting SAE to ViiV/GSK/PPD will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and 
verification of the relationship of each SAE to IP/study participation (causality) 
within 72 hours of SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool 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, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM
SAE Reporting to GSK via Paper CRF

If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and scan and email it to the Medical Monitor

Contacts for SAE reporting can be found in the SRM


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11.9.
Appendix 9: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart Guidelines
Study treatment refers to all drugs evaluated in the study and therefore includes ViiV 
study intervention and non-ViiV ART therapies that can be used in combination with 
ViiV products or other ART interventions.
A liver stopping event is an occurrence of predefined liver chemistry changes (ALT, 
bilirubin and or INR) that trigger discontinuation of study treatment and requirement of 
additional actions and follow up assessments to be performed.
A liver monitoring event is as an occurrence of predefined liver chemistry changes (ALT, 
bilirubin and or INR) that triggers increased monitoring of the participant’s liver 
chemistries, but no action is taken with study treatment unless liver chemistry stopping 
criteria are met.
11.9.1.
Liver Chemistry Stopping Criteria:  Required Actions and Follow 
up Assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
If baseline ALT ≤1.5x ULN
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks (with bilirubin <2xULN and no 
signs or symptoms of acute hepatitis or hypersensitivity)
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
Cannot Monitor
ALT 5xULN but <8xULN and cannot be monitored every 1 - 2 weeks
Symptomatic3
ALT 3xULN with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity
If baseline ALT >1.5x ULN
ALT-absolute
ALT ≥5x baseline OR >500 U/L (whichever occurs first)
ALT Increase
ALT ≥3x baseline but <5x baseline persists for ≥2 weeks (with bilirubin 
<2xULN and no signs or symptoms of acute hepatitis or hypersensitivity)
Bilirubin1, 2
ALT ≥3x baseline OR >300 U/L (whichever occurs first) and bilirubin ≥2xULN
Cannot Monitor
ALT ≥3x baseline but <5x baseline and cannot be monitored every 1 - 2 weeks
Symptomatic3
ALT ≥3x baseline and symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity.


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Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study intervention.

Report the event to the Medical Monitor
within 24 hours.

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2.

Complete the liver imaging and/or liver biopsy 
eCRFs if these tests are performed.

Perform liver event follow up assessments. 

Monitor the participant until liver chemistries
resolve, stabilise, or return to within baseline 
(see MONITORING below).

Do not restart participant with study 
intervention unless allowed per protocol and 
VSLC approval is granted (refer to Section
11.9.2).

If restart is not allowed or not granted, 
permanently discontinue study intervention 
and may continue participant in the study for 
any protocol specified follow up assessments.
MONITORING:

Make every reasonable attempt to have 
participants return to clinic within 24 hours for 
repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments. 

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline.

A specialist or hepatology consultation is 
recommended.
Make every attempt to carry out liver event 
follow-up assessments at the central 
laboratory as described below:

Viral hepatitis serology, including:

Hepatitis A immunoglobulin M (IgM) 
antibody;

HBsAg and hepatitis B core 
antibody;

Hepatitis C RNA;

Hepatitis E IgM antibody.

Cytomegalovirus IgM antibody.

Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).

Syphilis screening.

Drugs of abuse screen, including alcohol.

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use 
in the preceding week [James, 2009]).  
The site must contact the Medical Monitor 
when this test is required.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 60 hours of last 
dose4.

Serum CPK and lactate dehydrogenase 
(LDH).

Gamma glutamyl transferase [GGT], 
glutamate dehydrogenase [GLDH], and 
serum albumin

International normalized ratio (INR)

Fractionate bilirubin, if total bilirubin 
1.5xULN.

Obtain complete blood count with 


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differential to assess eosinophilia.

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, fatigue, decreased 
appetite, nausea, vomiting, abdominal 
pain, jaundice, fever, or rash as relevant 
on the AE report form.

Record use of concomitant medications 
on the concomitant medications report 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake eCRF.
CPK - creatine phosphokinase
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  


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Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
If baseline ALT ≤1.5x ULN, 
ALT ≥5x ULN and <8xULN and 
bilirubin <2xULN without symptoms 
believed to be related to liver injury 
or hypersensitivity, monitor 
participant every 2 weeks until 
resolution to ALT <5x ULN.

Notify the Medical Monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study intervention  

Participant must return every 1 – 2 weeks for 
repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until resolution or 
stabilisation (ALT <5×ULN on 2 consecutive 
evaluations) 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above
If baseline ALT >1.5x ULN, 
ALT ≥3x baseline and <5x baseline 
and bilirubin <2xULN without 
symptoms believed to be related to 
liver injury or hypersensitivity, 
monitor participant every 2 weeks 
until resolution to ALT <3x baseline
Reference
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
11.9.2.
Study Intervention Restart after Stopping for Liver Criteria
If a participant meets liver chemistry stopping criteria do not restart/rechallenge 
participant with study treatment unless:

ViiV Healthcare Safety and Labelling Committee (VSLC) approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the participant
If VSLC approval to restart/rechallenge subject with study treatment is not granted, then 
subject must permanently discontinue study treatment and may continue in the study for 
protocol-specified follow up assessments.
In Phase III, drug restart may be considered for liver events with a clear underlying 
cause (e.g., biliary, pancreatic events, hypotension, acute viral hepatitis), if not associated 
with drug-induced liver injury, alcoholic hepatitis or hypersensitivity, and drug not 


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associated with human leukocyte antigen (HLA) marker of liver injury, when liver 
chemistries improve to within 1.5x baseline and ALT<3xULN) (Table 6, Figure 4).
Drug Restart
Phase III “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
•
drug-induced liver injury (DILI)
•
alcoholic hepatitis
Study intervention is held while labs and evaluation is completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval (Figure 4):

PI requests consideration of drug re-initiation for a participant stable or improving on 
study intervention, who exhibits liver chemistry elevation meeting participant 
stopping criteria, which is transient, non-drug-related, and liver chemistries improve 
to within 1.5x baseline and ALT< 3xULN. 

In setting of a definitive non-study-drug-related diagnosis (e.g., acute viral or 
syphilitic hepatitis), restart will be considered once ALT <3x ULN (for 
participants with baseline ALT <1.5x ULN) or < 3x baseline ALT value (for 
participants with baseline ALT >1.5x ULN).

Medical monitor and Clinical Safety Physician to review the participant’s diagnosis, 
restart risk factors and complete checklist (Table 6).
The LOC medical director (ViiV Healthcare and GSK where applicable) should 
be informed that study intervention restart is under consideration and of the final 
decision, whether or not to proceed.
Table 6
Checklist for Phase III drug restart after well-explained liver injury 
(e.g., biliary, pancreatic, hypotensive events, congestive heart 
failure, acute viral hepatitis), improving to liver chem.1.5x baseline 
& ALT<3xULN
Yes
No
Was participant stable or improving on study intervention?
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)

study intervention has an HLA genetic marker associated with liver injury 
(e.g., lapatinib, abacavir, amoxicillin/clavulanate)
Previous drug history


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
Relevant physicians must review and agree on request for drug restart:  

Safety Team Leader, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader.

Hepatotoxicity Panel consultation is available.

Justification for drug restart outlining the benefit and risk for this participant must be 
recorded by GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) Physician 
and sent to the VSLC Secretary.
VSLC must approve drug re-initiation and dosing regimen
Figure 4
VSLC process for drug restart approval or disapproval
1.
1. Andrade, 2009; 2. Papay, 2009; 3. Hunt, 2010
Medical Monitor, GCSP Physician and PI actions for Restart following VSLC 
decision
Medical Monitor and (Global Clinical Safety and Pharmacovigilance) GCSP 
Physician Actions

Medical Monitor must notify PI of VSLC’s restart decision and recommended 
dosing regimen in writing and Medical Monitor must record note in study files.


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
The Safety Review Team must record restart outcomes and the GCSP Physician 
must send these to the VSLC
All severe reactions (restart associated with bilirubin>2xULN or jaundice, or 
INR1.5), SAEs or fatalities with drug restart must be immediately reported to 
Line Management, VSLC Chair, VP Global Medical Strategy and EU Qualified 
Person for Pharmacovigilance. 
Principal Investigator Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of drug 
restart, as required. 

If drug re-initiation VSLC-approved, the participant must provide informed consent 
with a clear description of possible benefits and risks of drug administration 
including recurrent, more severe liver injury or possible death.

The participant’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed once weekly for ‘restart’ cases for one month or 
for as long as clinically indicated following drug re-initiation.  If participant exhibits 
protocol-defined liver chemistry elevations, study intervention should be 
discontinued as protocol specified.
VSLC and the IRB/IEC must be informed of the participant’s outcome following 
drug restart.
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
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009; 8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010; 
52:2216-2222. 
Papay JI, Clines D, Rafi R, et al.  Drug-induced liver injury following positive drug 
rechallenge.  Regul Tox Pharm. 2009; 54:84-90. 


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11.10.
Appendix 10: Regulatory, Ethical and Study Oversight 
Considerations
11.10.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
11.10.2.
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. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
11.10.3.
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. 


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
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.
11.10.4.
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.
11.10.5.
Committees Structure
Full details of the methods, timing, decision criteria and operating characteristics of the 
Independent Data Monitoring Committee (IDMC) will be pre-specified in the IDMC 
Charter.
11.10.6.
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.


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
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
11.10.7.
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 
ViiV/GSK site or other mutually-agreeable location.

ViiV/GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with 
ViiV/GSK Policy.
11.10.8.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
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. 


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11.10.9.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
11.10.10. Study and Site Closure
ViiV/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 ViiV/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 intervention development


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11.11.
Appendix 11:  Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events Version 2.1, 
March 2017
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
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Clinical adverse
event NOT
identified 
elsewhere in
the
grading table
Mild symptoms
causing no or 
minimal 
interference
with
usual social & 
functional
activities with
intervention not
indicated
Moderate symptoms
causing greater
than minimal
interference with
usual social &
functional
activities with
intervention 
indicated
Severe symptoms
causing inability
to perform usual
social & 
functional
activities
with
intervention or 
hospitalization 
indicated
Potentially life-
threatening
symptoms causing
inability to perform
basic self-care 
functions with
intervention
indicated to prevent 
permanent impairment, 
persistent disability, or
death
Major Clinical Conditions Cardiovascular
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Arrhythmia
(by ECG or physical
examination)
Specify 
type, if 
applicable
No symptoms
AND No
intervention 
indicated
No symptoms AND
Non-urgent 
intervention 
indicated
Non-life-
threatening 
symptoms 
AND Non-
urgent
intervention
indicated
Life-threatening 
arrhythmia OR
Urgent intervention
indicated


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


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1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 
2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-2107C
Cardiovascular
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Hemorrhage
(with significant
acute blood loss)
NA
Symptoms AND
No transfusion
indicated
Symptoms
AND
Transfusion of
≤2 units
packed RBCs 
indicated
Life-threatening 
hypotension OR
Transfusion of > 2
units packed RBCs (for 
children, packed RBCs
> 10 cc/kg) indicated
Prolonged PR 
Interval or AV
Block
Report only one
> 16 years of age
PR interval 0.21
to
< 0.25 seconds
PR interval ≥ 
0.25 seconds 
OR Type I
2nd degree AV
block
Type II 2nd
degree AV
block OR
Ventricular
pause ≥
3.0 seconds
Complete AV block
≤ 16 years of age
1st degree AV
block
(PR interval
> normal for
age and rate)
Type I 2nd degree
AV block
Type II 2nd
degree AV
block OR
Ventricular
pause ≥
3.0 seconds
Complete AV block
Prolonged QTc
Interval2
0.45 to 0.47
seconds
> 0.47 to
0.50 
seconds
> 0.50 seconds 
OR
≥ 0.06 seconds 
above baseline
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated
serious ventricular
dysrhythmia)
Thrombosis or
Embolism
Report only one
NA
Symptoms AND
No intervention 
indicated
Symptoms
AND
Intervention 
indicated
Life-threatening 
embolic event (e.g., 
pulmonary
embolism, thrombus)
2 As per Bazett’s formula


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Dermatologic
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Alopecia (scalp only) Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference
with usual social
& functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
NA
NA
Bruising
Localized to
one area
Localized to
more than one 
area
Generalized
NA
Cellulitis
NA
Non-parenteral 
treatment
indicated (e.g.,
oral antibiotics, 
antifungals, 
antivirals)
IV treatment 
indicated
(e.g., IV 
antibiotics, 
antifungals, 
antivirals)
Life-threatening 
consequences (e.g., 
sepsis, tissue 
necrosis)
Hyperpigmentation
Slight or
localized 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Hypopigmentation
Slight or
localized 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Petechiae
Localized to
one area
Localized to
more than one 
area
Generalized
NA


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Pruritus3
(without skin lesions)
Itching causing
no or minimal 
interference
with usual social
& functional
activities
Itching causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Itching causing 
inability to
perform usual
social & 
functional
activities
NA
Rash
Specify 
type, if 
applicable
Localized rash
Diffuse rash
OR Target
lesions
Diffuse rash
AND Vesicles 
or limited 
number of
bullae or 
superficial 
ulcerations of 
mucous 
membrane 
limited to one 
site
Extensive or
generalized bullous
lesions OR Ulceration
of mucous membrane 
involving
two or more 
distinct mucosal
sites OR
Stevens-Johnson
syndrome OR
Toxic epidermal
necrolysis
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions
section (page 23 in source DAIDS Table).
Endocrine and Metabolic
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Diabetes Mellitus
Controlled
without 
medication
Controlled with 
medication OR
Modification of 
current
medication 
regimen
Uncontrolled
despite treatment 
modification OR
Hospitalization
for immediate 
glucose control
indicated
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end
organ failure)


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Gynecomastia
Detectable by
study 
participant,
caregiver, or 
physician AND
Causing no or 
minimal
interference with 
usual social & 
functional
activities
Obvious on
visual inspection
AND Causing
pain with greater
than minimal 
interference with 
usual social & 
functional
activities
Disfiguring
changes AND
Symptoms 
requiring
intervention or
causing inability
to perform usual
social
& 
functional 
activities
NA
Hyperthyroidism
No symptoms
AND Abnormal 
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Thyroid 
suppression
therapy indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
Life-threatening 
consequences 
(e.g., thyroid
storm)
Hypothyroidism
No symptoms
AND Abnormal
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Thyroid 
replacement
therapy indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
Life-threatening 
consequences 
(e.g., myxedema 
coma)
Lipoatrophy4
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference
with usual
social &
functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Lipohypertrophy5
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference with 
usual social & 
functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and
abdomen
Gastrointestinal
PARAMETE
R
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENIN
Anorexia
Loss of appetite 
without
decreased oral
intake
Loss of appetite 
associated with 
decreased oral
intake without
significant weight
loss
Loss of
appetite 
associated
with 
significant
weight loss
Life-threatening 
consequences OR
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total
parenteral nutrition)
Ascites
No symptoms
Symptoms
AND
Intervention 
indicated (e.g.,
diuretics,
therapeutic 
paracentesis)
Symptoms 
recur or persist
despite 
intervention
Life-
threatening 
consequences
Bloating or 
Distension
Report only one
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
Symptoms causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing inability
to perform usual
social & 
functional
activities
NA


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PARAMETE
R
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENIN
Cholecystitis
NA
Symptoms AND
Medical
intervention 
indicated
Radiologic, 
endoscopic,
or operative
intervention
indicated
Life-threatening 
consequences 
(e.g., sepsis,
perforation)
Constipation
NA
Persistent 
constipation 
requiring regular
use of dietary 
modifications, 
laxatives, or
enemas
Obstipation
with manual
evacuation 
indicated
Life-threatening 
consequences 
(e.g., 
obstruction)
Diarrhea
≥ 1 year of age
Transient 
or 
intermitten
t episodes 
of
unformed stools 
OR Increase of ≤ 
3 stools over
baseline
24 h
i d
Persistent
episodes of
unformed to 
watery stools OR
Increase of 4 to 6 
stools over
baseline per 24-
hour period
Increase of ≥7 
stools per 24-
hour period OR
IV fluid 
replacement 
indicated
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)
< 1 year of age
Liquid stools 
(more unformed
than usual) but
usual number of
stools
Liquid stools with 
increased number
of stools OR Mild 
dehydration
Liquid stools with 
moderate 
dehydration
Life-threatening 
consequences (e.g., 
liquid stools 
resulting in severe 
dehydration, 
hypotensive shock)
Dysphagia or
Odynophagia
Report only
one and 
specify 
location
Symptoms but
able to eat usual
diet
Symptoms causing 
altered dietary
intake with no
intervention 
indicated
Symptoms 
causing severely
altered dietary
intake with 
intervention
indicated
Life-threatening 
reduction in oral
intake
Gastrointestinal
Bleeding
Not requiring 
intervention
other than iron 
supplement
Endoscopic 
interventio
n indicated
Transfusion  
indicated
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)


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PARAMETE
R
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENIN
Mucositis or 
Stomatitis
Report only
one and 
specify 
location
Mucosal erythema
Patchy 
pseudomembranes 
or ulcerations
Confluent 
pseudomembrane
s or ulcerations 
OR Mucosal
bleeding with
minor trauma
Life-threatening 
consequences (e.g., 
aspiration, choking)
OR Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding
Nausea
Transient (< 24 
hours) or 
intermittent
AND No or
minimal 
interference
with oral intake
Persistent
nausea resulting
in
decreased oral
intake for 24 to 48
hours
Persistent nausea 
resulting in
minimal oral
intake for > 48 
hours OR
Rehydration 
indicated (e.g.,
IV fluids)
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)
Pancreatitis
NA
Symptoms with 
hospitalization
not indicated
Symptoms
with 
hospitalization 
indicated
Life-threatening 
consequences 
(e.g., circulatory
failure, 
hemorrhage,
sepsis)
Perforation
(colon or rectum)
NA
NA
Intervention 
indicated
Life-
threatening 
consequences 
Proctitis
Rectal discomfort 
with no
intervention 
indicated
Symptoms causing 
greater than
minimal 
interference with 
usual social & 
functional
activities OR
Medical 
intervention 
indicated
Symptoms 
causing inability
to perform usual
social & 
functional
activities OR
Operative 
intervention
indicated
Life-threatening 
consequences 
(e.g., 
perforation)
Rectal Discharge
Visible discharge
Discharge 
requiring the use 
of pads
NA
NA


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PARAMETE
R
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENIN
Vomiting
Transient or 
intermittent
AND No or
minimal 
interference
with oral intake
Frequent
episodes with no
or mild 
dehydration
Persistent
vomiting 
resulting in 
orthostatic 
hypotension OR
Aggressive 
rehydration
indicated (e.g., IV
fl id )
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)
Musculoskeletal
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Arthralgia
Joint pain
causing no or
minimal 
interference
with usual social
& functional
activities
Joint pain causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Joint pain
causing 
inability to
perform usual
social & 
functional
activities
Disabling joint pain 
causing inability to 
perform basic self-
care functions
Arthritis
Stiffness or joint 
swelling causing
no or minimal 
interference
with usual social
& functional
activities
Stiffness or joint 
swelling causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Stiffness or
joint swelling
causing 
inability to
perform usual
social & 
functional
activities
Disabling joint
stiffness or swelling
causing inability to
perform
basic self-care functions
Myalgia
(generalized)
Muscle pain 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Muscle pain
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Muscle pain
causing 
inability to
perform usual
social & 
functional
activities
Disabling muscle pain 
causing inability to 
perform basic self-
care functions


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Osteonecrosis
NA
No symptoms 
but with
radiographic 
findings AND
No operative 
intervention 
indicated
Bone pain with 
radiographic 
findings OR
Operative 
intervention
indicated
Disabling bone
pain with
radiographic 
findings causing 
inability to perform
basic self-care functions
Osteopenia6
≥ 30 years of age
BMD t-score
-2.5 to -1
NA
NA
NA
< 30 years of age
BMD z-score
-2 to -1
NA
NA
NA
Osteoporosis6
≥ 30 years of age
NA
BMD t-score < -2.5 Pathologic 
fracture (e.g.,
compression 
fracture causing
loss of vertebral
height)
Pathologic fracture 
causing life-
threatening 
consequences
< 30 years of age
NA
BMD z-score < -2
Pathologic 
fracture (e.g.,
compression 
fracture causing
loss of vertebral
height)
Pathologic fracture 
causing life-
threatening 
consequences
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific 
Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK.
2007: Printed by the University of Sheffield


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Neurologic
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute CNS Ischemia NA
NA
Transient
ischemic attack
Cerebral vascular 
accident (e.g.,
stroke with
neurological 
deficit)
Altered Mental
Status (for
Dementia, see 
Cognitive,
Behavioral, or 
Attentional
Disturbance below)
Changes causing
no or minimal 
interference with 
usual social & 
functional
activities
Mild lethargy or 
somnolence 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Confusion,
memory 
impairment,
lethargy, or 
somnolence 
causing inability
to perform usual
social & 
functional 
activities
Delirium OR
Obtundation
OR Coma
Ataxia
Symptoms
causing no or
minimal 
interference with 
usual social & 
functional
activities OR No
symptoms with
ataxia detected 
on examination
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Disabling symptoms 
causing inability to 
perform basic self-
care functions
Cognitive,
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention 
deficit disorder)
Specify type, if
applicable
Disability
causing no or
minimal 
interference
with usual social
& functional
activities OR
Specialized 
resources not 
indicated
Disability causing 
greater than
minimal 
interference with 
usual social & 
functional
activities OR
Specialized 
resources on part-
time basis 
indicated
Disability
causing 
inability to
perform usual
social & 
functional
activities OR
Specialized 
resources on a 
full- time basis 
indicated
Disability causing 
inability to
perform
basic self-care
functions
OR
Institutionalization 
indicated


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PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Developmental
Delay
< 18 years of
age
Specify type, if
applicable
Mild
developmental 
delay, either
motor or
cognitive, as 
determined by 
comparison with
a developmental 
screening tool 
appropriate for
the setting
Moderate 
developmental
delay, either
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting
Severe
developmental
delay, either
motor or
cognitive, as 
determined by 
comparison
with a 
developmental
screening tool 
appropriate for
the setting
Developmental 
regression, either
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting
Headache
Symptoms 
causing no or
minimal 
interference
with usual social
& functional
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Symptoms 
causing inability
to perform
basic self-care
functions
OR Hospitalization 
indicated OR
Headache with
significant impairment
of alertness or other
neurologic function
Neuromuscular 
Weakness 
(includes 
myopathy and 
neuropathy)
Specify type, if
applicable
Minimal muscle 
weakness 
causing no or
minimal 
interference
with usual social
& functional
activities OR No
symptoms with
decreased 
strength on 
examination
Muscle weakness 
causing greater
than minimal
interference with
usual social & 
functional
activities
Muscle 
weakness 
causing inability
to perform usual
social
& 
functional 
activities
Disabling muscle 
weakness causing 
inability to
perform
basic self-care
functions OR
Respiratory muscle 
weakness impairing
ventilation
Neurosensory 
Alteration
(includes 
paresthesia and
painful 
neuropathy)
Specify type, if
applicable
Minimal
paresthesia 
causing no or 
minimal
interference
with usual social
& functional
activities
OR No
symptoms 
with sensory 
alteration on 
examination
Sensory alteration
or paresthesia 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Sensory
alteration or 
paresthesia 
causing inability
to perform usual
social & 
functional
activities
Disabling sensory 
alteration or
paresthesia causing
inability to perform
basic self-care 
functions


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PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Seizures
New Onset
Seizure
≥ 18 years of
age
NA
NA
1 to 3 seizures
Prolonged and
repetitive seizures 
(e.g., status 
epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
< 18 years of
age (includes 
new or pre-
existing febrile 
seizures)
Seizure lasting < 
5 minutes with < 
24 hours 
postictal state
Seizure lasting 5 to
<
20 minutes with
< 24 hours 
postictal state
Seizure lasting
≥ 20 minutes 
OR > 24 hours 
postictal state
Prolonged and
repetitive seizures 
(e.g., status 
epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
Pre-existing
Seizure
NA
Increased
frequency from
previous level of
control without 
change in seizure 
character
Change in
seizure 
character either
in duration or
quality (e.g.,
severity or 
focality)
Prolonged and
repetitive seizures 
(e.g., status 
epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
Syncope
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope)
Loss of 
consciousness 
with no
intervention 
indicated
Loss of 
consciousness 
AND
Hospitalization
or intervention
required
NA
Pregnancy, Puerperium, and Perinatal
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Stillbirth (report
using mother’s 
participant ID)
Report only one
NA
NA
Fetal death 
occurring at ≥ 
20 weeks 
gestation
NA
Preterm Birth
(report using
mother’s 
participant ID)
Live birth at 34 to
< 37 weeks 
gestational
age
Live birth at 28 to
< 34 weeks 
gestational
age
Live birth at 24 to
< 28
weeks 
gestational
age
Live birth at < 24
weeks gestational age


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PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Spontaneous 
Abortion or 
Miscarriage7
(report using
mother’s 
participant ID)
Report only one
Chemical 
pregnancy
Uncomplicated 
spontaneous 
abortion or
miscarriage
Complicated 
spontaneous 
abortion or
miscarriage
NA
7 Definition: A pregnancy loss occurring at < 20 weeks gestational age
Psychiatric
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Insomnia
Mild difficulty 
falling asleep, 
staying asleep,
or waking up
early causing
no or minimal 
interference
with usual
social &
functional
activities
Moderate 
difficulty falling
asleep, staying
asleep, or 
waking up early 
causing more 
than
minimal
interference with
usual social & 
functional
activities
Severe difficulty 
falling asleep,
staying asleep, or
waking up early
causing
inability to
perform usual
social &
functional
activities
requiring
intervention or
hospitalization
NA
Psychiatric 
Disorders 
(includes anxiety, 
depression,
mania, and 
psychosis)
Specify disorder
Symptoms
with 
intervention
not indicated
OR Behavior
causing no or
minimal 
interference
with usual
social & 
functional
activities
Symptoms with 
intervention 
indicated OR
Behavior causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Symptoms with 
hospitalization 
indicated OR
Behavior
causing 
inability to
perform usual
social & 
functional
activities
Threatens harm to self 
or others OR Acute 
psychosis OR
Behavior causing
inability to perform
basic self-care 
functions


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Suicidal Ideation or
Attempt
Report only one
Preoccupied
with thoughts 
of death AND
No wish to kill
oneself
Preoccupied
with thoughts 
of death AND
Wish to kill 
oneself with no 
specific plan or 
intent
Thoughts of
killing oneself
with partial
or complete plans
but no attempt to
do so OR
Hospitalization
indicated
Suicide attempted
Respiratory
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute 
Bronchospasm
Forced
expiratory 
volume in 1
second or peak
flow reduced to
≥ 70 to < 80%
OR Mild
symptoms
with intervention
not indicated
Forced
expiratory 
volume in 1
second or peak
flow 50 to
< 70% OR
Symptoms with
intervention
indicated OR
Symptoms 
causing greater
than minimal 
interference with
usual social &
functional activities
Forced
expiratory 
volume in 1
second or peak
flow 25 to
< 50% OR
Symptoms 
causing
inability to
perform usual
social & 
functional
activities
Forced expiratory 
volume in 1 second
or peak flow < 25%
OR Life-threatening 
respiratory or 
hemodynamic 
compromise OR
Intubation
Dyspnea or 
Respiratory
Distress
Report only one
Dyspnea on 
exertion with no
or minimal 
interference
with usual
social &
functional
activities OR
Wheezing OR
Minimal increase 
in
respiratory rate
for age
Dyspnea on
exertion causing
greater than 
minimal
interference with
usual social & 
functional
activities OR
Nasal flaring OR
Intercostal
retractions OR
Pulse oximetry
90 to < 95%
Dyspnea at rest 
causing inability
to perform usual
social
& functional
activities OR
Pulse oximetry
< 90%
Respiratory failure 
with ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation)


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Sensory
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENIN
G
Hearing Loss
≥ 12 years of age
NA
Hearing aid
or 
intervention
not indicated
Hearing aid or 
intervention
indicated
Profound bilateral 
hearing loss (> 80
dB at
2 kHz and above) OR
Non-serviceable 
hearing
(i.e., >50 dB
audiogram and
<50% speech 
discrimination)
< 12 years of age
(based on a 1, 2, 3, 4,
6 and 8
kHz 
audiogram)
> 20 dB 
hearing loss 
at ≤ 4 kHz
> 20 dB hearing
loss at > 4 kHz
> 20 dB 
hearing loss at 
≥ 3 kHz in one 
ear with
additional
speech
language
related
services 
indicated
(where 
available) OR
Hearing loss 
sufficient to
indicate 
therapeutic 
intervention, 
including
hearing aids
Audiologic indication
for cochlear implant
and additional
speech- language 
related
services indicated
(where available)
Tinnitus
Symptoms 
causing no or
minimal 
interference
with usual social
& functional
activities with
intervention not
indicated
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities with
intervention 
indicated
Symptoms 
causing 
inability to
perform 
usual social
& functional
activities
NA
Uveitis
No symptoms
AND Detectable 
on examination
Anterior uveitis 
with symptoms 
OR Medical
intervention 
indicated
Posterior or
pan- uveitis 
OR Operative 
intervention
indicated
Disabling visual loss 
in affected eye(s)


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENIN
G
Vertigo
Vertigo causing
no or minimal 
interference
with usual social
& functional
activities
Vertigo causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Vertigo
causing 
inability to
perform 
usual social
& functional
activities
Disabling vertigo 
causing inability to 
perform basic self-
care functions
Visual Changes
(assessed from baseline)
Visual
changes
causing no or 
minimal 
interference
with usual
social &
functional
activities
Visual changes 
causing greater
than minimal
interference with
usual social & 
functional
activities
Visual
changes 
causing
inability to 
perform usual
social
& functional
activities
Disabling visual loss 
in affected eye(s)
Systemic
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute Allergic
Reaction
Localized
urticaria (wheals)
with no medical
intervention 
indicated
Localized
urticaria with
intervention 
indicated OR
Mild 
angioedema
with no
intervention 
indicated
Generalized
urticaria OR
Angioedema
with intervention
indicated OR
Symptoms of
mild
bronchospasm
Acute anaphylaxis 
OR Life-threatening 
bronchospasm OR
Laryngeal edema
Chills
Symptoms causing
no or minimal 
interference with
usual social &
functional activities
Symptoms 
causing greater
than minimal 
interference
with usual
social &
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
NA


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Cytokine Release
Syndrome8
Mild signs and 
symptoms
AND Therapy
(i.e., antibody
infusion) 
interruption not 
indicated
Therapy (i.e., 
antibody
infusion) 
interruption 
indicated AND
Responds
promptly to
symptomatic 
treatment OR
Prophylactic 
medications
indicated for ≤
24 hours
Prolonged
severe signs and
symptoms OR
Recurrence of 
symptoms
following initial
improvement
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator support)
Fatigue or 
Malaise
Report only one
Symptoms causing
no or minimal 
interference with
usual social &
functional activities
Symptoms 
causing greater
than minimal 
interference
with usual
social &
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Incapacitating
symptoms of fatigue or
malaise causing
inability to perform
basic self-care 
functions
Fever (non-
axillary 
temperatures 
only)
38.0 to < 38.6°C or
100.4 to < 101.5°F
≥ 38.6 to <
39.3°C
or ≥ 101.5 to
< 102.7°F
≥ 39.3 to < 40.0°C
or
≥ 102.7 to <
104.0°F
≥ 40.0°C or ≥ 104.0°F
Pain9 (not
associated with
study agent 
injections and
not specified
elsewhere)
Specify location
Pain causing no
or minimal
interference with
usual social & 
functional
activities
Pain causing 
greater than 
minimal 
interference
with usual
social &
functional
activities
Pain causing
inability to
perform usual 
social & 
functional 
activities
Disabling pain causing 
inability to perform
basic self-care
functions OR
Hospitalization
indicated
Serum Sickness
10
Mild signs 
and 
symptoms
Moderate signs 
and symptoms
AND
Intervention 
indicated (e.g., 
antihistamines)
Severe signs and 
symptoms AND
Higher level 
intervention
indicated (e.g.,
steroids or IV 
fluids)
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator support)
Underweight11
> 5 to 19 years 
of
age
WHO BMI z-score
< -1 to -2
WHO BMI z-
score
< -2 to -3
WHO BMI z-
score
< -3
WHO BMI z-score
< -3 with life-
threatening 
consequences


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
2 to 5 years of
age
WHO BMI z-score
< -1 to -2
WHO Weight-
for- height z-
score
< -2 to -3
WHO Weight-
for- height z-
score < -3
WHO Weight-for-
height z-score < -3 with
life- threatening
consequences
< 2 years of age WHO BMI z-score
< -1 to -2
WHO Weight-
for- length z-
score
< -2 to -3
WHO Weight-
for- length z-
score < -3
WHO Weight-for-
length z-score < -3 with
life- threatening
consequences
Unintentional 
Weight Loss 
(excludes 
postpartum 
weight loss)
NA
5 to < 9% loss 
in body weight
from baseline
≥ 9 to < 20%
loss in body
weight from 
baseline
≥ 20% loss in body 
weight from baseline 
OR Aggressive 
intervention indicated
(e.g., tube feeding,
total parenteral 
nutrition)
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness 
of breath.
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section
(page 23 in source DAIDS Table).
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy,
marked discomfort, and/or dyspnea
11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following
URLs:
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5
to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5
years of age.
Urinary
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Urinary Tract
Obstruction
NA
Signs or
symptoms of
urinary tract 
obstruction
without 
hydronephrosis 
or renal
dysfunction
Signs or
symptoms of 
urinary tract 
obstruction with 
hydronephrosis 
or renal
dysfunction
Obstruction
causing life-
threatening 
consequences


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Site Reactions to Injections and Infusions
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain
or
Tenderness
Report only one
Pain or
tenderness 
causing no or 
minimal
limitation of
use of limb
Pain or tenderness 
causing greater
than minimal
limitation of use 
of limb
Pain or
tenderness 
causing inability
to perform usual
social
& functional
activities
Pain or tenderness 
causing inability to 
perform basic self-
care function OR
Hospitalization 
indicated
Injection Site 
Erythema or 
Redness12
Report only one
> 15 years of age
2.5 to < 5 cm in 
diameter OR
6.25 to
< 25 cm2
surface area
AND
Symptoms 
causing no or
minimal
interference with 
usual social & 
functional
activities
≥ 5 to < 10 cm in 
diameter OR ≥ 25
to
< 100 cm2
surface area OR
Symptoms 
causing greater
than minimal
interference
with usual social &
functional activities
≥ 10 cm in
diameter OR ≥ 
100 cm2 surface 
area OR
Ulceration OR
Secondary
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage 
OR Symptoms 
causing inability
to perform usual
social & 
functional
activities
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis involving
dermis or deeper
tissue)
≤ 15 years of age
≤ 2.5 cm
in 
diameter
> 2.5 cm in
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm
or thigh)
≥ 50% surface 
area of the 
extremity 
segment involved 
(e.g., upper arm
or thigh) OR
Ulceration OR
Secondary 
infection OR
Phlebitis OR
Sterile
abscess OR
Drainage
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis involving
dermis or deeper
tissue)
Injection Site
Induration or 
Swelling
Report only one
> 15 years of
age
Same as for 
Injection
Site 
Erythema
or Redness,
> 15 years 
of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≤15 years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years
of age
Injection Site 
Pruritus
Itching localized
to the injection
site that is 
relieved 
spontaneously or
in
< 48 hours 
of 
treatment
Itching beyond
the injection site 
that is not
generalized OR
Itching localized
to the injection
site requiring ≥ 
48 hours 
treatment
Generalized 
itching causing
inability
to 
perform
usual
social
& 
functional 
activities
NA
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or 
measured surface area.
Laboratory Values*
Chemistries
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acidosis
NA
pH ≥ 7.3 to < LLN
pH < 7.3
without life-
threatening 
consequences
pH < 7.3 with life-
threatening 
consequences
Albumin,
Low
(g/dL;
g/L)
3.0 to < LLN
30  to < LLN
≥ 2.0 to < 3.0
≥ 20  to < 30
< 2.0
< 20
NA
Alkaline 
Phosphatase, 
High
1.25 to <
2.5 x ULN
2.5  to < 5.0 x ULN
5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Alkalosis
NA
pH > ULN to ≤ 7.5
pH > 7.5
without life-
threatening 
consequences
pH > 7.5 with life-
threatening 
consequences
ALT or SGPT,
High
Report only one
1.25 to <
2.5 x ULN
2.5 to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Amylase 
(Pancreatic) or
Amylase (Total),
High
Report only one
1.1  to < 1.5 x
ULN
1.5 to < 3.0 x ULN
3.0  to < 5.0 x
ULN
≥ 5.0 x ULN
AST or SGOT,
High
Report only one
1.25 to <
2.5 x ULN
2.5  to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Bicarbonate, Low
(mEq/L; mmol/L)
16.0 to <  LLN
16.0 to <  LLN
11.0 to < 16.0
11.0 to < 16.0
8.0  to < 11.0
8.0  to < 11.0
< 8.0
< 8.0
Bilirubin
Direct
Bilirubin13, 
High
> 28 days of age
NA
NA
> ULN with
other signs 
and symptoms 
of
hepatotoxicity.
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure)
≤ 28 days of age ULN to ≤ 1 mg/dL > 1 to ≤ 1.5 mg/dL
> 1.5 to ≤2
mg/dL
> 2 mg/dL
Total Bilirubin,
High
> 28 days of
age
1.1 to < 1.6 x
ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x
ULN with
other signs 
and symptoms 
of 
hepatotoxicity.
≥ 5.0 x ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure).
≤ 28 days of age See Appendix 
A  in Source 
DAIDS Table. 
Total Bilirubin
for Term and
Preterm 
Neonates
See Appendix A
in Source 
DAIDS Table. 
Total Bilirubin
for Term and
Preterm 
Neonates
See 
Appendix A
in Source 
DAIDS 
Table. Total
Bilirubin for 
Term and
Preterm 
Neonates
See Appendix A in 
Source DAIDS Table.
Total Bilirubin for
Term and Preterm
Neonates
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age
10.6  to < 11.5
2.65 to < 2.88
11.5 to < 12.5
2.88 to < 3.13
12.5  to < 13.5
3.13 to < 3.38
≥ 13.5
≥ 3.38
< 7 days of age
11.5 to < 12.4
2.88 to < 3.10
12.4 to < 12.9
3.10 to < 3.23
12.9 to < 13.5
3.23 to < 3.38
≥ 13.5
≥ 3.38


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Calcium (Ionized),
High
(mg/dL; mmol/L)
> ULN to < 6.0
> ULN to < 1.5
6.0 to < 6.4
1.5 to < 1.6
6.4 to < 7.2
1.6 to < 1.8
≥ 7.2
≥ 1.8
Calcium, Low
(mg/dL; mmol/L)
≥ 7 days of age
7.8  to < 8.4
1.95 to < 2.10
7.0  to < 7.8
1.75 to < 1.95
6.1  to < 7.0
1.53 to < 1.75
< 6.1
< 1.53
< 7 days of age
6.5  to < 7.5
1.63 to < 1.88
6.0 to < 6.5
1.50 to < 1.63
5.50 to < 6.0
1.38 to < 1.50
< 5.50
< 1.38
Calcium (Ionized),
Low
(mg/dL; mmol/L)
< LLN to 4.0
< LLN to 1.0
3.6 to < 4.0
0.9 to < 1.0
3.2 to < 3.6
0.8 to < 0.9
< 3.2
< 0.8
Cardiac 
Troponin I, 
High
NA
NA
NA
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory
Creatine Kinase,
High
3 to < 6 x ULN
6 to < 10x ULN
10 to < 20 x
ULN
≥ 20 x ULN
Creatinine, High
*Report only one
1.1 to 1.3 x ULN
> 1.3 to 1.8 x ULN 
OR Increase to 1.3
to
< 1.5 x
participant’s 
baseline
> 1.8  to < 3.5
x ULN OR
Increase to 1.5
to < 2.0 x 
participant’s
baseline
≥ 3.5 x ULN OR
Increase of ≥ 2.0 x
participant’s baseline
Creatinine 
Clearance14
or eGFR, Low
*Report only one
NA
< 90 to 60 ml/min
or ml/min/1.73 m2
OR
10 to < 30%
decrease from
participant’s 
baseline
< 60 to 30
ml/min or 
ml/min/1.73
m2
OR
30 to < 50% 
decrease from 
participant’s
baseline
< 30 ml/min or 
ml/min/1.73 m2
OR
≥ 50% decrease from 
participant’s baseline or 
dialysis needed
Glucose
(mg/dL; mmol/L)
Fasting, High
110 to 125
6.11 to < 6.95
> 125 to 250
6.95 to < 13.89
> 250 to 500
13.89 to < 27.75
≥ 500
≥ 27.75
Nonfasting, High
116 to 160
6.44 to < 8.89
> 160 to 250
8.89 to < 13.89
> 250  to 500
13.89  to < 27.75
≥ 500
≥ 27.75


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age
55  to 64
3.05 to <3.55
40  to < 55
2.22 to < 3.05
30  to < 40
1.67 to < 2.22
< 30
< 1.67
< 1 month of age
50 to 54
2.78 to < 3.00
40 to < 50
2.22 to < 2.78
30 to < 40
1.67 to < 2.22
< 30
< 1.67
Lactate, High
ULN to < 2.0
x ULN
without 
acidosis
≥ 2.0 x ULN
without acidosis
Increased
lactate with pH 
< 7.3 without
life- threatening 
consequences
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences
Lipase, High
1.1  to < 1.5 x
ULN
1.5  to < 3.0 x ULN
3.0  to < 5.0 x
ULN
≥ 5.0 x ULN
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol,
Fasting, High
≥ 18 years of
age
200  to < 240
5.18 to < 6.19
240  to < 300
6.19 to < 7.77
≥ 300
≥ 7.77
NA
< 18 years of
age
170  to < 200
4.40 to < 5.15
200 to < 300
5.15 to < 7.77
≥ 300
≥ 7.77
NA
LDL, Fasting,
High
≥ 18 years of
age
130  to < 160
3.37 to < 4.12
160 to < 190
4.12 to < 4.90
≥ 190
≥4.90
NA
> 2 to < 18
years of age
110  to < 130
2.85 to < 3.34
130 to < 190
3.34 to < 4.90
≥ 190
≥ 4.90
NA
Triglycerides,
Fasting, High
150 to 300
1.71 to 3.42
>300  to 500
>3.42 to 5.7
>500 to < 1,000
>5.7 to 11.4
> 1,000
> 11.4
Magnesium15,
Low
(mEq/L;
mmol/L)
1.2  to < 1.4
0.60 to < 0.70
0.9  to < 1.2
0.45 to < 0.60
0.6  to < 0.9
0.30 to < 0.45
< 0.6
< 0.30
Phosphate, Low
(mg/dL; mmol/L)
> 14 years of age
2.0 to < LLN
0.65 to < LLN
1.4 to < 2.0
0.45 to < 0.65
1.0 to < 1.4
0.32 to < 0.45
< 1.0
< 0.32
1 to 14 years of
age
3.0  to < 3.5
0.97 to < 1.13
2.5  to < 3.0
0.81 to < 0.97
1.5  to < 2.5
0.48 to < 0.81
< 1.5
< 0.48


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
< 1 year of age
3.5  to < 4.5
1.13 to < 1.45
2.5  to < 3.5
0.81 to < 1.13
1.5  to < 2.5
0.48 to < 0.81
< 1.5
< 0.48
Potassium, High
(mEq/L; mmol/L)
5.6  to < 6.0
5.6  to < 6.0
6.0  to < 6.5
6.0  to < 6.5
6.5  to < 7.0
6.5  to < 7.0
≥ 7.0
≥ 7.0
Potassium, Low
(mEq/L; mmol/L)
3.0  to < 3.4
3.0  to < 3.4
2.5  to < 3.0
2.5  to < 3.0
2.0  to < 2.5
2.0  to < 2.5
< 2.0
< 2.0
Sodium, High
(mEq/L; mmol/L)
146  to < 150
146  to < 150
150  to < 154
150  to < 154
154  to < 160
154  to < 160
≥ 160
≥ 160
Sodium, Low
(mEq/L; mmol/L)
130  to < 135
130  to < 135
125  to < 130
125  to < 130
121  to < 125
121  to < 125
≤ 120
≤ 120
Uric Acid, High
(mg/dL; mmol/L)
7.5  to < 10.0
0.45 to < 0.59
10.0 to < 12.0
0.59 to < 0.71
12.0 to < 15.0
0.71 to < 0.89
≥ 15.0
≥ 0.89
eGFR - estimated glomerular filtration rate
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be 
reported to DAIDS in an expedited time frame unless it meets protocol-specific reporting requirements.
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of
the total bilirubin
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in
mL/min/1.73m2). Sites should choose the method defined in their study and when not specified, use the 
method most relevant to the study population.
*Reminder: Choose the method that selects for the higher grade
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114
Hematology
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Absolute CD4+
Count, Low
(cell/mm3; cells/L)
> 5 years of age
(not HIV infected)
300 to < 400
300 to < 400
200 to <  300
200 to < 300
100 to < 200
100  to < 200
< 100
< 100


2017N331008_06
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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Absolute 
Lymphocyte
Count, Low
(cell/mm3;
cells/L)
> 5 years of
age 
(not HIV infected) 
600  to < 650
< 0.600 x 109 to < 
0.650 x 109
500  to < 600
0.500 x 1099 to 
< 0.600 x 109
350 to < 500
0350 x 109 to 
< 0.500 x 109
< 350
< 0.350 x 109
Absolute 
Neutrophil
Count (ANC),
Low
(cells/mm3;
cells/L)
> 7 days of
age
800 to 1,000
0.800 x 109 to
1.000 x 109
600 to 799
0.600 x 109 to
0.799 x 109
400 to 599
0.400 x 109 to
0.599 x 109
< 400
< 0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to
1.500 x 109
1,000 to 1,249
1.000 x 109 to
1.249 x 109
750 to 999
0.750 x 109 to
0.999 x 109
< 750
< 0.750 x 109
≤ 1 day of age
4,000 to 5,000
4.000 x 109 to
5.000 x 109
3,000 to 3,999
3.000 x 109 to
3.999 x 109
1,500 to 2,999
1.500 x 109 to
2.999 x 109
< 1,500
< 1.500 x 109
Fibrinogen,
Decreased
(mg/dL; g/L)
100  to < 200
1.00 to < 2.00
OR
0.75 to < 
1.00 x LLN
75  to < 100
0.75 to < 1.00
OR
≥ 0.50 to < 
0.75 x LLN
50  to < 75
0.50 to < 0.75
OR
0.25 to < 
0.50 x
LLN
< 50
< 0.50
OR
< 0.25 x LLN
OR Associated
with gross 
bleeding
Hemoglobin16,
Low
(g/dL; mmol/L)17
≥ 13 years of age
(male only)
10.0 to 10.9
6.19 to 6.76
9.0 to < 10.0
5.57 to < 6.19
7.0 to < 9.0
4.34 to < 5.57
< 7.0
< 4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
57 days of age to
< 13 years of
age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of
age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72


2017N331008_06
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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
22 to 35 days of
age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of
age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59
INR, High
(not on
anticoagulation
therapy)
1.1  to < 1.5 x
ULN
1.5  to < 2.0 x ULN 2.0  to < 3.0 x
ULN
≥ 3.0 x ULN
Methemoglobin
(% hemoglobin)
5.0  to < 10.0%
10.0 to < 15.0%
15.0 to < 20.0%
≥ 20.0%
PTT, High
(not on
anticoagulation
therapy)
1.1  to < 
1.66 x
ULN
1.66 to < 
2.33 x ULN
2.33 to < 
3.00 x
ULN
≥ 3.00 x ULN
Platelets, Decreased
(cells/mm3;
cells/L)
100,000  to
< 125,000
100.000 x 109 to
< 125.000 x 109
50,000 to
< 100,000
50.000 x 109 to
< 100.000 x 109
25,000 to
< 50,000
25.000 x 109 to
< 50.000 x 109
< 25,000
< 25.000 x 109
PT, High
(not on
anticoagulation
therapy
1.1  to < 
1.25 x
ULN
1.25 to <
1.50 x ULN
1.50 to <
3.00 x
ULN
≥ 3.00 x ULN
WBC,
Decreased
(cells/mm3;
cells/L)
> 7 days of
age
2,000 to 2,499
2.000 x 109 to
2.499 x 109
1,500 to 1,999
1.500 x 109 to
1.999 x 109
1,000 to 1,499
1.000 x 109 to
1.499 x 109
< 1,000
< 1.000 x 109
≤ 7 days of age
5,500 to 6,999
5.500 x 109 to
6.999 x 109
4,000 to 5,499
4.000 x 109 to
5.499 x 109
2,500 to 3,999
2.500 x 109 to
3.999 x 109
< 2,500
< 2.500 x 109
16 Male and female sex are defined as sex at birth. For transgender participants 13 years of age who have 
been on hormone therapy for more than 6 consecutive months grade hemoglobin based on the gender with 
which they identify (i.e., a transgender female should be graded using the femaile sex at birth hemoglobin 
laboratory values).
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading
hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result
must be converted to g/dL using appropriate conversion factor for the particular laboratory


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Urinalysis
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENIN
G
Glycosuria
(random 
collection tested
by dipstick)
Trace to 1+ or
≤ 250 mg
2+ or ˃ 250 to
≤ 500 mg
> 2+ or > 500 mg
NA
Hematuria (not
to be reported
based on dipstick
findings or on 
blood believed to
be of menstrual
origin)
6 to < 10 RBCs
per high power
field
≥ 10 RBCs per
high power field
Gross, with or 
without clots 
OR With RBC
casts OR
Intervention 
indicated
Life-
threatening 
consequences
Proteinuria
(random 
collection tested
by dipstick)
1+
2+
3+  or higher
NA
Appendix A: Total Bilirubin Table for Term and Preterm Neonates
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENIN
G
Total Bilirubin18,
High
(mg/dL;
µmol/L)19
Term Neonate20
< 24 hours of
age
4 to < 7
68.4 to < 119.7
7 to < 10
119.7 to < 171
10  to < 17
171  to < 290.7
≥ 17
≥ 290.7
24 to < 48
hours of age
5 to < 8
85.5 to < 136.8
8 to < 12
136.8 to < 205.2
12  to < 19
205.2  to < 324.9
≥ 19
≥ 324.9
48 to < 72
hours of age
8.5 to < 13
145.35 to < 222.3
13 to < 15
222.3 to < 256.5
15  to < 22
256.5  to < 376.2
≥ 22
≥ 376.2
72 hours to < 7
days of age
11 to < 16
188.1 to < 273.6
16 to < 18
273.6 to < 307.8
18  to < 24
307.8  to < 410.4
≥ 24
≥ 410.4
7 to 28 days of
age
(breast feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
≥ 25
≥ 427.5


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENIN
G
7 to 28 days of
age
(not breast
feeding)
1.1 to < 1.6 x ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x ULN ≥ 5.0 x ULN
Preterm
Neonate20
35 to < 37
weeks 
gestational
age
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
32 to < 35
weeks 
gestational age 
and
< 7 days of age
NA
NA
10 to < 14
171 to < 239.4
≥ 14
≥ 239.4
28 to < 32
weeks 
gestational age 
and
< 7 days of age
NA
NA
6 to < 10
102.6 to < 171
≥ 10
≥ 171
< 28 weeks 
gestational age 
and
< 7 days of age
NA
NA
5 to < 8
85.5 to < 136.8
≥ 8
≥ 136.8
7 to  28 days of
age
(breast feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
≥ 25
≥ 427.5
7 to 28 days of
age
(not breast
feeding)
1.1 to < 1.6 x ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x ULN ≥ 5.0 x ULN
18 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin
normal ranges in the first week of life followed by the benign phenomenon of breast milk jaundice after
the first week of life. Severity grading in this appendix corresponds approximately to cut-offs for
indications for phototherapy at grade 3 and for exchange transfusion at grade 4.
19 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L.
20 Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks gestational age; 
preterm, as < 35 weeks gestational age; and neonate, as 0 to 28 days of age.
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. Mar 2017. Available from: https://rsc.tech-res.com/docs/default-source/safety/daids-
ae-grading-table-mar2017.pdf (date accessed: 24 Jan 2018).


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11.12.
Appendix 12:  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 percentage should only be considered if the count is missing.

HIV infection, stage 0

Indicates early HIV infection, inferred from a negative or indeterminate HIV test 
result within 180 days of a positive result.  The criteria for stage 0 supersede and are 
independent of criteria used for other stages.

HIV infection, stage 1

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of ≥500 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%.

HIV infection, stage 2

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of 200 to 499 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%.

HIV infection, stage 3 (AIDS)

Laboratory confirmation of HIV infection, and
o
CD4+ T-lymphocyte count of <200 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or
o
Documentation of an AIDS-defining condition (see below).

Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte 
count of >200 cells/L and a CD4+ T-lymphocyte percentage of total lymphocytes 
of >14%. 

HIV infection, stage unknown

Laboratory confirmation of HIV infection, and
o
No information on CD4+ T-lymphocyte count or percentage, and
o
No information on presence of AIDS-defining conditions.

Stage-3-defining opportunistic illnesses in HIV infection

Candidiasis of bronchi, trachea, or lungs 

Candidiasis of oesophagus 

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary 


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
Cryptococcosis, extrapulmonary 

Cryptosporidiosis, chronic intestinal (>1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related 

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
oesophagitis (onset at age >1 month)

Histoplasmosis, disseminated or extrapulmonary 

Isosporiasis, chronic intestinal (>1 month's duration) 

Kaposi's sarcoma 

Lymphoma, Burkitt's (or equivalent term) 

Lymphoma, immunoblastic (or equivalent term) 

Lymphoma, primary, of brain 

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary 

Mycobacterium tuberculosis of any site, pulmonary, disseminated or extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis jirovecii pneumonia 

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy 

Salmonella septicaemia, recurrent 

Toxoplasmosis of brain, onset at age >1 month 

Wasting syndrome attributed to HIV.


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11.13.
Appendix 13: Country-specific requirements
United Kingdom
This requirement has been included based on requests from the Medicines and Healthcare 
products Regulatory Agency (MHRA) to include information on the specific duration of 
the Continuation Phase/Study Intervention for similar Phase III trials being conducted 
with dolutegravir.
Study Duration
In this study, the date of last study intervention administration in the UK will be 
determined by the completion of the 52 week randomized phase of the study for the last 
UK participant enrolled (it will not be determined by the completion of the Continuation 
Phase).  The last participant will be enrolled by Q1 2020/Q2 2020, and hence the last 
study intervention administration will occur by Q1 2021/Q2 2021. (Note: The 
Continuation Phase is intended to provide participants receiving DTG/3TC FDC with 
post-study access to DTG/3TC FDC until DTG plus 3TC is approved as a 2-drug regimen 
in their local countries.  For participants in the UK, the Continuation Phase is not
anticipated to be required as the 2-drug regimen of DTG/3TC FDC is anticipated to be 
approved by Q3/Q4 2020.
Sweden and Denmark
A country specific protocol amendment, 208090 Amendment 03/SWE-DEN-1, was 
previously published on 29-July-2019 for Sweden and Denmark to remove all references
to the Continuation Phase. Participants in Sweden and Denmark in both treatment arms 
will finish the study at Week 52. This amendment was a regulatory requirement for 
Sweden and Denmark to update the protocol with a clear time for the study´s conclusion 
based on scientific basis without any reference to market approval.  Protocol text in the 
current global protocol amendment 04 related to the continuation phase does not apply to 
Sweden and Denmark. A summary of sections that reference the continuation phase is 
included here:

Section 1: Protocol Summary, Section 1.2: Study Schematic, 

Section 1.3: Schedule of Activities and footnotes

Section 2.3.1: Risk Assessment, 

Section 3: Objectives and Endpoints

Section 4.1: Overall Design

Section 4.3: Participant and Study Completion 

Section 6.7: Concomitant Therapy

Section 6.8: Treatment after the end of the study

Section 7.1: Discontinuation of study intervention
China
A country specific protocol amendment, 208090 Amendment 03/CHI-1, was previously 
published on 31-May-2019 for China based on a requirement to perform all laboratory


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analysis in-country and the unavailability of laboratory support in-country to conduct all 
of the protocol required analyses. Updates from global protocol amendment 04 will be 
incorporated into a country specific amendment for China, 208090 Amendment 04/CHI-
1.


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11.14.
Appendix 14: 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 participant’s 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 Dolutegravir Clinical Trial Investigators and Study Staff” was issued on 
March 25th, 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 March 25, 2020 “Memo to Dolutegravir Clinical Trial 
Investigators and Study Staff” 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. 
11.14.1.
Changes to Study Visits and Study Procedures

When site staff resources are limited due to COVID-19, abbreviated study visits 
may proceed without conducting all protocol-specified additional assessments 
(e.g. lab tests, questionnaires, etc.). If laboratory testing will be missed for more 
than one consecutive visit, medical monitor pre-notification is required, and all 
efforts should be made to find alternative approaches for lab testing. 

Consider alternative travel options for participants, if possible. 


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
When central laboratory testing is not possible at a particular visit, tests for 
management of participant safety, including HIV-1 RNA may be performed at an 
appropriately authorised/accredited local laboratory (or other relevant clinical 
facility), if this can be done within local restrictions on physical distancing. The 
site should proactively inform PPD/the sponsor about such instances. Local 
laboratory results done as per routine follow-up, including HIV-1 RNA, may be 
used to inform safety and patient management decisions.  Results should be 
retained in source records and added to the eCRF.
o
If labs are collected on site and cannot be processed (either via central lab 
shipping, or local labs), freeze (and maintain at correct temperature for 
later processing) those samples that are sent frozen. Please safely discard 
ambient samples per site standards.

When on-site visits are reduced, it is important that the investigator continue 
collecting relevant clinical information, including AEs/SAEs, from the participant 
through alternative means, e.g. by telephone contact. The assessment should 
include inquiries to determine if the participant has been impacted by COVID-19.  
Other protocol assessments and procedures as specified in the Schedule of 
Activities should be completed where possible (e.g. answer questions, update 
concomitant medications, emphasize adherence, plan/schedule participants return 
for next scheduled visit). This information should be placed in source records and 
entered into the eCRF when next possible. If the eC-SSRS assessment is able to 
be completed as part of the remote telephone visit, participants can complete the 
eC-SSRS at home by providing them with the activation code and the phone 
number or URL.  Where possible, the site should be in contact with the participant 
before and after the completion of the assessment to ensure proper follow-up of 
positive alerts and have plans in place for addressing any positive results, and 
referring for care as necessary. The HIV TSQ and SDM questionnaires may be 
completed over the phone.

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.
11.14.2.
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 


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the investigator contacting the participant by telephone or video call and obtaining verbal 
consent, supplemented with email confirmation.  
Any alternative informed consent procedure must be undertaken only after site 
IRB/Ethics Committee agreement and approval.
Any updated informed consent form or other participant-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.
The changes to the protocol, including COVID-19 related changes may be implemented 
before an ICF including COVID-19 related updates will be signed.
11.14.3.
Direct-To-Patient (DTP) Shipment of Study IP 
If a participant is unable to attend a study visit or to come to the site to pick-up 
investigational product (IP) due to site restrictions, or due to an inability to travel to the 
site (for personal precaution/sequestration, or government mandated travel restrictions, 
etc.), sites can consider DTP shipments of drug, from the site, to the participant, to ensure 
access to medicines.  All other options, including alternative travel options for 
participants, should be considered before reverting to DTP shipments.

If the study site is considering DTP shipment of 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. 

Enough IP to bridge to the next scheduled study visit can be supplied. For 
example, if the next visit is 12 weeks away, a 12-week supply can be dispensed 
via the IRT system
NOTE: When the visit interval is only 4 weeks, then at least 8 weeks of IP can be 
provided to the participant

Ensure local courier vendors, or vendors of hospital pharmacies, can ensure 
proper in-transit temperature monitoring, have enough shipper boxes and 
temperature loggers and can document storage conditions during IP 
transportation.

Where temperature monitoring is not available, oral DTG/3TC FDC can be 
shipped at ambient temperatures with couriers that can provide shipper boxes 
capable of maintaining the shipment temperature storage requirements as 
described in the study guides. The risk of going outside of the excursion ranges 


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listed in the study guide should be evaluated and documented. Proper 
documentation of the shipment should be maintained. In all cases IP 
accountability must be maintained, and all DTP dispensing documentation should 
be reflected in source records and dispensing logs per GCP.

Please refer to your CRA or local study manager for support with the DTP 
process, ensuring reference to current sponsor guidance and arrangement of a 
courier that can support shipment of IP directly to participants.

Remember that any courier deliveries can be affected by limitations of 
movements imposed by governments in relation to COVID-19. 

Local courier vendors should be equipped to reduce risks of COVID-19 
contamination during transportation.
11.14.4.
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.
If any participants are being considered for enrolment into clinical studies for COVID-19 
treatment or vaccinations, please consult with the study medical monitor to ensure that 
relevant drug interactions are considered and to ensure that continued study participation 
remains appropriate. The protocols do not allow for enrolment in other interventional 
studies, though, there may be exceptions in this pandemic. Please discuss with the study 
team and Medical monitor.
11.14.5.
COVID-19 Specific Data Capture
11.14.5.1. 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 DTP 
supply of IP and remote study visits 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 
DTP supply of IP, 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 should be clearly identified as such 
within the protocol deviation description and summarised separately. 


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All deviations need to be documented in the participant’s source records and placed in a 
dedicated COVID-19 folder.  The site should continue to manage and submit protocol 
deviations per local requirements.
11.14.5.2. Capturing COVID-19 Specific AEs and SAEs
It is important for the study team to describe COVID-19 related adverse events/serious 
adverse and their impact on study data and outcomes. Standardization of case definitions 
will facilitate future data analysis. 
Please use the following guidance: 
1.
AEs should continue to be evaluated as to whether they meet SAE criteria as 
defined in the protocol, and if so, submitted according to established SAE 
reporting requirements. SAEs and AEs should be submitted following usual study 
procedures and timelines. 
2.
When an in-person clinic visit is not possible, please conduct a remote telehealth 
visit to assess for, and document any AEs/SAEs.
3.
Investigators should use the WHO definition to classify COVID-19 cases. The 
definition below, released March 20, 2020, represents a time point for 
standardized collection. We recognize definitions are likely to continue to evolve. 
When reporting both serious and non- serious adverse events (related to COVID-
19 infection), investigators should use the following Verbatim terms: 
a) Suspected COVID-19 infection; or 
b) Probable COVID-19 infection; or 
c) Confirmed COVID-19 infection 
4.
Sites should contact the study Medical Monitor for questions related to definitions 
and reporting, and decisions around impact to study drug continuation. 
5.
A new COVID-19 infection Case Report Form will be added to the eCRF to 
collect additional details about the reported COVID-19 AE or SAE data. It is 
important to collect the correct information from each participant reporting a 
COVID-19 AE or SAE. Therefore, please use the CRF templates to help you 
collect this information for all COVID-19 related AEs/SAEs, once available.


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WHO Case Definition (March 20, 2020 Version) (https://www.who.int/publications-
detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov)): 
Suspected case: 
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset; 
OR 
B. A patient with any acute respiratory illness AND in contact (see definition of 
“contact” below) with a confirmed or probable COVID-19 case (see definition of 
contact) in the last 14 days prior to symptom onset; 
OR 
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation. 
Probable case: 
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory). 
OR 
B. A suspect case for whom testing could not be performed for any reason. 
Confirmed case: 
A person with laboratory confirmation of COVID-19 infection, irrespective of clinical 
signs and symptoms. 
Covid-19 Contact:
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case: 
1. Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes; 
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. 


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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.


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11.15.
Appendix 15: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 01, 26-MAR-2018
Overall Rationale for the Amendment: A global amendment applicable to all 
participating countries to clarify entry criteria, correct errors and improve consistency.
Section # and Name
Description of Change
Brief Rationale
Section 1.2: Schema
Section 8.1.3: Exploratory 
Efficacy Endpoints
Section 9.4.1:  Efficacy 
Analyses
Changed DTG + 3TC to DTG/3TC FDC
To improve 
consistency
Section 1.3:  Schedule of 
Activities (SoA)
X was removed at Week 4 and Week 52 for PK 
sampling 
To correct an error 
in the original 
protocol
Section 2.3.1: Risk 
Assessment
Updated DTG: Drug induced liver injury (DILI) and 
other clinically significant liver chemistry elevations 
to add: ‘A review of postmarketing data found that 
the number of cases reporting particularly severe 
liver dysfunction was found to be very low in the 
context of exposure to DTG and DTG/ABC/3TC. 
The reported cases of severe liver dysfunction 
(including acute hepatic failure) are complex with 
potential confounding factors but in a very small 
number of cases, drug-induced liver injury is likely 
and the role of DTG containing regimens cannot 
be ruled out particularly in those involving DTG 
with ABC/3TC or DTG/ABC/3TC.’
To provide updated 
language to further 
inform risk 
assessment
Section 4.1: Overall Design, 
Protocol Title, Short Title
Updated Phase IIIb to Phase III
To clarify study 
Phase
Section 5.1:  Inclusion Criteria
Inclusion criterion 5 was updated to add ‘or from 
tenofovir disoproxil fumarate (TDF) to tenofovir 
alafenamide (TAF)’ to read ‘A switch from a PI 
boosted with RTV to the same PI boosted with 
cobicistat is allowed (and vice versa). A switch 
from lamivudine (3TC) to emtricitabine (FTC) or 
from tenofovir disoproxil fumarate (TDF) to 
tenofovir alafenamide (TAF) is also allowed (and 
vice versa).’
Inclusion criterion 6 updated ’30 days’ to ’28 days’ 
to read ‘A WOCBP who agrees to follow the 
To clarify the study 
population intended 
to be enrolled; to 
align inclusion 
criterion 6 with the 
28 day Screening 
period


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Section # and Name
Description of Change
Brief Rationale
contraceptive guidance in Section 11.3.2 during the 
treatment period from 28 days prior to the first dose 
of study medication and until the last dose of study 
medication and completion of the follow-up visit. 
The investigator should evaluate the effectiveness 
of the contraceptive method in relationship to the 
first dose of study intervention.’
Section 5.2:  Exclusion Criteria
Exclusion Criterion 5 was updated to add 
‘Participants with a documented history of chronic 
HBV and current undetectable HBV DNA while on 
a TAF/TDF regimen are excluded.’
Exclusion Criterion 20 was updated to remove ‘with 
the exception of Grade 4 lipid abnormalities’ to 
read ‘Any verified Grade 4 laboratory abnormality.  
A single repeat test is allowed during the Screening 
period to verify a result.’
To clarify the study 
population intended 
to be enrolled
Amendment 02, 14-NOV-2018
Overall Rationale for the Amendment: A global amendment applicable to all 
participating countries to update the study design including length of study, updates to the 
eligibility criteria and removing the option to remain on the study if the participant 
becomes pregnant.  Additional changes were made to manage and mitigate risks
following identification of a potential safety issue related to neural tube defects in infants 
born to women with exposure to dolutegravir at the time of conception.  A sub-study was 
added to collect data on participants who withdraw for meeting CVW or PVW criteria. 


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Section # and Name
Description of Change
Brief Rationale
Section 1.1, Synopsis
Section 1.2, Schema
Section 1.3, Schedule of 
Activities
Section 2.1, Study Rationale
Section 3, Objectives and 
Endpoints
Section 4.1, Overall Design
Section 4.2, Number of 
Participants
Section 4.3, Participant and 
Study Completion
Section 4.4, Scientific 
Rationale for Study Design
Section 6.8, Treatment after 
the end of the study
Section 7.2, Withdrawal from 
the Study
Section 8.1.3, Exploratory 
Efficacy Endpoints
Study rationale updated based on shortened study 
design; minor updates to clarify several objectives 
and endpoints and removal of other objectives and 
endpoints to reflect updated study design; overall 
design section and Intervention groups and 
duration sections were updated to reflect a 52 
week study.  Participants on CAR will no longer 
switch at Week 52 as the study will end.  Only 
participants in the D3 arm will have the opportunity 
to enter a continuation phase; number of 
participants section was updated to reflect current 
goal to include 20% women and include a goal of 
approximately 20% participants on 
efavirenz/emtricitabine/tenofovir disoproxil 
fumarate and approximately 20% aged ≥50 years; 
study schematic updated based on shortened 
study design; schedule of activities updated based 
on shortened study design; the SDM will now be 
collected every 24 weeks during the continuation 
phase to address shortened study design; updated 
SoA footnotes as required.
To reflect 
shortened study 
design from 104 
weeks to 52 weeks
Section 1.3, Schedule of 
Activities
Section 1.4, Pregnancy SoA
Section 2.3, Risk/Benefit 
Assessment
Section 4.1, Overall Design
Section 4.3, Participant and 
Study Completion
Section 4.4, Scientific 
Rationale for Study Design
Section 6.8, Treatment after 
the end of the study
Section 7.2, Withdrawal from 
the Study
Section 8.2.6, Pregnancy
Section 8.2.7, Infant Outcomes
Section 8.2.8, Lactation
Section 8.5, Pharmocokinetics
Section 9, Statistical 
Considerations
Section 11.4. Appendix 4: 
Contraceptive Guidance and 
Collection of Pregnancy 
Information
Removed all text related to permitting participants 
to remain on study if they become pregnant; 
removed risk related to use in pregnancy as this is 
no longer permitted and added risk related to 
Neural Tube Defects; updated all sections to 
remove information related to PK sampling in 
pregnant participants; updated withdrawal criteria 
related to pregnancy; contraceptive guidance 
updated to remove double barrier method and 
collection of pregnancy information updated
To reflect updated 
study design to 
remove the option 
to remain on the 
study if the 
participant 
becomes pregnant; 
Updated to manage 
and mitigate risks 
following 
identification of a 
potential safety 
issue related to 
neural tube defects 
in infants born to 
women with 
exposure to 
dolutegravir at the 
time of conception.  
Section 5, Study population
Inclusion criteria 5 and 6 and exclusion criterion 28 
updated
To further clarify 
the study 
population
Section 1.1, Synopsis
Section 4.1, Overall Design
Section 7.1.1.2 Managing 
Added reference to and details of new CVW or 
PVW sub-study
A CVW or PVW 
sub-study was 
added to collect 


2 0 1 7 N 3 3 1 0 0 8 _ 0 6
C O N FI D E N TI A L
2 0 8 0 9 0
1 6 7
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
P artici p a nts M e eti n g 
Pr ec a uti o n ary Vir ol o gic 
Wit h dr a w al ( P V W) or 
C o nfir m e d Vir ol o gic 
Wit h dr a w al ( C V W) Crit eri a
S ecti o n 1 1. 2, A p p e n dix 2: A 
S u b -st u dy of Vir ol o gic 
Re s p o ns e t o S u bs e q u e nt A R T 
aft er Disc o nti n u ati o n fr o m 
2 0 8 0 9 0 f or M e eti n g C V W or 
P V W Crit eri a
a d diti o n al d at a o n 
p artici p a nts w h o 
wit h dr a w fr o m 
2 0 8 0 9 0 st u dy f or 
m e eti n g C V W or 
P V W crit eri a
S ecti o n 8. 8, Bi o m ark ers
S ecti o n 1 1. 7, A p p e n dix 7 
Cli nic al L a b or at ory T ests
U p d at e d t o a d d Uri n e R B P/cr e ati ni n e r ati o a n d 
Uri n e B 2 M/cr e ati ni n e r ati o a n d cl arify t h at R B P a n d 
B 2 M will b e uri n e s a m pl e o nly a n d n ot bl o o d
T o f u rt h er cl arify 
w h at bi o m ark ers 
will b e c oll ect e d 
d uri n g t his st u dy
S ecti o n 1. 3, Sc h e d ul e of 
Activiti es
S ecti o n 8. 1 0. 1, HI V -1 
Ex pl or at ory A n alysis
U p d at e d t o a d d vir al D N A q u a ntit ati o n a n d i ncl u d e   
l a n g u a g e ar o u n d c oll ecti o n of P B M Cs/ w h ol e bl o o d
T o all o w f o r 
a d diti o n al Vir ol o gy 
ex pl or at ory a n alysis
S ecti o n 1 1. 9, A p p e n dix 9: Liv er 
S af ety: R e q uir e d Acti o ns a n d 
F oll o w -u p Ass ess m e nts a n d 
St u dy I nt erv e nti o n R est art 
G ui d eli n es
Liv er s af ety r e q uir e m e nts w er e u p d at e d 
U p d at e d t o ali g n 
wit h c urr e nt Vii V 
S af ety a n d 
L a b elli n g 
C o m mitt e e ( V S L C) 
g ui d eli n es
Titl e P a g e, A ut h ors
S ecti o n 2, I ntr o d ucti o n
S ecti o n 2. 2, B ack gr o u n d
S ecti o n 8. 1, Effic acy 
Ass ess m e nts
S ecti o n 8. 5, P h ar m ac oki n etics
S ecti o n 8. 9 H e alt h Ec o n o mics 
a n d O utc o m es R es e arc h
S ecti o n 9, St atistic al 
C o nsi d er ati o ns
S ecti o n 1 0, R ef er e nc es
A ut h ors list u p d at e d t o a d d
, 
a n d 
a n d t o r e m ov e 
, 
a n d 
; Cl arifyi n g d et ails r e g ar di n g P K 
c oll ecti o n f or ov er d os e a d d e d; S ecti o n 8. 9 H e a di n g 
u p d at e d t o i ncl u d e o utc o m es r es e arc h; T a bl e 2 
u p d at e d t o a d d r ec e nt st u di es a n d ot h er mi n or 
c h a n g es; r ef er e nc es u p d at e d
T o r efl ect mi n or 
u p d at es f or cl arity 
a n d a d diti o n al 
r ec e nt d at a a d d e d 
f or c o m pl et e n ess
A m e n d me nt 0 3, 2 5- M A R -2 0 1 9
O ver all R at i o n ale f or t he A me n d me nt:
P P D
A gl o bal a me n d me nt , f or a d mi nistrati ve 
p ur p oses, a p plica ble t o all partici pati n g c o u ntries . E dits t o i ncrease clarit y ar o u n d 
c ollecti o n of vir ol o g y s peci me ns f or a d diti o nal testi n g, t he ti mi n g of t he e C S S R S 
q uesti o n naire i n relati o n t o me dicati o n a d mi nistrati o n, a n d f oll o w -u p f or A Es were ma de. 
A d diti o nal c ha n ges were ma de t o c orrect e diti n g err ors relate d t o t he ta bles f or li ver 
st o p pi n g criteria, w hic h c o ntai ne d b ot h G S K a n d Vii V-s pecific st o p pi n g criteria. T his 
a me n d me nt re m o ve d t he G S K i nf or mati o n. N o c ha n ges were ma de t o t he Vii V-s pecific 
criteria t hat was i ncl u de d i n t he pre vi o us versi o n.  
P P D
P P D
P P D
P P D
P P D


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Section # and Name
Description of Change
Brief Rationale
Section 1.3, Schedule of Activities
Updated SoA footnote “d” for clarity
Add language for clarity
Section 7.1.2, Liver Chemistry 
Stopping Criteria
Removed algorithm and added 
verbiage to clarify when discontinuation 
of study intervention is required
Correction of editing errors 
inadvertently left in the 
previous protocol version
Add language for clarity
Section 8.10.1, HIV-1 Exploratory 
Analysis
Clarified language around use of 
samples for additional testing 
Add language for clarity
Section 11.9 Appendix 9: Liver 
Safety: Required Actions and 
Follow-up Assessments and Study 
Intervention Restart Guidelines
Clarified language for required actions 
and follow-up for liver events
Add language for clarity
Section 11.9.1, Liver Chemistry 
Stopping Criteria:  Required 
Actions and Follow up 
Assessments
Removed duplicate criteria from table
Correction of editing errors 
inadvertently left in the 
previous protocol version
Section 11.9.2, Study Intervention 
Restart after Stopping for Liver 
Criteria
Updated Section title
Clarified language for ViiV-specific 
criteria for restart after stopping for a 
liver event
Correction of editing errors
Add language for clarity
Amendment 03/CHI-1, 31-MAY-2019
Overall Rationale for the Country-Specific Amendment: This is a country-specific
amendment for administrative purposes applicable only to China. All edits removed those
tests which are not able to be conducted in China due to laboratory limitations. These
include collection of specific virology specimens for virological testing of linkage and
minority species analyses, low level HIV-1 RNA quantitation, viral DNA quantitation,
measurement of viral replicative capacity all biomarkers, and those of telomerase
function and length. Additionally, in the event of any liver stopping events, the
requirements for serum acetaminophen, and blood samples for pharmacokinetic (PK)
analysis were deleted for the same reason.
Section # and Name
Description of Change
Brief Rationale
Section 8.8, Biomarkers 
Removed all biomarkers 
Will not be conducted in 
subjects at study sites in 
China. Remaining 
analytes/tests are
medically necessary
Section 8.10, HIV-1 Polymerase 
Viral Genotyping and Phenotyping
Revised description of specific
virology specimens and tests
performed.
Will not be conducted in 
subjects at study sites in 
China. Those tests which 
remain are medically 
necessary and not for 
exploratory purposes.
Section 8.10.1, HIV-1 Exploratory
Analysis
Section deleted.
Will not be conducted in 
subjects at study sites in 
China. Those tests which 
remain are medically 


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Section # and Name
Description of Change
Brief Rationale
necessary and not for 
exploratory purposes.
Section 1.3, Schedule of Activities
(SoA)
Deleted SoA list of tests and the
accompanying footnotes
bb,cc,dd,ee.and ff and updated order
of footnotes accordingly
Revised to reflect only
those tests to be
conducted in subjects at
study sites in China
Section 3. Objectives and 
Endpoints 
Deleted phenotypic resistance;
Exploratory section title revised to
Tertiary. Revised row two objectives
and endpoints and deleted row three
information
Revised for clarity
Section 7.1.1.2., Managing 
Participants Meeting Precautionary 
Virologic Withdrawal (PVW) or 
Confirmed Virologic Withdrawal 
(CVW) Criteria
Deleted phenotype/phenotypic from
section
Revised for clarity.
Section 8.1 Efficacy Assessments 
Clarified HIV RNA quantification
methods. Deleted text referring to
exploratory analyses
Revised for clarity
Section 8.4, Treatment of Overdose Removed text regarding plasma sample 
for PK analysis
Will not be conducted in
subjects at study sites in
China.
Section 8.5, Pharmacokinetics,
subsections Liver Event and 
Overdose
Statements regarding plasma sample 
for PK analysis were deleted
Will not be conducted in
subjects at study sites in
China
Section 9.4.1. Efficacy Analyses 
and Section 9.4.2. Safety Analyses
Removed text referring to exploratory
analyses
Revised for clarity
Section 11.2.2., Sub-study 
Objectives and Endpoints
Subtitle for Table revised to Tertiary,
as this information from this substudy
is of medical importance
Revised for clarity
Section 11.7 Appendix 7: Clinical
Laboratory Tests, Table 5, Protocol
Required Safety Laboratory
Assessments
Revised table contents and footnotes
Revised to reflect only
those tests to be
conducted in subjects at
study sites in China .
Section 11.9.1, Liver Chemistry
Stopping Criteria: Required Actions
and Follow up Assessments
Removed text and accompanying
footnote regarding serum
acetaminophen and blood sample for
pharmacokinetic analysis
Will not be conducted in
subjects at study sites in
China .
Section 11.13, Country specific
requirements
The rationale for making this
amendment is provided.
All laboratory tests are
required to be conducted
within country.
Section 11.14, Protocol 
amendment history
All prior protocol amendments are
listed.
Standard practice to list
prior protocol
amendments


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Amendment 03/SWE-DEN-1, 29-JUL-2019
Overall Rationale for the Amendment: This is a country-specific amendment for
administrative purposes applicable only to Sweden and Denmark. All edits were made to
remove all reference to the Continuation Phase. Participants in both treatment arms will
now finish the study at Week 52. This amendment was required for Sweden and
Denmark to update the protocol with a clear time for the study´s conclusion based on
scientific basis without any reference to market approval.
Section # and Name
Description of Change
Brief Rationale
Section 1: Protocol Summary, 
Section 1.2: Study Schematic, 
Section 1.3: Schedule of Activities 
and footnotes
Section 2.3.1: Risk Assessment, 
Section 3: Objectives and 
Endpoints
Section 4.1: Overall Design
Section 4.3: Participant and Study 
Completion 
Section 6.7: Concomitant Therapy
Section 6.8: Treatment after the 
end of the study
Section 7.1: Discontinuation of 
study intervention
Section 11.13: Appendix 13, 
Country Specific Requirements
The continuation phase was removed 
from all applicable sections of the 
protocol.
This amendment was 
required for Sweden and 
Denmark to update the 
protocol with a clear time 
for the study´s conclusion 
based on scientific basis 
without any reference to 
market approval.