Clinical trial NCT03446573
Conditions: HIV Infections
Keywords: Switch study Non-inferiority Human immunodeficiency virus type 1 Tenofovir alafenamide Dolutegravir Lamivudine
Sponsor: ViiV Healthcare
Start date: 2018-01-18; Completion date: 2022-05-03
Enrollment: 743 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of the study is to establish if human immunodeficiency virus type 1 (HIV-1) infected adult participants with current virologic suppression on a \>=3-drug tenofovir alafenamide (TAF) based regimen (TBR) remain suppressed upon switching to a two-drug regimen of dolutegravir (DTG) 50 milligram (mg) + lamivudine (3TC) 300 mg. This study will also provide important information regarding the safety and participant satisfaction with this two-drug regimen. The primary objective of this trial is to demonstrate the non-inferior antiviral activity of switching to DTG + 3TC once daily compared to continuation of TBR over 48 weeks in HIV-1 infected, antiretroviral therapy (ART)-experienced, virologically suppressed participants. This study also will characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC compared to TBR through Week 144 and characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC through Week 200.

This will be a 200-week, Phase III, randomized, open-label, active-controlled, multicenter, parallel- group study. The study will include a screening phase (up to 28 days), a randomized early switch phase (Day 1 up to Week 148), a randomized late switch phase (Week 148 up to Week 200), and a continuation phase (post Week 200). HIV-1 infected adults on stable TBR will be randomized 1:1 to switch to DTG + 3TC once daily for up to 200 weeks, or to continue their TBR for 148 weeks, at which time and if HIV-1 ribonucleic acid (RNA) \<50 copies per milliliter (c/mL) at Week 144, these participants will switch to DTG + 3TC up to Week 200.

Detailed description:

Arms: arm 1: Participants will receive a single tablet of a two-drug regimen of DTG 50 mg + 3TC 300 mg once daily from Day 1 through Week 200 (Early and Late Switch Phase). arm 2: Participants will continue their TBR from Day 1 to Week 148 (Early Switch Phase), and eligible participants will switch to DTG + 3TC once daily from Week 148 to 200 (Late Switch Phase).
Interventions: intervention 1: DTG + 3TC intervention 2: TAF based regimen (TBR)
Intervention descriptions: intervention 1: DTG+3TC is supplied as white, oval, film-coated, fixed dose combination tablet. The tablets will be available in packed high density polyethylene (HDPE) bottles with induction seals and child-resistant closures. intervention 2: Participants will continue to receive their TBR.

Protocol documents:
Prot_002.pdf: 
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TI T L E P A G E
Di visi o n: W orl d w i de De vel o p me nt
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt
Title:
A P hase III, ra n d o mize d, m ultice nter, parallel -gr o u p, 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 pl us la mi v u di ne i n HI V 1 i nfecte d 
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De vel o p me nt P h ase:
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2015N242992_07
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ViiV Healthcare group of companies
204862
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N242992_00
2017-FEB-27
Original
2015N242992_01
2017-MAY-16
Amendment No. 1
Tenofovir alafenamide (TAF) was corrected by removal of the word “fumarate”. 
Clarification was provided in the overall design to specify that subjects randomized to 
TBR will switch to DTG + 3TC at Week 52 if HIV-1 RNA <50 c/mL at Week 48 (or 
upon retest by Week 52). 
Biomarkers of inflammation and mitochondrial function were removed as exploratory 
endpoints.  
A Week 96 endpoint was added to the measurement of biomarkers of telomerase 
function in a subset of subjects.
Cardiovascular biomarker measurements were removed as exploratory endpoints. 
Inclusion Criteria #5 was edited for clarity.  
Section 6.2, Protocol Permitted Substitutions, added.
The text defining the TBR comparators as investigational medicinal product was 
removed; TBR comparators will be provided in designated, specific countries only, as 
needed. 
The Time and Events Table was modified to clarify that whole blood samples may be 
utilized for virology and for telomere length measurements, and cryopreserved PBMCs 
will be used to evaluate telomerase activity.
Updated version of Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (v2.1), March 2017, was provided in Section 12.9.
Changes were made to the protocol text to reflect the addition of Country Specific 
requirements for Japan. 
Minor revisions were made to the text to correct errors and improve accuracy. 
2015N242992_02
2017-JUN-13
Amendment No. 2
The impetus for this protocol amendment was to update Appendix 5, Appendix 6 and 
Appendix 8 based on the ViiV Healthcare templates for these appendices which are 
appropriate for the HIV patient population. The prior versions of these appendices were 
based on a general GSK template and were not appropriate. During this process, other 
updates were made to the protocol which are summarized in Appendix 12.
2015N242992_03
2017-AUG-24
Amendment No.3
Amended to include: Addition of CD8+ Lymphocyte assessments, addition of 
inflammatory biomarkers assessments as new exploratory endpoints, revision of the 
sample size based on updated estimates for the primary endpoint for the investigational 
arm, and minor clarifications and corrections of typographical errors.


2015N242992_07
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ViiV Healthcare group of companies
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2015N242992_04
2017-DEC-07
Amendment No. 4
Amended to include pharmacokinetics assessments in the DTG/3TC FDC arm as 
exploratory endpoints; to update exclusion criterion 18 and remove its corresponding 
secondary endpoint no longer relevant; to add HbA1c and HOMA-IR assessments,
For clarification purposes, the AE severity gradings in Appendix 8, Section 13.8.6 
(Evaluating AEs and SAEs) were updated to be consistent with Appendix 9, Section 13.9. 
(Division of AIDS table for Grading Severity of Adult and Pediatric Adverse Events).  
This change has no impact on the investigator’s evaluation of adverse events.
Minor revisions were made to the text to provide updated information, correct errors and 
improve accuracy and consistency. Text was edited in Appendix 10, Section 13.10.2. to 
clarify wording for the country specific requirement for Japan.
2015N242992_05
2018-JUN-14
Amendment No. 5
Changes were made to the protocol 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.  Changes were also made to include 
updated text to address a higher number of participants screened than planned, to update 
references to the DTG IB to reflect the most current versions and to add clarification and 
correct minor typos.  
1. The Risk Assessment table (Section 4.6.1) was updated to include language regarding 
risk and mitigation of neural tube defects.
2. The withdrawal criteria (Section 5.4) were updated to include a reminder that 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.
3. The Time and Events table (Section 7.1). was updated to include a reminder for 
investigators to check at every visit that females of reproductive potential are 
avoiding pregnancy.
4. The modified list of highly effective methods for avoiding pregnancy in FRP (Section
13.3.1) was updated to exclude the double barrier method of contraception, which 
does not meet updated GSK/ViiV criteria for a highly effective method.
5. The Type and Number of Subjects (Section 4.3) and Sample Size Assumptions
(Section 9.2.1) were updated to address a higher number of participants screened than 
planned.
2015N242992_06
2018-AUG-29
Amendment No. 6
Changes were made to the protocol to update the study design to extend the Randomized 
Early Switch Phase through to 148 weeks instead of Week 52, delaying the late switch to 
Week 148 with long term follow-up through to completion of the study at Week 200.  


2015N242992_07
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ViiV Healthcare group of companies
204862
4
The rationale for this change is to collect and assess long-term comparative efficacy and 
safety data for DTG + 3TC FDC vs. a TAF-based regimen.  
2015N242992_07
2020-APR-27
Amendment No. 7
Changes were made to the protocol to introduce metabolic health exploratory objectives 
including metabolic syndrome, cardiovascular risk and other anthropomorphic measures 
to assess type and implication of weight change overtime. Additional on-treatment 
assessments from Week 144 through Week 196, include resting blood pressure, waist 
circumference and hip circumference. Changes were also made to include an additional 
appendix to provide standardized procedural guidance on obtaining the above mentioned 
measurements. A missing assessment of concomitant medication at Week 148 was also 
corrected. Results from the Botswana outcome surveillance study were updated for DTG 
and neural tube defects.


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2
 
To approve the clinical protocol amendment indicated below, reply to this email and state your approval. 
 
PROTOCOL NUMBER: 204862 
 
DOCUMENT IDENTIFIER:  2015N242992_07 
 
AMENDMENT NUMBER: 07 
PROTOCOL TITLE: A Phase III, randomized, multicenter, parallel‐group, non‐ inferiority study evaluating the efficacy, 
safety, and tolerability of switching to dolutegravir plus lamivudine in HIV 1 infected adults who are virologically 
suppressed 
 
Name of Sponsor Signatory: 
 
Sherene Shakib Min, MD, MPH 
Title of Sponsor Signatory: 
Vice President, Head of Clinical Development 
 
 
 


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M E DI C A L M O NI T O R/ S P O N S O R I N F O R M A T I O N P AG E
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2015N242992_07
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204862
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


2015N242992_07
CONFIDENTIAL
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8
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204862......................................................13
2.
INTRODUCTION....................................................................................................17
2.1.
Study Rationale ..........................................................................................17
2.2.
Brief Background ........................................................................................19
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................21
4.
STUDY DESIGN ....................................................................................................25
4.1.
Overall Design ............................................................................................25
4.2.
Treatment Arms and Duration.....................................................................26
4.2.1.
Screening Period (Up to 28 days) ................................................26
4.2.2.
Early Switch Phase (Day 1 up to Week 148)................................26
4.2.3.
Late Switch Phase (Week 148 to Week 200)...............................27
4.2.4.
Continuation Phase (Post Week 200) ..........................................28
4.3.
Type and Number of Subjects.....................................................................28
4.4.
Design Justification.....................................................................................28
4.5.
Dose Justification........................................................................................30
4.6.
Benefit:Risk Assessment ............................................................................31
4.6.1.
Risk Assessment .........................................................................32
4.6.2.
Benefit Assessment.....................................................................36
4.6.3.
Overall Benefit:Risk Conclusion...................................................36
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............37
5.1.
Inclusion Criteria.........................................................................................37
5.2.
Exclusion Criteria........................................................................................39
5.3.
Screening Failures......................................................................................41
5.4.
Withdrawal and Stopping Criteria................................................................41
5.4.1.
Virologic Criteria for Subject Management and Viral 
Resistance Testing ......................................................................43
5.4.1.1.
Subjects Meeting Virologic Management
Criteria........................................................................43
5.4.1.2.
Managing Subjects Meeting Precautionary 
Virologic Withdrawal (PVW) or Confirmed 
Virologic Withdrawal (CVW) Criteria...........................44
5.4.2.
Liver Chemistry Stopping Criteria ................................................48
5.4.2.1.
Study Treatment Restart ............................................49
5.5.
Subject and Study Completion....................................................................49
6.
STUDY TREATMENT ............................................................................................51
6.1.
Investigational Product and Other Study Treatment....................................51
6.2.
Protocol-Permitted Substitutions.................................................................51
6.3.
Treatment Assignment................................................................................51
6.4.
Planned Dose Adjustments.........................................................................52
6.5.
Blinding.......................................................................................................52
6.6.
Packaging and Labeling..............................................................................52
6.7.
Preparation/Handling/Storage/Accountability..............................................52
6.8.
Compliance with Study Treatment Administration.......................................53


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6.9.
Treatment of Study Treatment Overdose....................................................53
6.10.
Treatment after the End of the Study ..........................................................54
6.11.
Concomitant Medications and Non-Drug Therapies....................................54
6.11.1.
Permitted Medications and Non-Drug Therapies..........................54
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................55
6.11.2.1.
Prohibited Medications for Subjects Receiving 
DTG + 3TC.................................................................56
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................57
7.1.
Time and Events Table...............................................................................58
7.1.1.
Early Switch Phase Time and Events Table (Screening to 
Week 148) ...................................................................................58
7.1.2.
Late Switch Phase Time and Events Table: TBR subjects 
who switched to DTG + 3TC at Week 148 ...................................62
7.1.3.
Late Switch Phase Time and Events Table: DTG + 3TC 
arm ..............................................................................................64
7.2.
Screening and Critical Baseline Assessments ............................................67
7.2.1.
Screening Assessments ..............................................................67
7.2.2.
Baseline Assessments.................................................................68
7.3.
Efficacy.......................................................................................................68
7.3.1.
Efficacy Evaluations.....................................................................68
7.3.1.1.
Primary Efficacy Endpoint...........................................69
7.3.1.2.
Secondary Efficacy Endpoints ....................................69
7.3.1.3.
Exploratory Efficacy Endpoints ...................................69
7.4.
Safety .........................................................................................................70
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........70
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................70
7.4.1.2.
Method of Detecting AEs and SAEs ...........................71
7.4.1.3.
Follow-up of AEs and SAEs........................................71
7.4.1.4.
Cardiovascular and Death Events ..............................71
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................71
7.4.1.6.
Regulatory Reporting Requirements for SAEs............72
7.4.2.
Pregnancy ...................................................................................72
7.4.3.
Physical Exams ...........................................................................73
7.4.4.
Vital Signs....................................................................................73
7.4.5.
Electrocardiogram (ECG).............................................................73
7.4.6.
Clinical Safety Laboratory Assessments ......................................73
7.4.7.
Suicidal Risk Monitoring...............................................................76
7.5.
Biomarkers .................................................................................................77
7.6.
HIV-1 Polymerase Viral Genotyping and Phenotyping ................................77
7.6.1.
HIV-1 Exploratory Analysis ..........................................................78
7.7.
Value Evidence and Outcomes...................................................................78
7.8.
Pharmacokinetic Assessments ...................................................................79
8.
DATA MANAGEMENT ...........................................................................................79
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................80
9.1.
Hypotheses.................................................................................................80
9.2.
Sample Size Considerations.......................................................................80
9.2.1.
Sample Size Assumptions ...........................................................80


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9.2.1.1.
Rationale for non-inferiority margin.............................80
9.2.1.2.
Response and Virologic Failure rate 
assumptions ...............................................................81
9.2.2.
Sample Size Sensitivity................................................................82
9.2.3.
Sample Size Re-estimation or Adjustment...................................82
9.3.
Data Analysis Considerations .....................................................................82
9.3.1.
Analysis Populations....................................................................82
9.3.1.1.
Intent-to-Treat Exposed (ITT-E) Population ................82
9.3.1.2.
Per Protocol (PP) Population......................................82
9.3.1.3.
Safety Population .......................................................83
9.3.2.
Analysis Data Sets.......................................................................83
9.3.3.
Treatment Comparisons ..............................................................83
9.3.3.1.
Primary Comparison of Interest ..................................83
9.3.3.2.
Other Comparisons of Interest....................................84
9.3.4.
Interim Analysis ...........................................................................84
9.4.
Key Elements of Analysis Plan ...................................................................85
9.4.1.
Efficacy Analyses.........................................................................85
9.4.2.
Safety Analyses...........................................................................86
9.4.3.
Health Outcome Analyses ...........................................................87
9.4.4.
Viral genotyping/phenotyping Analyses .......................................87
9.4.5.
Pharmacokinetic Analysis............................................................87
10. STUDY GOVERNANCE CONSIDERATIONS........................................................88
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............88
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................88
10.3.
Quality Control (Study Monitoring) ..............................................................89
10.4.
Quality Assurance.......................................................................................89
10.5.
Study and Site Closure ...............................................................................89
10.6.
Records Retention......................................................................................90
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................91
10.8.
Independent Data Monitoring Committee....................................................91
11. PHARMACOKINETIC SUBSTUDY ........................................................................92
11.1.
Rationale for Pharmacokinetic Evaluation...................................................92
11.1.1.
Exploratory Objectives.................................................................92
11.1.2.
Exploratory Endpoints..................................................................92
11.1.3.
Pharmacokinetic Sample Collection.............................................92
11.1.4.
Bioanalysis of DTG and 3TC Samples.........................................94
11.1.5.
Pharmacokinetic Populations.......................................................94
11.1.6.
Pharmacokinetic Analyses...........................................................94
11.1.7.
Population PK..............................................................................95
12. REFERENCES.......................................................................................................96
13. APPENDICES......................................................................................................101
13.1.
Appendix 1: Abbreviations and Trademarks..............................................101
13.2.
Appendix 2: Toxicity Management ............................................................105
13.2.1.
Specific Toxicities/Adverse Event Management.........................106
13.2.1.1.
Liver Chemistry Stopping and Follow-up 
Criteria......................................................................106


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13.2.1.2.
Restarting Study Drug ..............................................106
13.2.1.3.
Decline in Renal Function.........................................107
13.2.1.4.
Proteinuria................................................................107
13.2.1.5.
Allergic reaction........................................................107
13.2.1.6.
Rash.........................................................................108
13.2.1.7.
Hypertriglyceridemia/Hypercholesterolemia..............108
13.2.1.8.
Creatine Phosphokinase (CPK) Elevation ................109
13.3.
Appendix 3:  Pregnancy Information .........................................................110
13.3.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) 
and Collection of Pregnancy Information ...................................110
13.3.2.
Collection of Pregnancy Information ..........................................110
13.4.
Appendix 4: Child-Pugh Classification ......................................................112
13.5.
Appendix 5: Liver Safety - Required Actions and Follow up 
Assessments ............................................................................................113
13.6.
Appendix 6:  Liver Safety - Study Treatment Restart Guidelines...............116
13.7.
Appendix 7: CDC Classification for HIV-1 Infection (2014)........................120
13.8.
Appendix 8: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................122
13.8.1.
Definition of Adverse Events......................................................122
13.8.2.
Definition of Serious Adverse Events.........................................123
13.8.3.
Definition of Cardiovascular Events ...........................................124
13.8.4.
Sentinel Events..........................................................................125
13.8.5.
Recording of AEs and SAEs ......................................................125
13.8.6.
Evaluating AEs and SAEs..........................................................126
13.8.7.
Reporting of SAEs and other events to ViiV/GSK/PPD ..............127
13.9.
Appendix 9: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version 2.1, March 2017............................128
13.10. Appendix 10: Protocol Recommendation for Assessment of Waist 
Circumference, Hip Circumference and Weight (Adapted from WHO 
STEPS Surveillance Manual, 2017) and for Resting Blood Pressure........156
13.10.1. Waist Circumference .................................................................156
13.10.2. Hip Circumference.....................................................................158
13.10.3. Weight .......................................................................................159
13.10.4. Resting Blood Pressure .............................................................160
13.11. Appendix 11:  Country Specific Requirements..........................................161
13.11.1. United Kingdom .........................................................................161
13.11.2. Japan.........................................................................................161
13.12. Appendix 12 Protocol Changes.................................................................162
13.12.1. Amendment 01 (2017-MAY-16): A global amendment 
applicable to all participating countries.......................................162
13.12.2. Protocol changes for Amendment 02 (2017-JUN-13) from 
Amendment 01 (2017-MAY-16): A global amendment 
applicable to all participating countries.......................................169
13.12.3. Protocol changes for Amendment 03 (2017-AUG-24) from 
Amendment 02 (2017-JUN-13): A global amendment 
applicable to all participating countries.......................................171
13.12.4. Protocol changes for Amendment 04 (2017-DEC-07) from 
Amendment 03 (2017-AUG-24): A global amendment 
applicable to all participating countries.......................................189


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13.12.5. Protocol changes for Amendment 05 (14-JUN-2018) from 
Amendment 04 (2017-DEC-07): A global amendment 
applicable to all participating countries.......................................207
13.12.6. Protocol changes for Amendment 06 (29-AUG-2018) from 
Amendment 05 (14-JUN-2018)..................................................211
13.12.7. Protocol changes for Amendment 07 (27-APR-2020) from 
Amendment 06 (29-AUG-2018) .................................................255


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1.
PROTOCOL SYNOPSIS FOR STUDY 204862
Rationale
Study 204862 is being conducted to establish if human immunodeficiency virus type 1 
(HIV-1) infected adult subjects with current virologic suppression on a ≥3-drug tenofovir 
alafenamide (TAF) based regimen (TBR) remain suppressed upon switching to a two-
drug regimen of dolutegravir (DTG) 50 mg + lamivudine (3TC) 300 mg.  This study also 
will provide important information regarding the safety of, and patient satisfaction with 
this two-drug regimen. This trial is designed to demonstrate the non-inferior antiviral 
activity of switching to DTG + 3TC once daily compared to continuation of TBR over 48 
weeks.  This study also will characterize the long-term antiviral activity, tolerability and 
safety of DTG + 3TC compared to TBR through Week 144 and characterize the long-
term antiviral activity, tolerability and safety of DTG + 3TC through Week 200.
Objective(s)/Endpoint(s)
Objective
Endpoint
Primary
To demonstrate the non-inferior antiviral 
activity of switching to DTG +3TC once daily 
compared to continuation of TBR over 48 
weeks in HIV-1 infected, ART therapy (ART)-
experienced, virologically suppressed subjects
Virologic failure endpoint as per FDA snapshot 
category at Week 48
Secondary
To demonstrate the antiviral activity of 
switching to DTG +3TC once daily compared to 
continuation of TBR over 48 weeks 
Proportion of subjects with plasma HIV-1 RNA 
<50 copies c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 24 weeks, 96 
weeks and 144 weeks
Virologic failure endpoint as per FDA 
snapshot category at Weeks 24, 96 and 144
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL at Weeks 24, 96 and 144 using the 
Snapshot algorithm for the ITT-E population
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
over 24, 48, 96 and 144 weeks
Change from Baseline in CD4+ cell count and 
in CD4+/CD8+ cell counts ratio at Weeks 24,
48, 96 and 144
Incidence of disease progression (HIV-
associated conditions, AIDS, and death) 
through Weeks 24, 48, 96, and 144
To evaluate the safety and tolerability of DTG + 
3TC once daily compared to TBR over time
Incidence and severity of AEs and laboratory 
abnormalities through 144 weeks
Proportion of subjects who discontinue 
treatment due to AEs through 144 weeks
To evaluate the effects of DTG + 3TC once 
daily on fasting lipids over time compared to 
TBR
Change from Baseline in fasting lipids at Weeks 
24, 48, 96 and 144


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Objective
Endpoint
To assess viral resistance in subjects meeting 
Virologic Withdrawal Criteria
Incidence of observed genotypic and phenotypic 
resistance to ARVs for subjects meeting 
Virologic Withdrawal Criteria 
To evaluate renal (in urine and blood) and 
bone (in blood) biomarkers in subjects treated 
with DTG + 3TC compared to TBR
Change from Baseline in renal and bone 
biomarkers at Weeks 24, 48, 96 and 144
To assess health related quality of life for 
subjects treated with DTG + 3TC compared to 
TBR
Change from Baseline in health status using EQ-
5D-5L at Weeks 24, 48, 96 and 144 (or 
Withdrawal from the study)
Overall Design
This is a 200-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of replacing a 
TBR with a two-drug regimen of DTG + 3TC in HIV-infected adults who are 
virologically suppressed and stable on a TBR.  The study will include a Screening Phase 
(up to 28 days), a Randomized Early Switch Phase (Day 1 up to Week 148), a 
Randomized Late Switch Phase (Week 148 up to Week 200), and a Continuation Phase 
(post Week 200) if DTG + 3TC fixed dose combination (FDC) is not yet approved and 
available locally.  Approximately 550 HIV-1 infected adults who are on a stable TBR 
will be randomized 1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for up to 
200 weeks, or to continue their TBR for 148 weeks, at which time and if HIV-1 RNA 
<50 c/mL at Week 144 (or upon retest by Week 148), these subjects will switch to 
DTG + 3TC up to Week 200. For subjects randomized to the TBR, provisions will be in 
place, as needed and after discussion with the study team, to assist patients in obtaining 
their TBR during the study.  For subjects who switch to DTG + 3TC at Week 148, a 
separate Late Switch Phase Time and Events Table is provided in Section 7.1.2 as these 
participants will be monitored closely for the first 24 weeks post-switch. Subjects who 
remain on DTG + 3TC will follow a separate Late Switch Phase Time and Events Table 
in Section 7.1.3.
The primary endpoint for the study is the proportion of participants who meet the 
Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat Exposed (ITT-E) 
population.  The Week 48 primary analysis will take place after the last subject has had 
their Week 48 viral load assessed, including any retests.  Subjects randomized to 
DTG + 3TC will receive DTG + 3TC up to Week 200.  Subjects randomized to TBR will 
have a Week 148 switch visit, allowing approximately 4 weeks for subjects who have a 
viral load ≥50 c/mL at Week 144 to have a retest prior to switch.  The study will continue 
for at least 200 weeks.
The sample size is such that the study has 90% power to demonstrate non-inferiority 
using a 4% margin, assuming a true 2 % virologic failure rate at Week 48 and using a
2.5% one-sided alpha level.
A pharmacokinetic (PK) substudy in the DTG+3TC arm will be conducted to evaluate 
DTG and 3TC concentrations using a sparse PK sampling approach at designated visits 


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(See Section 11). In addition, intensive PK samples will be collected from a subgroup of 
subjects (approximately 30) enrolled at selected sites with the capability to perform 
intensive PK sampling. 
An Independent Data Monitoring Committee (IDMC) will be 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 this study.
Treatment Arms and Duration
The study will include a Screening Phase (up to 28 days), a Randomized Early Switch 
Phase (Day 1 up to Week 148), a Randomized Late Switch Phase (Week 148 up to Week 
200) and a Continuation Phase (post Week 200) if DTG + 3TC FDC is not yet approved 
and available locally.  Subjects randomized to DTG + 3TC will receive DTG + 3TC up to 
Week 200.  Subjects randomized to TBR will continue to take their current regimen up to 
Week 144, at which time and if HIV-1 RNA <50 c/mL at Week 144 (or upon retest by 
Week 148), these subjects will switch to DTG + 3TC up to Week 200.  Randomization 
will be stratified by baseline third agent class (protease inhibitor [PI], integrase inhibitor 
[INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]).
The primary analysis at Week 48 will take place after the last subject completes up to 52 
weeks on therapy, to allow for the collection of a confirmatory viral load measurement in 
subjects presenting with HIV-1 RNA 50 c/mL at the Week 48 visit.  The secondary 
analysis at Week 24 will take place after the last subject completes up to 28 weeks on 
therapy, to allow for the collection of a confirmatory viral load measurement in subjects 
presenting with HIV-1 RNA 50 c/mL at the Week 24 visit.  Further secondary analyses 
will take place at Week 96, 144 and 196. 
All subjects who successfully complete 200 weeks of treatment will complete the study 
and transition to locally approved and available DTG + 3TC fixed-dose combination 
(FDC) and be managed as per standard of care at their study site. Prior to completion of 
the Week 200 visit, sites will need to have confirmation that DTG + 3TC FDC is locally 
available for study subjects. If DTG + 3TC FDC is not yet approved and available 
locally, ViiV Healthcare will continue to provide study drug in a Continuation Phase 
until: 
DTG + 3TC FDC is locally approved for use as a 2-drug regimen, and available to 
subjects (e.g., through public health services or through their usual health 
insurance payer), or
the subject no longer derives clinical benefit, or 
the subject meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC dual regimen is terminated.
Assessments during the Continuation Phase are limited and will include plasma HIV-1 
RNA and collection of AEs/SAEs.  
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 


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boosted with ritonavir to the same PI boosted with cobicistat and vice versa.  Protocol 
waivers or exemptions are not allowed.  Therefore, adherence to the study design 
requirements is essential and required for study conduct.  
Type and Number of Subjects
The target population to be enrolled is virologically suppressed subjects with HIV-1 
infection on a stable TAF-based antiretroviral therapy (ART) with no evidence or history 
of drug resistance.  
Assuming 30% screen failure rate, approximately 800 HIV-1-infected adult subjects will 
be screened to achieve 550 randomized subjects for a total of 275 evaluable subjects per 
treatment group. The study closed screening on 18 May 2018 with a total of 933 screened 
subjects and a total of 743 subjects were randomised.
Analysis
This study is designed to show that the antiviral effect of switching to a simplified 
two-drug regimen of DTG + 3TC once-daily is not inferior to continuation of TBR at 
week 48 in HIV-1 infected ART-experienced subjects.
Non-inferiority can be concluded if the upper bound of a two-sided 95% confidence 
interval for the difference in failure rates between the two treatment arms is smaller than 
4%. If rd is the virologic failure rate on DTG + 3TC and rf is the virologic failure rate on 
the current ART regimen, then the hypotheses can be written as follows:
H0:  rd - rf ≥ 4%                   H1: rd - rf < 4%
The primary analysis at Week 48 will take place after the last subject has had their 
Week 48 viral load assessed, including a retest if required.  The primary analysis method 
for the proportion of virologic failure at Week 48 will be a Cochran-Mantel Haenszel test 
stratified by baseline third agent class (PI, INI, or NNRTI).  A non-inferiority margin of 
4% will be used for this comparison, where if the upper bound of the 95% confidence 
interval (CI) of the difference in failure rate between the 2 study arms is not more than 
4%, non-inferiority will be demonstrated. 


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2.
INTRODUCTION
Current human immunodeficiency virus (HIV) treatment guidelines recommend 
antiretroviral treatment (ART) regimens consisting of two nucleoside/nucleotide 
analogue reverse transcriptase inhibitors (NRTIs) as a “backbone” combined with a third 
agent from the non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor 
(ritonavir-boosted) (PI/RTV), or integrase strand transfer inhibitor (INSTI) classes 
[BHIVA, 2016; DHHS, 2016; EACS, 2015; IAS-USA, 2016].  These regimens are highly 
efficacious and generally well tolerated.  However, since these regimens will need to be 
taken life-long, there is growing concern about their long-term toxicities and cost.  As the 
potential for toxicities and cost are directly related to the number of antiretrovirals 
(ARVs) used, there is great interest from patients and clinicians in regimens that 
minimize the number of ARVs without sacrificing long-term antiviral efficacy.  
Dolutegravir (DTG) is a potent dual cation binding INSTI, exhibiting rapid and potent 
(2.5 log10) reduction in viral load and a high barrier to resistance.  In addition, DTG lacks 
many of the frequent drug interactions associated with other medications commonly 
taken by HIV-positive patients.  The efficacy, pharmacokinetic (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].  DTG’s efficacy and high barrier to 
resistance has been demonstrated in several DTG-based trials [Raffi, 2013; Walmsley, 
2013; Clotet, 2014].
Lamivudine (3TC) is a potent cytidine nucleoside analogue with a favorable long-term 
safety profile.  Available since 1995 as a single agent (EPIVIR), it is also available as 
part of three backbone fixed-dose combination (FDC) products (COMBIVIR, 
EPZICOM/KIVEXA and TRIUMEQ).  Although 3TC monotherapy quickly selects for 
resistance due to a single point mutation at position M184V, 3TC retains residual 
antiviral activity against such mutants and helps prevent the emergence of resistance to 
other NRTI’s [Eron, 1995; Kuritzkes, 1996].  
A single tablet regimen (STR) of two potent, well-characterized and well-tolerated 
ARVs, DTG plus 3TC, may provide a novel 2-drug regimen that provides effective 
long-term antiviral suppression while limiting the risk of adverse reactions associated 
with ARV’s.  The combination of 3TC with DTG, with its high barrier to resistance, and 
ability to confer a rapid decline in HIV-1 ribonucleic acid (RNA), may be less likely to 
select for resistance. The expected efficacy and safety of a dual STR of DTG plus 3TC 
will make it suitable for both treatment-naïve individuals, and as a replacement treatment 
for ≥3-drug ART in virologically suppressed (“switch”) patients.
2.1.
Study Rationale
Contemporary potent 3-drug antiretroviral treatment has led to remarkable declines in 
morbidity and mortality in treated HIV-infected persons. However, this longer life 
expectancy has been accompanied by higher rates of non-acquired immunodeficiency 
syndrome (AIDS)-defining events (NADEs) such as cardiovascular disease, liver disease 
and cancer. These NADES are now the leading causes of morbidity and mortality among 
treated HIV-infected persons. The aetiologies of these NADEs are multi-factorial and 


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may include chronic inflammation and immune activation, behavioural and lifestyle-
related factors, co-morbidities and the adverse effects of ART. In addition, as HIV-
infected persons live longer, aging-associated co-morbidities are being seen with greater 
frequency, and this multi-morbidity often requires concomitant use of other medications. 
As ART needs to be taken life long, there is an unmet need for streamlined regimens that 
can minimize antiretroviral-related long-term toxicities and drug-drug interactions while 
maintaining viral suppression. Even modest improvements in side effects will have a big 
impact on the tolerability of, and adherence to life-long treatment regimens.
Two-drug antiretroviral regimens may maintain virologic suppression while minimizing 
the adverse effects from cumulative drug exposure and preserving future antiretroviral 
treatment options. While contemporary regimens avoid many of the liabilities of older 
agents, the consequences of long-term exposure to a 2-NRTI backbone remain uncertain. 
Compared to tenofovir disoproxil fumarate (TDF)-based regimens, tenofovir alafenamide 
(TAF) based regimens (TBRs) are associated with short-term improvements in renal and 
bone biomarkers in both treatment-naive and treatment-experienced persons [Genvoya, 
2016].  However, the use of TAF leads to much higher intracellular tenofovir diphosphate 
(DP) levels compared to TDF, and the consequences of the long-term exposure to high 
intracellular tenofovir levels are unknown. 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 HIV-infected patients [Leeansyah, 2013]. Of a multitude of NRTIs 
studied in vitro, tenofovir at therapeutic concentrations was found to produce 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 
TAF-regimens deliver four fold higher intracellular levels of tenofovir-DP (the active 
entity for both HIV-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. With the 
increasing incidence of aging-related co-morbidities that comes with longer lifespan, 
drug-drug interactions from polypharmacy are an increasingly important issue. The use of 
cobicistat- and ritonavir-containing regimens may increase the risk of potentially harmful 
drug-drug interactions, and hence the need for optimized regimens involving drugs with 
minimal potential for such interactions. 
Finally, if a 2-drug ART regimen is shown to be as effective and safe as conventional 
3-drug regimens, the lower cost associated with taking one less drug for the lifetime of an 
HIV-infected person will have substantial individual and societal individual benefits.
One of the potential risks of a 2-drug regimen is the increase in virologic failure 
associated with the emergence of drug resistance.  DTG, with its higher barrier to 
resistance, may reduce the risk of treatment-emergent resistance in patients taking a 
2-drug regimen.  The pivotal Phase 3 studies of DTG in naïve subjects have shown the 
absence of treatment-emergent INI or NRTI resistance mutations through 144+ weeks of 
treatment [Walmsley, 2013].  The absence of treatment emergent mutations to DTG or 
background agents in ART-naïve individuals, the potency of both DTG and 3TC, and the 


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well-tolerated safety profile of both drugs provides a strong rationale for the development 
of the DTG + 3TC STR as an important treatment option for patients.
The overall objective of the DTG + 3TC clinical development program is to develop a 
single tablet, fixed-dose, two-drug combination therapy regimen that is as effective as 3-
drug ART in treating HIV-1 infection, is safe and well tolerated in the long-term, and has 
a high barrier to the emergence of viral resistance.  A DTG + 3TC two-drug strategy may 
be effective in maintaining virologic suppression among treatment experienced subjects, 
while improving long-term safety and tolerability, and preserving future HIV-1 treatment 
options.
Study 204862 is being conducted to establish if human immunodeficiency virus type 1 
(HIV-1) infected adult subjects with current virologic suppression on a TBR remain 
suppressed upon switching to a two-drug regimen with DTG + 3TC. This trial is 
designed to demonstrate the non-inferior antiviral activity of switching to DTG + 3TC 
once daily compared to continuation of a TBR over 48 weeks.  To better understand the 
long-term differences in antiviral efficacy, safety and tolerability between DTG + 3TC 
and TAF-based regimens, the comparative phase of the study will be extended to 148 
weeks. The originally planned Week 52 Switch Visit in the TBR arm will be moved to 
Week 148 to allow for 2 additional years of comparative follow-up. This study will also 
characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC 
through Week 200. Recent data have implicated the integrase inhibitor class and TAF-
based regimen with weight gain [Venter, 2019; Sax, 2019] and further research is 
required to understand the mechanisms, type of weight gain and metabolic health 
implications of these observations. In the current study Week 48 primary analysis, we 
observed similar adjusted mean weight increase from baseline to Week 48 of 0.8 kg in 
both groups and the adjusted mean increase in BMI was 0.25 kg/m2 in the DTG/3TC 
group and 0.26 kg/m2 in the TAF-based regimen group [van Wyk, 2020].  In this protocol 
amendment to be implemented prior to the first study participant performing their Week 
144 visit, we are adding metabolic health and cardiovascular disease risk exploratory 
objectives. These include metabolic syndrome, cardiovascular risk and other 
anthropomorphic measures to explore potential implication of weight change overtime on 
metabolic health.
2.2.
Brief Background
By limiting the number of ARV’s to which a patient 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 drug-drug interactions 
(DDIs). Several studies have assessed the tolerability and durability of the virological 
response of a 2-drug ARV regimen as replacement for a ≥3-drug ARV regimen in 
individuals who were previously undetected on triple drug therapy.  One such study was 
the OLE study which was an open label study in virologically suppressed HIV-1 infected 
individuals (HIV-1 RNA < 50 copies/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 dual regimen of LPV/r + 
3TC [Arribas, 2015].  The primary endpoint was the proportion of patients free of 
therapeutic failure at 48 weeks. In a modified Intent to Treat (m-ITT) analysis, dual 


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therapy with LPV/r + 3TC demonstrated non-inferior efficacy and comparable safety to 
LPV/r + 2 NRTIs, as maintenance therapy in virologically suppressed patients (91.5% vs. 
90.9% respectively; 95% Confidence Interval (CI): -0.6% to 8.1%).
The SALT study [Perez-Molina, 2015] was a 96-week multicenter, randomized, open-
label, clinical trial that compared atazanavir (ATV/r + 3TC with ATV/r + 2NRTIs 
(selected at the discretion of the investigator) in HIV-infected patients 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 
patients receiving triple therapy vs. 83.6% of patients switched to dual therapy had 
maintained HIV-RNA levels < 50 copies/mL thus establishing non-inferiority between 
these two treatment arms (difference between the arms 5.2; -4.8 to 15.2).  
More recently, an INI-containing oral 2-drug regimen, cabotegravir (CAB) + rilpivirine 
(RPV), was evaluated as a maintenance therapy in HIV-infected persons who had 
virologic suppression after 24 weeks of 3-drug ART [Margolis, 2015]. The CAB + RPV 
arms showed comparative antiviral efficacy as the EFV + 2 NRTIs arm. Following 
72 weeks of two-drug maintenance therapy (Week 96), in the ITT maintenance = exposed 
population, 86% of CAB + RPV subjects and 83% of EFV + 2 NRTIs subjects remained 
virologically suppressed. Virologic failure was seen in 4% of the CAB arms and 2% of 
the EFV+2 NRTI arm.
GEMINI-1 and GEMINI-2 are two identical global, double-blind, multicentre Phase III 
studies evaluating the efficacy and safety of DTG + 3TC once daily in treatment-naïve 
HIV-1-infected adults with Screening HIV-1 ≤500,000 c/mL.  At 48 weeks, dual therapy 
with DTG + 3TC demonstrated non-inferior efficacy to DTG + TDF/FTC (in the primary 
endpoint: proportion of subjects with plasma HIV-1 RNA<50 c/ml by FDA Snapshot in 
the pooled ITT-E population [DTG/3TC n=716; DTG/TDF/FTC n= 717] 91% vs. 93%
respectively, adjusted difference (95% CI) -1.7 (-4.4, 1.1).  Across both studies, 6 
participants on DTG + 3TC and 4 participants on DTG + TDF/FTC met protocol-defined 
virologic withdrawal criteria and none had treatment-emergent INSTI or NRTI resistance 
mutations.  Overall, the rates of AEs were similar between arms, with low rates of 
withdrawals due to AEs for both arms [Cahn, 2018]. 
TAF, a HIV-1 nucleotide analogue reverse transcriptase inhibitor (NRTI), is a novel 
targeted prodrug of tenofovir that has demonstrated antiviral efficacy similar to and at 
much lower dose than that of TDF. TAF has also shown improvement in surrogate 
laboratory markers of renal and bone safety as compared to TDF in clinical trials in 
combination with other antiretroviral drugs. Combinations of TAF-containing regimens 
including rilpivirine/FTC/TAF (Odefsey), elvitegravir (EVG)/cobicistat/FTC/TAF 
(Genvoya) and FTC/TAF (Descovy) + a 3rd agent (INI, NNRTI or boosted PI) are 
indicated for the treatment of HIV-1 infection in adults and pediatric patients 12 years of 
age and older who have no ART history or to replace the current ARV regimen in those 
who are virologically-suppressed (HIV-1 RNA<50 copies/mL) on a stable ARV regimen 
for at least 6 months with no history of treatment failure and no known substitutions 
associated with resistance [Odefsey, 2016; Genvoya, 2016; Descovy, 2016].  


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objective
Endpoint
Primary
To demonstrate the non-inferior antiviral 
activity of switching to DTG +3TC once daily 
compared to continuation of TBR over 48 
weeks in HIV-1 infected, ART therapy (ART)-
experienced, virologically suppressed subjects
Virologic failure endpoint as per FDA snapshot 
category at Week 48
Secondary
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 48 weeks 
Proportion of subjects with plasma HIV-1 RNA 
<50 copies c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 24, 96 and 144
weeks 
Virologic failure endpoint as per FDA 
snapshot category at Weeks 24, 96 and 144
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL at Weeks 24, 96 and 144 using the 
Snapshot algorithm for the ITT-E population
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
over 24, 48, 96 and 144 weeks
Change from Baseline in CD4+ cell count and 
in CD4+/CD8+ cell count ratio at Weeks 24, 
48, 96 and 144
Incidence of disease progression (HIV-
associated conditions, AIDS, and death) 
through Weeks 24, 48, 96 and 144
To evaluate the safety and tolerability of DTG + 
3TC once daily compared to TBR over time
Incidence and severity of AEs and laboratory 
abnormalities through 144 weeks
Proportion of subjects who discontinue 
treatment due to AEs through 144 weeks
To evaluate the effects of DTG + 3TC once 
daily on fasting lipids over time compared to 
TBR
Change from Baseline in fasting lipids at Weeks 
24, 48, 96 and 144
To assess viral resistance in subjects meeting 
Virologic Withdrawal Criteria
Incidence of observed genotypic and phenotypic 
resistance to ARVs for subjects meeting 
Virologic Withdrawal Criteria 
To evaluate renal (in urine and blood) and 
bone (in blood) biomarkers in subjects treated 
with DTG + 3TC compared to TBR
Change from Baseline in renal and bone 
biomarkers at Weeks 24, 48, 96 and 144
To assess health related quality of life for 
subjects treated with DTG + 3TC compared to 
TBR
Change from Baseline in health status using EQ-
5D-5L at Weeks 24, 48, 96 and 144 (or 
Withdrawal from the study)


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Objective
Endpoint
Exploratory
To evaluate the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4) on 
antiviral and immunological responses to DTG 
+ 3TC compared to TBR 
Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with plasma 
HIV-1 RNA <50 c/mL using the Snapshot 
algorithm at Weeks 24, 48, 96 and 144
Change from Baseline in CD4+ cell counts at 
Weeks 24, 48, 96 and 144 by patient 
subgroups
To assess willingness to switch for subjects 
treated with DTG + 3TC compared to TBR
Reasons for Willingness to Switch at Day 1
To evaluate biomarkers of telomerase function 
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48, 96 and 144
To evaluate inflammation biomarkers and 
insulin resistance in a subset of subjects 
treated with DTG+ 3TC compared to TBR
Change from Baseline in inflammation 
biomarkers and homeostasis model of 
assessment-insulin resistance (HOMA-IR) at 
Weeks 48, 96 and 144
To describe body morphology at Week 144 in 
subjects treated with DTG + 3TC and TBR

Waist to height ratio at Week 144 in each 
arm

Waist to hip ratio at Week 144 in each arm
To assess metabolic health and Cardiovascular 
disease risk at Week 144 in subjects treated 
with DTG + 3TC and TBR

Proportions of subjects with Metabolic 
Syndrome at Week 144 in each arm

Change from Baseline in Framingham risk 
Score through Week 144 in each arm

Change from Baseline in resting Blood 
Pressure at Week 144 in each arm
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 196

Incidence and severity of AEs and 
laboratory abnormalities over 196 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 196 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 196

Change from Baseline in renal and bone 
biomarkers at Week 196

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 


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Objective
Endpoint
function at week 196
To describe body morphology at Week 196 in 
subjects treated with DTG + 3TC since the 
Early Switch Phase

Waist to height ratio at Week 196

Waist to hip ratio at Week 196 
To assess metabolic health and Cardiovascular 
disease risk at Week 196 in subjects treated 
with DTG + 3TC since the Early Switch Phase

Proportions of subjects with Metabolic 
Syndrome at Week 196 

Change from Baseline in Framingham risk 
Score through Week 196

Change from Baseline in resting Blood 
Pressure at Week 196 
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 196

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 196

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at week 196
To assess body morphology at Week 196 in 
subjects switching to DTG + 3TC in the Late 
Switch Phase

Change in waist to height ratio from Switch 
to Week 196

Change in waist to hip ratio from Switch to 
Week 196 
To assess metabolic health and Cardiovascular 
disease risk at Week 196 in subjects treated 
with DTG + 3TC since the Late Switch Phase

Proportions of subjects with and incidence 
of Metabolic Syndrome at Week 196 

Change from Baseline in Framingham risk 
Score through Week 196

Change from Baseline in resting Blood 
Pressure at Week 196 


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Objective
Endpoint
To assess the steady-state DTG and 3TC 
exposure in HIV-1 infected patients
Steady state plasma PK parameters of DTG and 
3TC will be assessed using intensive PK 
collected at week 4.
To characterize the DTG and 3TC steady-state 
PK of the DTG/3TC FDC in HIV-1 infected 
patients
Population estimates of DTG and 3TC PK 
parameters (e.g. apparent clearance [CL/F], 
apparent volume of distribution [V/F]) using DTG 
and 3TC intensive and sparse plasma 
concentrations at Weeks, 4, 8, 12, 24, 36 and 48


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4.
STUDY DESIGN
4.1.
Overall Design
This is a 200-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of replacing a 
TBR with a two-drug regimen of DTG + 3TC in HIV-infected adults who are 
virologically suppressed and stable on a TBR.  The study will include a Screening Phase 
(up to 28 days), an Early Switch Phase (Day 1 up to Week 148) a Late Switch Phase 
(Week 148 up to Week 200), and a Continuation Phase (post Week 200) if DTG + 3TC 
FDC is not yet approved and available locally.  Approximately 550 HIV-1 infected adults 
who are on a stable TBR will be randomized 1:1 to switch to DTG + 3TC once daily 
(DTG + 3TC arm) for up to 200 weeks, or to continue their TBR for 148 weeks, at which 
time and if HIV-1 RNA <50 c/mL at Week 144 (or upon retest by Week 148), these 
subjects will switch to DTG + 3TC up to Week 200. For subjects randomized to the 
TBR, provisions will be in place, as needed and after discussion with the study team, to 
assist patients in obtaining their TBR during the study.  For subjects who switch to 
DTG + 3TC at Week 148, a separate Late Switch Phase Time and Events Table is 
provided in Section 7.1.2 as these participants will be monitored closely for the first 24 
weeks post-switch. Subjects who remain on DTG + 3TC will follow a separate Late 
Switch Phase Time and Events Table in Section 7.1.3.
The primary endpoint for the study is the proportion of participants who meet the 
Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat Exposed (ITT-E) 
population.  The Week 48 primary analysis will take place after the last subject has had 
their Week 48 viral load assessed, including any retests. Subjects randomized to DTG + 
3TC will receive DTG + 3TC up to Week 200.  Subjects randomized to TBR will have a 
Week 148 switch visit, allowing approximately 4 weeks for subjects who have a viral 
load ≥50 c/mL at Week 144 to have a retest prior to switch.  The study will continue for 
at least 200 weeks.
All subjects who successfully complete 200 weeks of treatment will complete the study 
and transition to locally approved and available DTG + 3TC fixed-dose combination 
(FDC) and be managed as per standard of care at their study site.  Prior to completion of 
the Week 200 visit, sites will need to have confirmation that DTG + 3TC FDC is locally 
available for study subjects. If DTG + 3TC FDC is not yet approved and available 
locally, ViiV Healthcare will continue to provide study drug in a Continuation Phase as 
outlined in Section 4.2.4.
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.  Protocol 
waivers or exemptions are not allowed.  Adherence to the study design requirements, 
including those specified in the Time and Events Table (Section 7.1), 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. 


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An Independent Data Monitoring Committee (IDMC) will be instituted to ensure external 
objective medical and/or statistical review of efficacy and safety in order to protect the 
ethical interests and well-being of subjects and to protect the scientific validity of 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 
will be pre-specified in the IDMC Charter. Communication received from the IDMC 
regarding the status of the study will be shared with investigators in a timely manner.
A pharmacokinetic (PK) substudy in the DTG+3TC arm will be conducted to evaluate 
DTG and 3TC concentrations using a sparse PK sampling approach at designated visits 
(See Section 11). In addition, intensive PK samples will be collected from a subgroup of 
subjects (approximately 30) enrolled at selected sites with the capability to perform 
intensive PK sampling.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM), which is available on the 
online Study Web Portal. The SRM will provide site personnel with administrative and 
detailed technical information.
Figure 1
Study Schematic
4.2.
Treatment Arms and Duration
4.2.1.
Screening Period (Up to 28 days)
Randomization may occur as soon as all screening procedures and entry criteria data are 
confirmed and available on file at the site.  The Screening of up to 28 days is to allow 
receipt of all screening assessment results, to enable source document verification of 
entry criteria and to accommodate scheduling. 
4.2.2.
Early Switch Phase (Day 1 up to Week 148)
Subjects who fulfil all eligibility requirements will be randomly assigned 1:1 to receive 
DTG + 3TC FDC once daily up to Week 200, or continue their TBR up to Week 148.  
The DTG + 3TC and TBR will be administered in an open-label fashion throughout the 
study.  For subjects randomized to the TBR, provisions will be in place, as needed and 


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after discussion with the study team, to assist patients in obtaining their TBR during the 
study. 
Following the Week 144 visit, subjects will stay on DTG + 3TC or their TBR for another 
4 weeks so that the result from the Week 144 HIV-1 RNA testing is known.  All subjects 
with a viral load 50 c/mL must have plasma HIV-1 RNA levels re-assessed within 
approximately 2-4 weeks.  This will allow any subject in the TBR arm with a viral load 
50 c/mL at Week 144 to have their viral load confirmed by a second measurement 
performed within approximately 2-4 weeks while still on their TBR regimen.  
The primary analysis will take place after the last subject completes up to 52 weeks on 
therapy, to allow for the collection of a confirmatory viral load measurement in subjects 
presenting with HIV-1 RNA 50 c/mL at the Week 48 visit.  If the retest HIV-1 RNA is 
<50 c/mL, then the subject will be considered to have met the criteria for virologic 
responder by Food Drugs and Administration (FDA)’s Snapshot algorithm at Week 48.  
If the retest HIV-1 RNA is 50 c/mL, then the subject will be considered to be a virologic 
non-responder at Week 48 by Snapshot.  
The secondary analysis at Week 24 will take place after the last subject completes up to 
28 weeks on therapy, as needed, to allow for the collection of a confirmatory viral load 
measurement in subjects presenting with HIV-1 RNA 50 c/mL at Week 24.
The secondary analysis at Week 96 will take place after the last subject completes up to 
100 weeks on therapy, as needed, to allow for the collection of a confirmatory viral load 
measurement in subjects presenting with HIV-1 RNA 50 c/mL at Week 96.
The secondary analysis at Week 144 will take place after the last subject completes up to
148 weeks on therapy, as needed, to allow for the collection of a confirmatory viral load 
measurement prior to Week 148 switch visit in subjects presenting with HIV-1 RNA 
50 c/mL at Week 144.  If the retest HIV-1 RNA is <50 c/mL, subjects in the TBR arm 
will be considered eligible to switch to DTG + 3TC at Week 148.  If the retest HIV-1 
RNA is 50 c/mL, the subjects in the TBR arm will be considered ineligible to switch to 
DTG + 3TC.  Subjects who are ineligible to switch will be withdrawn from the study.  
Thus, the treatment extension up to Week 148 will allow for as complete an assessment 
as possible of treatment response in the analysis at Week 144 within the Snapshot 
window.
4.2.3.
Late Switch Phase (Week 148 to Week 200)
At Week 144, subjects randomly assigned to DTG + 3TC and with HIV-1 RNA 
<50 c/mL will continue on that treatment through Week 200.  At Week 148, subjects 
randomly assigned to continue their TBR and with HIV-1 RNA <50 c/mL at Week 144
(or upon retest) will switch to DTG + 3TC once daily and be followed up to Week 200. 
For subjects who switch to DTG + 3TC at Week 148, a separate Late Switch Phase Time 
and Events Table is provided in Section 7.1.2 as these participants will be monitored 
closely for the first 24 weeks post-switch. Subjects who remain on DTG + 3TC will 
follow a separate Late Switch Phase Time and Events Table in Section 7.1.3.


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The analysis at Week 196 will take place after the last subject completes 200 weeks on 
therapy, as needed, to allow for the collection of a confirmatory viral load measurement 
in subjects presenting with HIV-1 RNA 50 c/mL at Week 196.
4.2.4.
Continuation Phase (Post Week 200)
At the end of the study at Week 200, subjects will transition to locally approved and 
available DTG + 3TC FDC and be managed as per standard of care at their study site.  
Prior to completion of the Week 200 visit, sites will need to have confirmation that 
DTG + 3TC FDC is locally available for study subjects. If DTG + 3TC FDC is not yet 
approved and available locally, ViiV Healthcare will continue to provide study drug in a 
Continuation Phase until:
DTG + 3TC FDC is locally approved for use as a 2-drug regimen, and available to 
subjects (e.g., through public health services or through their usual health 
insurance payer), or
the subject no longer derives clinical benefit, or 
the subject meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC dual regimen is terminated.
Assessments during the Continuation Phase are limited and will include plasma HIV-1 
RNA and collection of AEs/SAEs. 
4.3.
Type and Number of Subjects
The target population to be enrolled is HIV-1 infected adults who are virologically 
suppressed on a TBR (As a first-line regimen with specific allowed switches as defined in 
inclusion criterion 5) and with no evidence or history of ARV drug-resistance.  
Assuming 30% screen failure rate, approximately 800 HIV-1-infected adult subjects will 
be screened to achieve 550 randomized subjects for a total of 275 evaluable subjects per 
treatment group.  The study closed screening on 18 May 2018 with a total of 933 
screened subjects and a total of 743 subjects were randomized. 
4.4.
Design Justification
The design of this study (1:1 randomized, open-label, active-controlled, multicenter, 
parallel group, non-inferiority study) is well established for confirming the 
non-inferiority of an investigational agent compared with an active ART standard-of-care 
regimen and generally is accepted by regulatory authorities as rigorous proof of antiviral 
activity.  The primary endpoint, proportion of subjects 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 subjects 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].


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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 HIV-infected persons who were virologically suppressed on a 
3-drug regimen were switched to a 2-drug regimen. In OLE, switching to a 2-drug 
regimen of LPV/r + 3TC/FTC was non-inferior to continuing a 3-drug regimen of LPV/r 
+ 2 NRTIs in HIV-infected persons who were virologically stable on LPV/r + 2 NRTIs 
[Arribas, 2015]. Protocol-defined virologic failure was 2.7% in either arm. In SALT, 
ATV/r + 3TC was non-inferior to a ATV/r + 2 NRTIs in maintaining virologic 
suppression in HIV-infected patients who switched ART for reasons of toxicity, 
intolerance or simplification; virologic failure was seen in 4% and 3% of the 2- and 3-
drug arms, respectively [Perez-Molina, 2015].  More recently, an INI-containing oral 2-
drug regimen, cabotegravir (CAB) + rilpivirine (RPV), was evaluated as a maintenance 
therapy in HIV-infected persons who had virologic suppression after 24 weeks of 3-drug 
ART [Margolis, 2015]. The CAB + RPV arms showed comparative antiviral efficacy as 
the EFV + 2 NRTIs arm. Following 72 weeks of two-drug maintenance therapy (Week 
96), in the ITT maintenance = exposed population, 86% of CAB + RPV subjects and 
83% of EFV + 2 NRTIs subjects remained virologically suppressed. Virologic failure 
was seen in 4% of the CAB arms and 2% of the EFV+2 NRTI arm.
TAF-based regimens including rilpivirine/FTC/TAF, EVG/cobicistat/FTC/TAF, and 
FTC/TAF + either INI, NNRTI or boosted PI are indicated for the treatment of HIV-1 
infection in adults and pediatric patients 12 years of age and older who have no ART 
history or to replace the current ARV regimen in those who are virologically-suppressed 
(HIV-1 RNA<50 copies/mL) on a stable ARV regimen for at least 6 months with no 
history of treatment failure and no known substitutions associated with resistance 
[Odefsey, 2016; Genvoya, 2016; Descovy, 2016]. Switching to EVG/cobicistat/FTC/TAF
from one containing either TDF/FTC/EFV, TDF/FTC/ATV/r, TDF/FTC/ATV/cobicistat 
or TDF/FTC/EVG/cobicistat was non-inferior for maintenance of viral suppression and 
led to improvements in surrogate markers of bone and renal function [Mills, 2016].
Similarly, switching the background regimen from TDF/FTC to TAF/FTC was non-
inferior in maintaining virological suppression [Gallant, 2016]. TBR’s are not 
recommended in patients with estimated creatinine clearance below 30 mL/min, or in 
patients with severe hepatic impairment.
In this study, subjects will be randomized 1:1 to switch to DTG + 3TC from a TBR at 
Day 1 or stay on their TBR for up to 148 weeks.  The primary endpoint will be evaluated 
at Week 48 using a 4% non-inferiority (NI) margin.  This study is evaluating the rate of 
Snapshot algorithm measured virological failure in already suppressed subjects to test the 
hypothesis that maintenance of the suppression of HIV-1 replication by DTG + 3TC will 
be non-inferior to that observed in the TBR arm of the study through Week 48.  To assess 


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the durability of HIV-1 RNA suppression by DTG + 3TC, subjects will remain on DTG + 
3TC through Week 200.
After Week 96, study visits will be extended to every 6 months (instead of 12 weekly 
visits) except in countries where visits are required every 3 months per standard of care.  
For subjects who switch to DTG + 3TC at Week 148, a separate Late Switch Phase Time 
and Events Table is provided in Section 7.1.2 as these participants will be monitored 
closely for the first 24 weeks post-switch. Subjects who remain on DTG + 3TC will 
follow a separate Late Switch Phase Time and Events Table in Section 7.1.3.  This 
amended design will allow a longer period of comparison of antiviral efficacy, safety and 
tolerability between DTG + 3TC and TAF-based regimens.  Long-term comparison of 
outcomes between regimens is important in a disease where treatment is provided life-
long.  
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 TBRs with food, and wide variety of 
potential drug-drug interactions.  An increase in pill burden could hinder compliance 
substantially and discourage subject enrolment.  The use of the FDA snapshot algorithm 
for assessing the proportion of subjects with virologic failure as an objective primary 
endpoint will help reduce biases inherent to an open label study design.
4.5.
Dose Justification
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 drug-drug 
interactions 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 IBs 
and or Product Insert(s) for the respective products (refer to the most current version of 
product inserts and of the IB and any IB supplements [GSK Document Number
RM2007/00683/11, GSK Document Number 2017N352880_00, GSK Document Number 
2017N352880_01]; Dolutegravir Product Insert, 2017; Epivir Product Insert, 2017).
A double-dummy design could not be undertaken given the increase in pill burden that 
would result from blinding, and the variable dosing requirements with food for each 
unique TBR.  
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 


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bilayer tablet demonstrated bioequivalence to the single entity tablets for dolutegravir 
area under the curve zero to infinity (AUC(0-∞)) & maximum concentration (Cmax) and 
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. PK of the FDC components will be evaluated using a combination 
of intensive and sparse sampling. 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
DTG or 3TC can be found in the IBs and product labels.  
The following section outlines the risk assessment and mitigation strategy for DTG and 
3TC in this protocol.  Where available, the approved country product label should be 
referenced.  For the TBRs regimen, the approved country product labels for the 
respective drugs should be referenced.  


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4.6.1.
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 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. 
Subjects with history of allergy/sensitivity to any of the study drugs 
are excluded.
Specific/detailed toxicity management guidance is provided for rash 
(Section 13.2.1.6).
The subject informed consent form (ICF) includes information on 
this risk and the actions subjects 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 patients 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 subjects 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 subjects, likely contributed to significant 
elevations in liver chemistries.  
3TC:  Current treatment guidelines [DHHS, 2016; EACS, 2015] do 
not recommend monotherapy with 3TC for patients with HBV 
infection, which is what subjects randomised to DTG plus 3TC, 
would effectively be receiving.  Emergence of HBV variants 
associated with resistance to 3TC has been reported in HIV-1-
Subjects 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)

Subjects positive for Hepatitis B surface antigen (+HBsAg)

Subjects 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 first 48 weeks of the study, and for HCV therapy based on 
interferon or for any drugs that have a potential for adverse 
drug-drug interactions with study treatment throughout the 
entire study period. 
Specific/detailed liver stopping criteria and toxicity management 


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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 IBs for additional information
infected patients who have received 3TC-containing antiretroviral 
regimens in the presence of concurrent infection with HBV.  
Additionally, discontinuation of 3TC in HBV co-infected subjects can 
result in severe exacerbations of hepatitis B.
guidance is provided for suspected DILI or other clinically significant 
liver chemistry elevations (Section 13.2).
DTG: Psychiatric 
disorders
DTG: Psychiatric disorders including suicidal ideation and 
behaviors are common in HIV-infected patients. Events of suicidal 
ideation, attempt, behaviour and completion were observed in 
clinical studies of DTG, primarily in subjects 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 
favorable 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.  
Subjects who in the investigator’s judgment, pose a significant 
suicidality risk, are excluded from participating.
Because of the elevated risk in the HIV- infected population, 
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 subjects who experience signs of suicidal ideation or 
behaviour (See Section 7.4.7).
The subject informed consent form includes information on the risk 
of depression and suicidal ideation and behavior.    
DTG: Increased rates 
of virologic failure/ 
Observed Resistance
Virologically suppressed subjects switching from stable ART to 
DTG + 3TC may experience virologic failure/breakthrough and 
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 subjects.
3TC:  M184V is the common single mutation that leads to full 
resistance to 3TC.  
Subjects with any switch to a second line regimen due to previous 
virologic failure and subjects with evidence of pre-existing viral 
resistance mutation (including M184I/V) are excluded from this 
study.   
Genotypic resistance testing results must be reviewed by ViiV 
Virology to ensure subjects with exclusionary mutations are not 
randomized. 
Subjects will have HIV-1 RNA measured at routine study visits. An 
IDMC will be instituted to ensure external objective medical and/or 
statistical review of efficacy and safety.


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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 IBs for additional information
DTG: Theoretical 
serious drug interaction 
with dofetilide and
pilsicainide
Co-administration of DTG may increase dofetilide/pilsicainide 
plasma concentration via inhibition of organic cation transporter 
(OCT-2), resulting in potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide or pilsicainide is 
prohibited in the study (Section 6.11.2.1).
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 blockade 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 patients with renal dysfunction.  
Specific/detailed toxicity management guidance is provided for 
subjects who develop a decline in renal function (Section 13.2.1.3).
Creatinine clearance is calculated in all patients prior to initiating 
therapy and renal function (creatinine clearance and serum 
phosphate) will be monitored at all subsequent study visits.
Subjects with creatinine clearance <50 mL/min are excluded from 
participation in this study.
DTG: Creatine 
Phosphokinase (CPK) 
elevations
Asymptomatic CPK elevations mainly in association with exercise 
have been reported with DTG therapy.
Specific detailed toxicity management guidance is provided for 
subjects who develop Grade 3 to 4 CPK elevations 
(Section 13.2.1.8).
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 subject is eligible to participate if she is not pregnant, 
not lactating, and, if she is a female of reproductive potential, 
agrees to follow one of the options listed in the Modified List of 
Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 3, Section 13.3.1) 
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 


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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 IBs for additional information
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 and using 
home-based urine pregnancy tests at approximately 12 week 
intervals when study visits are extended to every 24 weeks.
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 patients). Serious/severe events will be managed appropriately including, but not limited 
to, withdrawal of study drug, and will be followed to resolution as per Sponsor’s standard medical monitoring practices.  
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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4.6.2.
Benefit Assessment
Individually, DTG and 3TC are conveniently dosed once daily, without need for a PK 
booster, and with limited safety implications resulting from theoretical or actual 
drug:drug interactions 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 
regimen.  Individually, DTG and 3TC in combination with other ARVs have 
demonstrated durable virologic and immunologic response. 
In general, switching subjects to a DTG + 3TC 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 drug-drug interactions.  Study participants also may benefit 
from the medical tests and screening procedures performed as part of this study.
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with DTG + 3TC are justified by the 
anticipated benefits that may be afforded to study subjects switching to this 2-drug 
regimen. 


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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the ViiV investigational product or other study 
treatment that may impact subject eligibility is provided in the Product Insert(s) for DTG 
and for 3TC.  
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
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 subjects, taking into consideration any local treatment practices or 
guidelines and good clinical practice (GCP).
5.1.
Inclusion Criteria
Eligible subjects 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 medication (e.g. no active substance abuse, acute major organ disease, or 
planned long-term work assignments out of the country).  
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Aged 18 years or older (or older where required by local regulatory agencies), at the 
time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. HIV-1 infected men or women.
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 ART for at least 6 months prior to screening. Only the 
following regimens are allowed:
a.
Subjects on a TAF-based regimen for at least 6 months as the initial regimen, or 
b. Subjects who switched from a TDF first regimen to TAF, without any changes to 
the other drugs in their regimen, and have been on the TAF-based regimen for at 


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least 3 months immediately prior to Screening, i.e., the only switch made is from 
TDF to TAF. This switch must have occurred due to tolerability/safety, access to 
medications, or convenience/simplification, and must NOT have been done for 
suspected or established treatment failure.  A switch from a PI boosted with RTV 
to the same PI boosted with cobicistat is allowed (and vice versa).
SEX
6.
Male or Female
A female subject 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 lactating, and 
at least one of the following conditions applies:
a. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
o Documented tubal ligation
o Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of 
bilateral tubal occlusion 
o Hysterectomy
o Documented Bilateral Oophorectomy
Post-menopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Section 13.3) from 30 days prior to the first 
dose of study medication and for at least 2 weeks after the last dose of study 
medication.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
All subjects participating in the study should be counseled on safer sexual practices 
including the use and benefit/risk of effective barrier methods (e.g., male condom) 
and on the risk of HIV transmission to an uninfected partner.
INFORMED CONSENT
7. Capable of giving signed informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.  Eligible subjects or their legal guardians must sign a written 
Informed Consent Form before any protocol-specified assessments are conducted.


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OTHER
8. Subjects enrolled in France must be affiliated to, or a beneficiary of, a social security 
category.  
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. Women who are 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. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh 
classification (see Section 13.4).
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:

Subjects positive for HBsAg are excluded.

Subjects negative for anti-HBs but positive for anti-HBc (negative HBsAg status) 
and positive for HBV DNA are excluded.  
Note: Subjects 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.
6. Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of 
the study, or anticipated need for HCV therapy based on interferon or for any drugs 
that have a potential for adverse drug-drug interactions with study treatment 
throughout the entire study period. 
7. Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without 
clear documentation of treatment).  Subjects who are at least 7 days post completed 
treatment are eligible.
8. History or presence of allergy or intolerance to the study drugs 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. Subjects who in the investigator’s judgment, poses a significant suicidality risk.  


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EXCLUSIONARY TREATMENTS PRIOR TO SCREENING OR DAY 1
11. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
12. Treatment with any of the following agents within 28 days of Screening

radiation therapy

cytotoxic chemotherapeutic agents

any systemic immune suppressant
13. 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.
14. Use of any regimen consisting of single or dual ART.
LABORATORY VALUES OR CLINICAL ASSESSMENTS AT SCREENING
15. Any evidence of major NRTI mutation or presence of any major INSTI 
resistance-associated mutation [Wensing, 2017] in any available prior resistance 
genotype assay test result, if known, must be provided to ViiV after screening and 
before randomization for review by ViiV Virology.  Refer to the most recent version 
of IAS Guidelines, SRM, and Section 7.2.1 (Screening Assessments) for more 
information. 
16. Any verified Grade 4 laboratory abnormality. 
17. Alanine aminotransferase (ALT) 5 times the upper limit of normal (ULN) or ALT 
3xULN and bilirubin 1.5xULN (with >35% direct bilirubin).
18. Creatinine clearance of <50 mL/min/1.73m2 via CKD-EPI method.
EXCLUSIONARY CRITERIA PRIOR TO SCREENING OR DAY 1
19. Within the 6 to 12 month window prior to Screening and after confirmed suppression 
to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL. 
20. Within the 6 to 12 month window prior to Screening and after confirmed suppression 
to <50 c/mL, 2 or more plasma HIV-1 RNA measurements 50 c/mL. 
21. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on 
current ART regimen, any plasma HIV-1 RNA measurement 50 c/mL. 
22. 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.
23. 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. 
COUNTRY SPECIFIC REQUIREMENTS
24. Subjects enrolled in France (or in other countries as required by local regulations or 
Ethics Committee/Institutional Review Board [IRB]) who: 
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 


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the experimental drug or vaccine, whichever is longer, prior to screening for the 
study, or 
participate simultaneously in another clinical study.
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events (see Section 7.4.1.6).
Subjects 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 subject be randomized in the absence of source documentation including prior
qualifying viral load data (as outlined in the Inclusion Criteria).
5.4.
Withdrawal and Stopping Criteria
Subjects permanently discontinuing study treatments are considered to be withdrawn 
from the study.  Similarly, subjects 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 treatment and from the 
study.  Withdrawn subjects will not be replaced.  
A subject may withdraw consent and discontinue participation in this study at any time at 
his/her own request. The investigator may also, at his or her discretion, discontinue the 
subject from participating in this study at any time (e.g. safety, behavioral or 
administrative reasons).  If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.  Subjects 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 subjects who withdraw from the study. 


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Subjects may have a temporary interruption to their study treatment for management of 
toxicities.  Such interruption of study treatment does not require withdrawal from the 
study.  However, consultation with the Medical Monitor is required.  
Subjects may be prematurely discontinued from the study for any of the following 
reasons:

Subject or Investigator non-compliance;

At the request of the subject, Investigator, GSK or ViiV Healthcare;

The subject requires concurrent prohibited medications during the course of the 
study.  The subject 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 subject.
Subjects must be discontinued from the study for any of the following reasons:

Virologic withdrawal criteria as specified in Section 5.4 are met;

For subjects in the TBR arm during the Early Switch Phase, plasma HIV-1 RNA 
50 c/mL at Week 144 with a confirmatory retest (see Section 5.4)

Subject is identified as having been mistakenly screened/randomized with 
exclusionary resistance (see Section 5.2)

Subject requires substitution or dose modification of DTG, 3TC or any component of 
their TBR; 

Liver toxicity where stopping criteria met and no compelling alternate cause is 
identified;

Renal toxicity are met and no compelling alternate cause is identified;

Grade 4 clinical or laboratory AE considered causally related to study drug; 

Allergic reaction or Rash criteria are met and no compelling alternate cause is 
identified.

Pregnancy (intrauterine), regardless of termination status of pregnancy (Section 
7.4.2).  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. 
If a subject is prematurely or permanently withdrawn from the study, the procedures 
described in the Time and Events Table for the in-clinic Withdrawal visit are to be 
performed.  All data from the Withdrawal visit will be recorded, as they comprise an 
essential evaluation that should be done prior to discharging any subject from the study.   
An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study 
medication for subjects with ongoing AEs, for any serious adverse events (SAEs) 
regardless of attributability, and also for any laboratory abnormalities that are considered 
to be AEs or potentially harmful to the subject, at the last on-study visit. 


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The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow-up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, three 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
5.4.1.
Virologic Criteria for Subject 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
5.4.1.1.
Subjects Meeting Virologic Management Criteria
Subjects 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.  Upon 
notification that a subject’s HIV-1 RNA plasma level qualifies him/her as meeting a 


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“virologic management” criterion, the Investigator should query the subject 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 
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 subject should receive full doses of all 
study drugs.

Confirmatory testing should be scheduled 2 to 4 weeks following any immunisation, 
during which time the subject should receive full doses of study drugs.

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 drugs.
The subject should have received full doses of study drugs for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA is done.  Sites should contact the Medical Monitor to 
discuss individual subjects, whenever necessary.    
5.4.1.2.
Managing Subjects Meeting Precautionary Virologic Withdrawal (PVW) 
or Confirmed Virologic Withdrawal (CVW) Criteria
Once a subject 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 a CVW criteria (see Figure 2).
Subjects may continue to receive study drug at the discretion of the investigator until 
results of resistance testing are available at which time the subject must be discontinued 
from the study, except in cases where subject samples have HIV-1 RNA <500 c/mL, as 
noted below.  A subject who meets a PVW or CVW criterion must be discontinued 
from the study.  Selection of post-study ART regimen for subjects with virologic failure 
will be recorded in the eCRF.  
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 subjects 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. Subjects 
with confirmed HIV-1 RNA levels between 200 c/mL and <500 c/mL should be 
transitioned off study drug within 30 days even if no resistance testing data becomes 
available, as genotype/phenotype data may not be reliably generated from plasma 


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samples collected from these subjects.  If the confirmed HIV-1 RNA level is ≥50 and 
<200 c/mL, and the decision is taken to withdraw the subject, resistance testing will not 
be done and the subject should be transitioned off study drug as soon as possible.
If a subject is prematurely discontinued from participation in the study, the Investigator 
must make every effort to perform the evaluations outlined in the Time and Events 
Schedule.  These data will be recorded, as they comprise an essential evaluation that 
needs to be done before discharging any subject 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 Time and Events Table
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.
Subject has met criteria for 
additional plasma HIV-1 RNA 
testing or possible withdrawal. 
If the subject 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, subject 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
Subject has met “Suspected 
Virologic Withdrawal Criterion 
(SVW)”
If previous plasma HIV-1 RNA 
was 50 c/mL, discontinue 
subject from study once 
resistance test results are 
availableb,d.
Subject 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. Subjects should have received full doses of study drug 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 subjects should be transitioned off study drug 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 subject must be withdrawn.  If 
the Investigator and the medical monitor agree that the subject 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 subject must be withdrawn.
d.
Subjects with confirmed HIV-1 RNA results in the range 200 c/mL to <500 c/mL, should be transitioned off study drug 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 subjects.


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5.4.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject 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
Liver Chemistry Stopping and Increased Monitoring Algorithm


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Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 
5xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 13.5.
5.4.2.1.
Study Treatment Restart
If subject meets liver chemistry stopping criteria, do not restart subject with study 
treatment unless:

ViiV 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 subject
If VSLC approval to restart 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.
Refer to Section 13.6 for full guidance.
5.5.
Subject and Study Completion
Subjects are considered to have completed the study if they satisfy one of the following: 

Randomly assigned to either treatment group and completed the Late Switch Phase at 
the Week 200 visit., and did not enter the Continuation Phase;


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
Randomly assigned to either treatment group, completed the Randomized Phase at the 
Week 200 visit, entered and completed the Continuation Phase, defined as remaining 
on study until:

DTG +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

the subject no longer derives clinical benefit, or 

the subject meets a protocol-defined reason for discontinuation, or 

development of the DTG plus 3TC dual regimen is terminated.
An in-clinic Follow-Up visit will be conducted approximately 4 weeks after the last dose 
of study medication for subjects with ongoing AEs, and serious adverse events (SAEs) 
and also any laboratory abnormalities that are considered to be AEs or potentially 
harmful to the subject, at the last on-study visit. Assessments at the Follow-up visit 
should reflect any ongoing complaints (e.g., blood draws to follow a laboratory 
abnormality).  The Follow-Up visit is not required for successful completion of the study.


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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.  All study treatments will be administered at the approved dosages
The investigational study drugs DTG and 3TC will be supplied by GSK/ViiV Healthcare 
as the fixed dose combination tablet DTG + 3TC. Subjects randomly assigned to continue 
their TBR for up to 148 weeks will not have drug provided as clinical trial material.  The 
individual components of the TBR will be recorded on the Concomitant ART Therapy 
(ConART) eCRF page.  For subjects randomized to the TBR, provisions will be in place, 
as needed and after discussion with the study team, to assist patients in obtaining their 
TBR during the study.
DTG + 3TC 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 treatment must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.  For further 
details on storage, access and administration of study treatments, refer to the SRM. 
Study Treatment
(Open Label Randomised Phase, Day 1 to Week 200)
Product name:
DTG + 3TC FDC
Formulation description:
Clinical Trial Material
Dosage form:
Tablet
Unit dose strength(s)/Dosage level(s):
50mg/300mg
Route of Administration:
Oral
Dosing instructions:
Take one tablet daily.
Physical description:
White, oval, film-coated tablets with ‘SV 137’ debossed on one 
face.  The tablets are packed in high density polyethylene 
(HDPE) bottles with induction seals, 2gm desiccant, and child-
resistant closures.  Each 60mL bottle contains 30 tablets.
6.2.
Protocol-Permitted Substitutions
A switch from a PI boosted with RTV to the same PI boosted with cobicistat is allowed.  
A switch from a PI boosted with cobicistat to the same PI boosted with RTV is allowed.
6.3.
Treatment Assignment
Informed consent must be obtained prior to any study procedures, including any 
screening assessment. 
Subjects will be assigned to study treatment 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 treatment 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 subjects. Subjects will be randomized in a 1:1 ratio to DTG + 3TC or to the 
continued TBR arm, in accordance with the computer generated randomization schedule.
Each subject will be assigned a unique identifier (designating the subject’s randomization 
code) and a unique treatment number which matches the randomized treatment 
assignment. 
Subjects 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.
Planned Dose Adjustments
No dose adjustments are permitted in this study for DTG + 3TC or for TBR. 
6.5.
Blinding
This will be an open-label study and therefore no blinding is required.  No summaries of 
the study data according to actual randomized treatment groups will be available to 
sponsor staff prior to the planned Week 24 preliminary analysis. Public presentation of 
the Week 24 analysis will not be done prior to last subject’s week 48 visit.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, designated site staff, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study treatment 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 


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investigator, where this is required by local laws, or is available upon request from 
ViiV/GSK.
Study treatment accountability will be evaluated using pill counts of unused DTG + 
3TC.  This assessment will be conducted each time the subject receives a new (refill) 
supply of DTG + 3TC through the Withdrawal visit or study completion. Study 
treatment accountability records must be maintained throughout the course of the 
study.  These data will be recorded in the subject’s CRF but will not be summarised 
for analysis purposes.
6.8.
Compliance with Study Treatment Administration
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
When subjects self-administer study treatment(s) at home, compliance with IP will be 
assessed through querying the subject during the site visits and documented in the source 
documents and CRF.  Treatment start and stop dates also will be recorded in the CRF.
Additionally, a record of the number of DTG + 3TC tablets dispensed to and taken by 
each subject must be maintained and reconciled with study treatment and compliance 
records.
6.9.
Treatment of Study Treatment Overdose
For this open-label study, any tablet intake exceeding the randomized daily number of 
tablets for DTG + 3TC will be considered an overdose [Dolutegravir Product 
Information, 2017; Epivir Product Information, 2017].  ViiV does not recommend 
specific treatment for an overdose of DTG + 3TC.  As appropriate, the Investigator 
should use clinical judgment and also refer to the prescribing information for the 
individual drugs used in the TBR in treating overdose in the TBR arm; ViiV are unable to 
recommend specific treatment.
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 7.4.1).  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 subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until DTG + 3TC can no longer be detected systemically 
(for at least 2 days).  

obtain a plasma sample for pharmacokinetic (PK) analysis within 60 hours from the 
date of the last dose of study treatment 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 CRF.
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 subject.
6.10.
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 subject’s medical condition.  At the end of the study at Week 200, 
subjects will transition to locally approved and available DTG + 3TC FDC and be 
managed as per standard of care at their study site.  Prior to completion of the Week 200
visit, sites will need to have confirmation that DTG + 3TC FDC is locally available for 
study subjects. If DTG + 3TC FDC is not yet approved and available locally, ViiV 
Healthcare will continue to provide study drug in a Continuation Phase until local 
availability.
Assessments during the Continuation Phase are limited (see Time and Events schedule, 
Section 7.1).  
6.11.
Concomitant Medications and Non-Drug Therapies
Subjects should be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
drug:drug interactions between such treatments and the study drugs. The investigator 
should evaluate any potential drug:drug interactions at every visit, including reviewing 
the most current version of the U.S. or local prescribing information for DTG, 3TC and 
the subjects’ TBR, especially if any new concomitant medications are reported by 
subjects.  All concomitant medications 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.
6.11.1.
Permitted Medications and Non-Drug Therapies
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 6.11.2).  Chemoprophylaxis for HIV-associated 
conditions is encouraged, if appropriate, at the discretion of the subject and their 
physician. All concomitant medications, blood products, and vaccines taken during the 
study will be recorded in the eCRF with dates of administration.
Because non-HIV vaccines may cause a temporary increase in the level of 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 
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.


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DTG + 3TC 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 study treatment 
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 glycemic control.
Clinical monitoring is recommended for subjects taking methadone, as methadone 
maintenance therapy may need to be adjusted in some subjects.
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 subject. 
6.11.2.
Prohibited Medications and Non-Drug Therapies
The following concomitant medications or therapies are not permitted at any time during 
the study:

HIV immunotherapeutic vaccines (see Section 6.11.1 for guidance regarding non-
HIV vaccines).

Other experimental agents, ART drugs not otherwise specified in the protocol, 
cytotoxic chemotherapy, or radiation therapy. 

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited through Week 200 (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 the 
conduct of the study, the Investigator must consult with the medical monitor.  HCV 
treatment based on interferon or any other medications that have a potential for 
adverse drug-drug interactions with study treatment, is prohibited during the conduct 
of the study. 

Acetaminophen is not to be used in patients with acute viral hepatitis [James, 2009].
For a detailed list of prohibited medications, please refer to the SRM. 
For information on prohibited medications and drug-drug interactions in relation to other 
antiretrovirals used in comparator regimens, please consult the latest local prescribing 
information.


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6.11.2.1.
Prohibited Medications for Subjects Receiving DTG + 3TC
Medications (or their equivalents) that may cause decreased concentrations of DTG 
and/or 3TC and must not be administered concurrently with DTG + 3TC: 

Carbamazepine

Oxcarbamazepine

Phenobarbital

Phenytoin

Rifampin

Rifapentine

St. John’s wort

Fampridine/Dalfampridine
The following medications are also prohibited for subjects receiving DTG:

Dofetilide (DTG may inhibit renal tubular secretion resulting in increased dofetilide 
concentrations and potential for toxicity).

Pilsicainide 
Note: Any prohibited medications that decrease dolutegravir concentrations should be 
discontinued for a minimum of four weeks or a minimum of three half-lives (whichever 
is longer) prior to the first dose.  Any other prohibited medications should be 
discontinued for a minimum of two weeks or a minimum of three half-lives (whichever is 
longer) prior to the first dose.


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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1.  
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SRM), which is available on 
the online Study Web Portal. The SRM will provide the site personnel with 
administrative and detailed technical information.


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7.1.
Time and Events Table
7.1.1.
Early Switch Phase Time and Events Table (Screening to Week 148)
Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108
(optional)b
120
132
(optional)b
144
148c
Clinical and Other Assessments
Written informed 
consent
X
Inclusion/Exclusion 
criteriae
X
X
Demography
X
Prior ART history
X
Medical historyf
X
Current medical 
conditions
X
Cardiovascular risk 
assessment, including 
vital signsg
X
Vital Signs: Resting 
Blood pressure (See 
Section 7.4.4 and 
Appendix 10)
X
X
X
Body Weight (BMI will 
be calculated within the 
eCRF)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs: Hip and 
waist circumference
(see Section 7.4.4 and 
Appendix 10)
X


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Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108
(optional)b
120
132
(optional)b
144
148c
HIV risk factors and 
mode of transmission
X
CDC HIV-1 
classification
X
X
HIV associated 
conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Columbia Suicidality
Severity Rating Scale
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symptom Directed 
Physical Exami
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGj
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious adverse events
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Willingness to Switchl
Xl
EQ-5D-5m
X
X
X
X
X
X
X
Laboratory Assessments
Quantitative plasma 
HIV-1 RNAn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subset 
(CD4+ at all visits and 
CD8+ at Baseline, and 
Weeks 24, 48, 96, 144 
and 196 only) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for storageo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108
(optional)b
120
132
(optional)b
144
148c
PT/INR
X
Fasting lipids and 
glucosep
X
X
X
X
X
Xq
Urinalysis and spot 
urine for protein 
analysisr
X
X
X
X
X
X
X
Pregnancy tests,t,u
S
U/Sv
S
S
S
S
S
S
S
S
S
S
S
S
S
S
U
S
HbsAg, anti-HBc, anti-
HBs, and HBV DNAw
X
HCV antibody
X
RPR
X
Insulin, HbA1c and 
renal, and bone marker 
analytes (blood/urine)x
X
X
X
X
X
Xq
Whole Blood (Virology)y
X
X
X
X
X
Whole Blood (Telomere 
length)z
X
X
X
X
Xaa
Cryopreserved 
PBMCsbb
X
X
X
X
Xaa
Inflammation 
biomarkers (Blood)cc
X
X
X
X
Xaa
Study Treatment
IVRS/IWRSdd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study 
treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment 
accountability (pill 
counts)
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108
(optional)b
120
132
(optional)b
144
148c
Pharmacokineticee
Intensive PK sample 
collection at selected 
sites for subset of ~30 
subjects (Fasting)ee
Xff
Dispense PK Diary 
Card to intensive PK 
sub-set
X
Sparse PK sample 
collectionee
Xgg
X
X
X
X
X
Dispense PK Diary 
Card to Sparse PK 
subjects
X
X
X
X
X
X
anti-HBc = antibody to hepatitis B core antigen, anti-HBs = hepatitis B surface antibody, ART = antiretroviral therapy, CDC = Centers for Disease Control and Prevention, DNA = 
deoxyribonucleic acid, HbA1c = Glycated hemoglobin, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus type 1, IVRS = interactive 
voice recognition system, IWRS = interactive web recognition system, PBMC = peripheral blood mononuclear cell, RNA = ribonucleic acid, RPR = rapid plasma reagin


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7.1.2.
Late Switch Phase Time and Events Table: TBR subjects who switched to DTG + 3TC at Week 148
TBR subjects switching at Week 148 are followed up at 4, 12 and 24 weeks post-switch after which 24 weekly visits are resumed.
Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
152
160
172
184 
(optional)b
196
200hh
Clinical and Other Assessments
Vital Signs: Resting Blood 
pressure (See Section 7.4.4 and 
Appendix 10)
X
X
X
X
Body Weight (BMI will be 
calculated within the eCRF)
X
X
X
X
X
X
X
X
X
Vital Signs: Hip and waist 
circumference (see Section 7.4.4
and Appendix 10)
X
X
X
HIV associated conditions
X
X
X
X
X
X
X
X
Columbia Suicidality Severity 
Rating Scale
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Symptom Directed Physical 
Exami
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Serious adverse events
X
X
X
X
X
X
X
X
X
EQ-5D-5Lm
X
X
Laboratory Assessments
Quantitative plasma HIV-1 RNAn
X
X
X
X
X
X
X
Lymphocyte subset (CD4+ at all 
visits and CD8+ at Baseline, and 
Weeks 24, 48, 96, 144 and 196
only) 
X
X
X
X
X
X
Plasma for storageo
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X


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Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
152
160
172
184 
(optional)b
196
200hh
Hematology
X
X
X
X
X
X
X
X
Fasting lipids and glucosep
X
Xq
Urinalysis and spot urine for 
protein analysisr
X
X
X
Pregnancy tests,t,u
S
S
S
S
S
S
S
S
Insulin, HbA1c and renal, and 
bone marker analytes 
(blood/urine)x
X
Xq
Whole Blood (Virology)y
X
X
Whole Blood (Telomere length)z
X
Xaa
Cryopreserved PBMCsbb
X
Xaa
Inflammation biomarkers 
(Blood)cc
X
Xaa
Study Treatment
IVRS/IWRSdd
X
X
X
X
X
X
X
X
X
Dispense study treatment
X
X
X
X
X
Study treatment accountability 
(pill counts)
X
X
X
X
X
X
X


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7.1.3.
Late Switch Phase Time and Events Table: DTG + 3TC arm
Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
160 
(optional)b
172
184 
(optional)b
196
200hh
Clinical and Other Assessments
Vital Signs: Resting Blood pressure (See 
Section 7.4.4 and Appendix 10)
X
X
X
X
Body Weight (BMI will be calculated within the 
eCRF)
X
X
X
X
X
X
X
X
Vital Signs: Hip and waist circumference (see 
Section 7.4.4 and Appendix 10)
X
X
X
HIV associated conditions
X
X
X
X
X
X
X
Columbia Suicidality Severity Rating Scale
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
Symptom Directed Physical Exami
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Serious adverse events
X
X
X
X
X
X
X
X
EQ-5D-5Lm
X
X
Laboratory Assessments
Quantitative plasma HIV-1 RNAn
X
X
X
X
X
X
Lymphocyte subset (CD4+ at all visits and 
CD8+ at Baseline, and Weeks 24, 48, 96, 144 
and 196 only) 
X
X
X
X
X
Plasma for storageo
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Fasting lipids and glucosep
X
Xq
Urinalysis and spot urine for protein analysisr
X
X
X
Pregnancy tests,t,u
S
S
S
S
S
S
S
Insulin, HbA1c and renal, and bone marker 
analytes (blood/urine)x
X
Xq
Whole Blood (Virology)y
X
X


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Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
160 
(optional)b
172
184 
(optional)b
196
200hh
Whole Blood (Telomere length)z
X
Xaa
Cryopreserved PBMCsbb
X
Xaa
Inflammation biomarkers (Blood)cc
X
Xaa
Study Treatment
IVRS/IWRSdd
X
X
X
X
X
X
X
X
Dispense study treatment
X
X
X
Study treatment accountability (pill counts)
X
X
X
X
X
a.
As soon as all Screening results are available, randomization may occur.
b.
This optional study visit is ONLY to be conducted in countries that require visits every 3 months per standard of care.
c.
Subjects with plasma HIV-1 RNA 50 c/mL at Week 144 must have HIV-1 RNA level re-assessed by a second measurement performed 2-4 weeks later. Subjects should have 
received full doses of study treatment for at least 2 weeks at the time of HIV-1 RNA re-assessment. Subjects randomized to DTG + 3TC do not attend a Week 148 switch visit.  
d.
An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study medication for subjects with the following conditions at the last on-study visit:  ongoing AEs, 
serious adverse events (SAEs) regardless of attributability, any laboratory abnormalities considered to be AEs or potentially harmful to the subject. Only the laboratory tests 
necessary to evaluate the AE/SAE/laboratory abnormality should be collected.
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 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.
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.
h.
On Day 1, the electronic Columbia Suicidality Severity Rating Scale eC-SSRS, patient completed questionnaire) is to be administered prior to randomization. 
i.
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. 
j.
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes.
k.
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and administration of study 
drug at Day 1. 
l.
Willingness to Switch Survey must be done prior to randomization.


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m.
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 196.
n.
See Virologic Withdrawal and Stopping Criteria Section of protocol (Section 5.4).
o.
Plasma samples for storage will be collected at each visit starting at Screening, 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 subjects meet 
Suspected and Confirmed Virologic Withdrawal criteria. 
p.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
q.
Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 24, 48, 96, 144 or 196.
r.
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
s.
Women of childbearing potential only. S=serum, U=urine. Pregnancy events will be captured starting at Day 1 following exposure to study drug.
t.
Remind females of reproductive potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements.  
u.
Beginning after Week 96, if study visits are every 24 weeks, participants who are women of child bearing potential must also do a home-based urine pregnancy test approximately
every 12 weeks between study visits at approximately Weeks 108, 132, 160 and 184 and during the Continuation Phase.  Site staff must contact the participants who are women 
of child bearing potential to remind them to complete the test and to verify and record pregnancy test results in the source documents.  The site must also complete the pregnancy 
status eCRF if a pregnancy occurs and report the pregnancy to ViiV/GSK per Section 13.3.2.
v.
Local serum pregnancy test on Day 1 is allowed if it can be done, and results obtained, within 24 hours prior to randomization
w.
HBV DNA testing will be performed for subjects with positive anti-HBc and negative HBsAg and negative anti-HBs (past and/or current evidence).  Subjects will have to return to 
the clinic to provide a sample for HBV DNA testing prior to randomisation.
x.
Blood sample for insulin, HbA1c, and renal and bone biomarker assessments: Renal: Cystatin C; Beta-2-Microglobulin; Retinol Binding Protein (RBP); Bone: bone specific 
alkaline phosphatase, procollagen type 1-N-propeptide, type 1 collagen cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin D.
y.
Whole blood (Virology) may be used for virologic analyses as described in the protocol. 
z.
Whole blood will be used for telomere length evaluation at Day 1, Week 48, Week 96, Week 144, Week 196 and at the Withdrawal visit.
aa. Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 48, 96, 144 or 196
bb. PBMCs will be collected, cryopreserved and stored in a subset of sites. These samples will be used for the measurement of telomerase activity.
cc. Blood sample for inflammation biomarker assessments: IL-6, hs-CRP, d dimer, sCD14, sCD163.
dd. At Screening, a subject number will be generated.
ee. PK sampling in subjects from the DTG/3TC FDC arm only, as detailed in Section 11.
ff.
Intensive PK sampling in a subset of subjects from the DTG/3TC FDC arm at select sites at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours post-dose. On the intensive PK day, 
patients are required to fast from 8 hours prior to dosing and then through 4 hours post-dose. Detailed in Section 11.
gg. At Week 4, subjects who performed intensive PK do not perform Sparse PK sampling.
hh. Subjects must return to the clinic for a Week 200 End of Study visit when transitioning to commercial supplies or to an alternate ART regimen, if appropriate. Do not dispense 
study treatment at this study completion visit unless the participant is entering the Continuation Phase.
ii.
Only in case of non-availability of DTG + 3TC FDC.  Subjects 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 with the exception of 
dispensing study treatment.


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7.2.
Screening and Critical Baseline Assessments
Written informed consent must be obtained from each potentially eligible subject 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, subjects will complete Screening 
assessments to determine subject eligibility. Each subject being screened for enrollment 
evaluation will be assigned a subject number at the Screening visit. This number will be 
given sequentially in chronological order of subject presentation according to a numeric 
roster provided by PPD.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  If they are being utilised in the study, Patient Reported 
Outcomes questionnaires should be completed by subjects before any other assessment at 
a clinic visit, in the order specified.
7.2.1.
Screening Assessments
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 (as 
detailed in the CRF) will be assessed at Baseline and assessments will include height, 
weight, blood pressure, smoking status and history, pertinent medical conditions (e.g., 
hypertension, diabetes mellitus), and family history of premature cardiovascular disease.  
Background information to be collected at Screening includes demography (year of birth, 
sex, race and ethnicity) and prior ART history.
Eligible subjects may be randomly assigned immediately as soon as all Screening 
assessments are complete and the results are available and documented.  All subjects will 
complete the Screening period of approximately 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 subject’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 subject be randomized in the 
absence of source documentation, even if there are delays in receipt of this 
information. A subject 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 and 
eCRF.  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 


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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 subject is identified as having been mistakenly 
screened/randomized with exclusionary resistance, they will be withdrawn.
Subjects with chronic active hepatitis B 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 subjects with 
positive anti-HBc and negative HbsAg and negative anti-HBs (past and/or current 
evidence).
All subjects will be screened for syphilis at screening. Subjects 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. Subjects who complete treatment after the 
screening window closes may be rescreened.
Subjects who meet all entry criteria are randomized and assigned a randomization 
number. Subjects not meeting all inclusion and exclusion criteria at initial screen may be 
rescreened and receive a new subject 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.  Subjects who are randomized into the trial and subsequently 
withdrawn from the study for any reason may not be rescreened.
7.2.2.
Baseline Assessments
At Day 1 and prior to randomization, any changes to the eligibility parameters must be 
assessed and any results required prior to randomization (e.g., Day 1 urine pregnancy test 
for women of childbearing potential) must be available and reviewed.
Other baseline information to be collected at Day 1 includes general medical history and 
current medical conditions.  Laboratory and health outcomes assessments will also be 
assessed.  Questionnaire/surveys are recommended to be administered at the beginning of 
the visit before any other assessments are conducted.  
7.3.
Efficacy
7.3.1.
Efficacy Evaluations
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
Table (Section 7.1).  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.


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Lymphocyte Subsets
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage, and absolute CD4+ and CD8+ lymphocyte counts) 
according to the Time and Events Table (Section 7.1).
CDC HIV-1 Classification and HIV Associated Conditions
HIV-associated conditions will be recorded as per the Time and Events Table (Section 
7.1).  HIV associated conditions will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection in Adults (see Section 13.7).  When assessing 
CDC stage at screening consider only the latest available CD4 T-cell count, including 
CD4 T-cell count at screening. If a stage-3–defining opportunistic illness has been 
diagnosed up to screening, then the stage is 3 regardless of CD4 T-cell count test results.
For Baseline CDC classification at Day 1 use latest CD4 T-cell count, including CD4 T-
cell count at baseline. If a stage-3–defining opportunistic illness has been diagnosed 
between screening and Day 1, then the stage is 3 regardless of CD4 T-cell count test 
results.
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.
7.3.1.1.
Primary Efficacy Endpoint
The primary endpoint will be the proportion of subjects with virologic failure endpoint as 
per FDA snapshot category at week 48 for the ITT-E population.
7.3.1.2.
Secondary Efficacy Endpoints

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Weeks 24,48, 96 and 
144 using the Snapshot algorithm for the ITT-E population

Percentage of subjects with viral failure endpoint as per FDA snapshot category at 
Weeks 24, 96 and 144

Change from Baseline in CD4+ lymphocyte count at Weeks 24, 48, 96, and 144 

Change from Baseline in CD8+ lymphocyte count and CD4+/CD8+ cell counts ratio 
at Weeks 24, 48, 96 and 144

Incidence of disease progression (HIV-associated conditions, AIDS and death).
7.3.1.3.
Exploratory Efficacy Endpoints

Proportion of subjects with plasma HIV-1 RNA <50 c/mL by patient subgroup(s) 
(e.g., by age, gender, Baseline CD4+) at Week 24, 48, 96 and 144 using the Snapshot 
algorithm for the ITT-E population


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
Change from Baseline in CD4+ cell counts at Weeks 24, 48, 96, 144 and 196 by 
patient subgroups
Additional exploratory efficacy endpoints for subjects treated with DTG + 3TC since the 
Early Switch Phase, and for subjects switching in the Late Switch Phase include:

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ and CD8+ lymphocyte count and CD4+/CD8+ cell 
counts ratio at Week 196

Incidence of disease progression (HIV associated conditions, AIDS and death) 
through Week 196.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 13.8.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a ViiV/GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact at the timepoints specified in the Time and Events Table.

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to ViiV/GSK within 24 hours, as 
indicated in Section 13.8.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify ViiV/GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to ViiV/GSK are provided 
in Section 13.8


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7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up.
7.4.1.4.
Cardiovascular and Death Events
For any CV events, whether or not they are considered SAEs, and all deaths, specific CV 
and Death sections of the CRF are required to be completed. These sections include 
questions regarding CV (including sudden cardiac death) and non-CV death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific CV section of the CRF 
within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.5.
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 13.7) 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 13.8.2), or

The event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual subject, or


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
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.
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to ViiV/GSK (or designee) of SAEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
ViiV has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  ViiV will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and ViiV/GSK policy and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from ViiV/GSK (or 
designee) will file it with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
7.4.2.
Pregnancy
Information on the occurrence of pregnancies in female subjects will be collected over 
the period starting at Screening and ending at the final Follow-up visit. Pregnancies that 
occur following the first dose of study drug will be reported to the Medical Monitor.  
Follow-up information will be collected for pregnancies occurring from Day 1 to the final 
Follow-up visit.  Beginning after Week 96, if study visits are 24 weeks apart, participants 
who are women of child bearing potential must also do a home-based urine pregnancy 
test approximately every 12 weeks between study visits at approximately Weeks 108, 
132, 160 and 184.  Site staff must contact the participants who are women of child 
bearing potential to remind them to complete the test and to verify and record pregnancy 
test results in the source documents. Site staff must complete the pregnancy status eCRF 
if a pregnancy occurs.  If a pregnancy is reported then the investigator should inform 
ViiV/GSK within 2 weeks of learning of the pregnancy and should follow the procedures 
outlined in Section 13.3.2.
Any female who becomes pregnant (intrauterine) while participating in this study must be 
withdrawn from the study and must discontinue study drug immediately.
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 


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complications and elective terminations for medical reasons must be reported as an AE or 
SAE.  Spontaneous abortions must be reported as SAEs.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment 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 
ARV products.  Additional information and a list of participating manufacturers/licensees 
are available from http://www.apregistry.com/.  
7.4.3.
Physical Exams
Physical exams should be conducted as part of normal routine clinical care but will not be 
collected systematically in the CRF.  Abnormalities noted during any exam must be 
recorded in the CRF (e.g. in the current medical conditions or AE logs).
7.4.4.
Vital Signs
At the Screening visit, vital signs will be measured in semi-supine position after 5 
minutes rest and will include height, weight, systolic and diastolic blood pressure and 
Body Mass Index (BMI). Systolic and diastolic resting blood pressure, body weight and 
BMI will also be assessed at each visit according to the Time and Events Table (Section 
7.1). Procedures to be followed for resting blood pressure and body weight assessments
are provided in Appendix 10.  Waist and hip circumference will be assessed from Week 
144 onwards according to the Time and Events Table (Section 7.1).  Procedures to be 
followed for waist and hip circumference assessments are provided in Appendix 10.
7.4.5.
Electrocardiogram (ECG)
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).
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Section 7.1, must be 
performed by central laboratory services, with the exception of exceptional circumstances 
during screening noted in Section 5.3. Laboratory assessments must be conducted in 
accordance with the Central Laboratory Manual, and Protocol Time and Events 
Schedule. Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, site/centre number, and visit date.
Details for the preparation and shipment of samples will be provided by the central 
laboratory and are detailed in the laboratory manual.  Reference ranges for all safety 
parameters will be provided to the site by the central laboratory.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g. AE, SAE or dose modification) 
the results must be recorded in the eCRF. Local laboratory services may be used to 


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verify pending laboratory parameters only after consultation and agreement with the 
study team.
Refer to the lab manual for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws. Haematology, clinical chemistry, urinalysis and 
additional parameters to be tested are listed in Table 1.  Labs will be graded automatically 
by the central lab according to the DAIDS toxicity scales (See Section 13.9 “Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events”).


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Table 1
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
Creatinine
Chloride
ALT
Albumin
Glucoseb
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Phosphate
GFR/Creatinine clearancec
Calcium
Protein
Cystatin-C (Day 1 only)
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+ lymphocyte counts and percent
CD8+ lymphocyte counts, percent and CD4+/CD8+ cell count ratio at Baseline and Weeks 24, 48, 96, 144 
and 196
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, blood/urine); and 
Beta-2-Microglobulin (B2M, blood/urine)g
Bone biomarkers including: Bone-specific alkaline phosphatase, procollagen type 1 N-propeptide, type 1 
collagen cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin Dg
Inflammation biomarkers including IL-6, hs-CRP, d dimer, sCD14 and sCD163g
HbA1c, Insulin, HOMA-IR
MCV = mean corpuscular volume, RBC = red blood cells, WBC = white blood cells, BUN = Blood urea nitrogen, 
AST=aspartate aminotransferase, ALT = alanine aminotransferase, CO2 = carbon dioxide, HDL = high density 
lipoprotein, LDL = low density lipoprotein, HbsAg= hepatitis B virus surface antigen, PT/INR = prothrombin 
time/international normalized ratio, 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 subjects 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 subjects with afternoon appointments.
e)
For subjects meeting virologic withdrawal criteria, plasma samples will be analyzed in attempt to obtain 


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genotype/phenotype data.
f)
Urine pregnancy test/ serum pregnancy test will be performed according to the Time and Events Table. 
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 25 hydroxy-Vitamin D.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
7.4.7.
Suicidal Risk Monitoring
Subjects with HIV infection occasionally may present with symptoms of depression 
and/or suicidality (suicidal ideation or behavior).  In addition, there have been some 
reports of depression, suicidal ideation and behavior (particularly in patients with a 
pre-existing history of depression or psychiatric illness) in some patients being treated 
with INIs, including DTG.  Therefore, it is appropriate to monitor subjects for suicidality 
before and during treatment. 
Subjects should be monitored appropriately and observed closely for suicidal ideation 
and behavior or any other unusual changes in behavior. It is recommended that the 
investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behavior. Subjects 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 behavioral suicidal events used in this scale are based on those used in the 
Columbia Suicide History Form [Posner, 2007].  Questions are asked on suicidal 
behavior, suicidal ideation, and intensity of ideation.  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 patient completed questionnaire specified in the Time and Events 
Table. 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 subject 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 behavior, a suicide attempt, or a 
completed suicide.  The investigator will exercise his or her medical and scientific 
judgment in deciding whether an event is possibly suicide-related. PSRAE forms should 


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be completed and reported to ViiV/GSK within 1 week of the investigator diagnosing a 
possible suicidality-related AE.
7.5.
Biomarkers
Blood and urine are being collected to perform renal and bone biomarker assessments.  In 
addition to measurements of serum creatinine, estimated GFR, and urinary excretion of 
albumin, protein, creatinine and phosphate, additional renal biomarkers include:
Renal biomarkers:

Cystatin C (blood), 

Retinol Binding Protein (RBP, blood/urine) 

Beta-2-Microglobulin (B2M, blood/urine).  
Bone biomarkers:

Bone-specific alkaline phosphatase

Procollagen type 1 N-propeptide 

Type 1 collagen cross-linked C-telopeptide 

Osteocalcin 

25 hydroxy-Vitamin D 
Blood is being collected to perform assessments of insulin resistance, biomarkers of 
inflammation and telomere function.
Inflammation biomarkers:

Interleukin-6 (IL-6) 

High-sensitivity C reactive protein (hs-CRP)

D-dimer

Soluble CD14 (sCD14)

Soluble CD163 (sCD163)
Insulin, HbA1c, and HOMA-IR
Telomere function: 

Whole blood will be used for measurement of telomere length.  

In a subset of sites, PBMCs will be collected, cryopreserved and stored for 
measurement of telomerase activity. 
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 25 
hydroxy-vitamin D.
7.6.
HIV-1 Polymerase Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide plasma for 
storage samples according to the Time and Events Table (for potential viral genotypic 


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and phenotypic analyses).  Subjects 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, labeling and shipping of these samples will be supplied 
separately.  Genotypic and phenotypic analyses may be carried out by Monogram 
Biosciences using, but not limited to, their Standard PhenoSense and GenoSure testing 
methods for 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 current ART for subjects meeting Virologic 
Withdrawal criteria. The virologic endpoint may also be assessed based on third-agent 
class.
7.6.1.
HIV-1 Exploratory Analysis
After meeting virologic withdrawal criteria, additional analyses for HIV-1 resistance 
may, for example, be carried out on peripheral blood mononuclear cell (PBMC/whole 
blood) samples collected at Baseline and/or on stored plasma samples from other relevant 
time points.  These analyses may include but are not limited to additional viral 
genotyping and/or phenotyping, as well as other virologic evaluations such as linkage and 
minority species analyses, low level HIV-1 RNA quantitation and measurement of viral 
replicative capacity.  HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase 
genotype and phenotype will also be determined on the last on-treatment isolates from 
subjects who have HIV-1 RNA 400 c/mL regardless of confirmatory HIV-1 RNA.
7.7.
Value Evidence and Outcomes
Health outcomes assessments will be conducted according to the Time and Events Table 
(Section 7.1).  Assessments are recommended to be administered 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 2 health outcomes assessments will be utilized in this study:
To assess the reason(s) for their participation and facilitate an understanding of subject’s 
willingness to switch, subjects will be asked a single item question prior to 
randomization.
The European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L), developed by 
EuroQol group, is a standardized, generic questionnaire that provides a profile of patient 
function and a global health state rating. The five-item measure has one question 
assessing each of five dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression and 5 levels for each dimension including no problems, slight 
problems, moderate problems, severe problems and extreme problems. The EQ-5D-5L 
also includes a visual analog scale (VAS) that assesses overall health [Herdman, 2011].


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7.8.
Pharmacokinetic Assessments
A PK substudy will be performed (see Section 11 for details).
8.
DATA MANAGEMENT

For this study, electronic Data Management (eDM) subject data will be entered 
into GSK/PPD defined CRFs, transmitted electronically to GSK or designee and 
combined with data provided from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK/PPD standards and data cleaning procedures to ensure the integrity of the 
data, e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by ViiV/GSK/PPD, and 
copies will be sent to the investigator to maintain as the investigator copy.  
Subject initials will not be collected or transmitted to ViiV/GSK according to 
GSK/PPD policy.


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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to show that the antiviral effect of switching to a simplified two-
drug regimen of DTG + 3TC once-daily is not inferior to continuation of their TBR at 
week 48 in HIV-1 infected ART-experienced subjects.
Non-inferiority can 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 4%. If rd is the virologic failure rate on DTG + 3TC and rf is the virologic 
failure rate on the current ART regimen, then the hypotheses can be written as follows:
H0:  rd – rf ≥ 4%                   H1: rd – rf < 4%
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Assuming a true 2% virologic failure rate in each arm, a non-inferiority margin of 4%, 
and a 2.5% one-sided significance level, this study requires 275 subjects per treatment 
arm.
This would provide 92% power to show non-inferiority for the proportion of subjects 
with virologic failure according to the FDA snapshot algorithm at 48 weeks post-switch. 
If we observed a 2% virologic failure rate for the non-switch subjects then non-inferiority 
would be declared if the observed treatment difference was less than or equal to 1.3
percentage points.
While the targeted study size was 550 randomised subjects (from a target of 800 screened 
subjects), the study was over-enrolled based on an unexpected surge in recruitment in the 
last week of screening, resulting in a total of 743 subjects randomized. 
This final sample size will provide 97.3% power to show non-inferiority with the current 
assumptions, and non-inferiority can be declared if the actual observed treatment 
difference in the trial is less than or equal to 1.6%. 
9.2.1.1.
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. Per the FDA 
document, typical rates of virological failure seen in switch studies range from 1 to 3 
percent and a margin of 4% for virologic failure rate is considered tolerable. Assuming 
2% virologic failure rate in both treatment arms, a 4% non-inferiority margin is 
considered comparable to a 10% to 12% non-inferiority margin using response rate as 


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endpoint. A margin of 4% was therefore chosen for the present study assuming 2% 
failure rate in both arms [CDER, 2015].
9.2.1.2.
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 HIV-1 infected ART-
experienced subjects. Taken together, these data suggest that a reasonable assumption for 
the true failure rate for the current ART control arm and the switch arm is 2%.
Table 2
Snapshot Response and Virologic Failure rates in previous switch 
studies
Week 48
Study
Treatment Arm
Response rate 
(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%)
SWORD 1 & 2l
CAR
95%
6/511 (1%)
DTG+RPV
95%
3/513 (<1%)
Week 24
STRIIVINGm
DTG + ABC/3TC STR
85%
1%
Current ART 
88%
1%
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 dual 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.
EVG/Cobistat/TDF/FTC, EFV/TDF/FTC, ATV/Cobistat/TDF/FTC, or RTV/ATV/TDF/FTC 
k.
[Gallant, 2016]
l.
[Libre, 2017]
m.
[Trottier, 2015]


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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 arm assuming a 2% failure rate in the current ART non-switch arm and a 4% 
margin.  
Figure 3
Sample size sensitivity for the Snapshot Virologic Failure
Power=90%, NI margin=4%, control arm failure rate=2%
N=275 per arm, NI margin=4%, control arm 
failure rate=2%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
The following populations will be assessed (the analysis population for genotypic and 
phenotypic analyses will be fully described in the reporting and analysis plan [RAP]):
9.3.1.
Analysis Populations
9.3.1.1.
Intent-to-Treat Exposed (ITT-E) Population
This population will consist of all randomized subjects who receive at least one dose of 
study medication. Subjects 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.
9.3.1.2.
Per Protocol (PP) Population
This population will consist of subjects in the ITT-E Population with the exception of 
significant protocol violators: e.g., violations which could affect the assessment of 
antiviral activity. The PP population will be used for sensitivity analyses of the primary 
efficacy measure.


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9.3.1.3.
Safety Population
The Safety Population is defined as all subjects who receive at least one dose of study 
medication. Subjects will be analyzed according to the actual treatments received. Unless 
otherwise stated, the Safety Population will be used for safety analyses.
9.3.2.
Analysis Data Sets
The primary analysis set of data is based on virologic failure defined by the FDA 
snapshot algorithm. With the exception below, virologic failure includes subjects 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; patients 
who discontinued study drug or study before Week 48 for lack or loss of efficacy and 
patients who are equal to or above 50 c/mL in the 48-week window.
A secondary analysis set of data is based on subjects’ responses at <50 c/mL calculated 
according to the FDA snapshot algorithm. This algorithm treats all subjects 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 subjects 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 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 subject 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 subjects 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 (TRDF) 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.
9.3.3.
Treatment Comparisons
9.3.3.1.
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 


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significance.  Treatment with DTG + 3TC will be declared non-inferior to the TBR 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 4%.
9.3.3.2.
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 is superior to the TBR 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 compared to continuation of TBR with 
respect to virologic success endpoint as per FDA snapshot category using a -8% 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.
9.3.4.
Interim Analysis
One analysis will be conducted to evaluate the primary objective of the protocol when all 
subjects have completed their Week 48 visit.  An interim analysis will be conducted 
when all subjects have completed their Week 24 visit.  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 last visit for the primary Week 48 analysis.  
Week 96, Week 144 and Week 196 data cuts and analyses will be conducted.  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 
will be made as the Week 24 analyses will be secondary, and other analyses are 
secondary/exploratory and will occur after the primary endpoint analysis at Week 48.
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].An IDMC will be instituted to ensure external 
objective medical and/or statistical review of efficacy and safety in order to protect the 
ethical interests and well-being of subjects and to protect the scientific validity of the 
study.  An ad-hoc review of data by the IDMC will be triggered whenever the number of 
CVWs in the DTG + 3TC arm exceeds thresholds pre-specified in the IDMC charter.  


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Full details of the methods, timing, decision criteria and operating characteristics will be 
pre-specified in the IDMC Charter.
9.4.
Key Elements of Analysis Plan
The study design is open-label. However the central ViiV/GSK team responsible for the
conduct and analysis of the study will not review any summaries of data grouped by
treatment prior to database freeze for the Week 24 analysis. 
9.4.1.
Efficacy Analyses
For the primary comparison, adjusted estimates of the difference in the rate of virologic 
failures 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 treated subjects, mk is the number of INI-, NNTRI-, or 
PI-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
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


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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.
Further efficacy analyses to assess the sensitivity of the primary endpoint will be 
performed and will be included in the RAP.
Changes from baseline in CD4+ lymphocyte count and in CD4+/CD8+ lymphocyte 
counts ratio and resistance data will be summarized.  The incidence of HIV-1 disease 
progression (AIDS and death) will be presented.
The proportion of subjects with plasma HIV-1 RNA <50 c/mL using the Snapshot 
algorithm and changes from baseline in CD4+ lymphocyte count will be summarized by 
subgroups (e.g., age, gender, race).
Data gathered after subjects 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, unless otherwise stated. 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 (CSR).
9.4.2.
Safety Analyses
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 drug, will be 
summarized by treatment group.  The proportion of subjects 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 and AEs leading to withdrawal will 
also be assessed by baseline third agent class.
Statistical analysis of selected biomarkers and fasting lipids may be performed overall 
and by subgroup.  Change from baseline in renal, inflammation and bone biomarkers will 
be summarized by treatment and visit.  Change from baseline in Telomerase function will 
be summarized by treatment and visit.  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 subjects with graded laboratory toxicities (based 


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on DAIDS categories) will be summarized by treatment group. The proportion of 
subjects 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 included in the RAP.
Waist to height ratio and waist to hip ratio will be summarized by visit.  Further details 
will be included in the RAP.
Metabolic syndrome will be calculated at Baseline, Week 144 and Week 196. Further 
details will be included in RAP.
9.4.3.
Health Outcome Analyses
The reasons for Willingness to Switch at Day 1 and the change from Baseline in health 
related quality of life (using EQ-5D-5L) will be summarised as detailed in Section 7.7.  
Details of the analyses to be performed will be specified in the RAP.
9.4.4.
Viral genotyping/phenotyping Analyses
The incidence of observed genotypic and phenotypic resistance to DTG, 3TC and other 
on-study ART will be summarized by treatment arm for subjects meeting confirmed 
virologic withdrawal criteria. Details of the analyses to be performed will be specified in 
the RAP.
9.4.5.
Pharmacokinetic Analysis
See Section 11 for details.


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10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, ViiV/GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with ViiV/GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

ViiV/GSK will provide full details of the above procedures, either verbally, in 
writing, or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional
assessments, can be initiated.


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10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and ViiV/GSK 
procedures, GSK monitors, or any third parties conducting the study on behalf of 
ViiV/GSK, will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and ViiV/GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF
will serve as the source document.
ViiV/GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and ViiV/GSK Standard 
Operating Procedures.

ViiV/GSK reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical 
issues or severe non-compliance. For multicenter studies, this can occur at one or 
more or at all sites.  

If ViiV/GSK determines such action is needed, ViiV/GSK will discuss the 
reasons for taking such action with the investigator or the head of the medical 
institution (where applicable).  When feasible, ViiV/GSK will provide advance 


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notification to the investigator or the head of the medical institution, where 
applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, 
ViiV/GSK will promptly inform all investigators, heads of the medical 
institutions (where applicable) and/or institution(s) conducting the study. 
ViiV/GSK will also promptly inform the relevant regulatory authorities of the 
suspension or premature discontinuation of the study and the reason(s) for the 
action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a ViiV/GSK audit or regulatory inspection) and must be available for 
review in conjunction with assessment of the facility, supporting systems, and 
relevant site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

The Investigator’s Site Files must be retained for 25 years from the date of the 
final CSR. ViiV Healthcare, GSK or PPD will inform the investigator of the 
retention period due date at the time when this CSR (or equivalent) is issued to 
the site, 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.  

The investigator must notify ViiV/GSK of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the site.


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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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 prior to last subject’s week 48 visit.
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 subjects, 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.
10.8.
Independent Data Monitoring Committee
An IDMC will be utilised in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter, which is available upon request.  Communications received from the IDMC 
regarding the status of the study will be shared with investigators in a timely manner.


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11.
PHARMACOKINETIC SUBSTUDY
11.1.
Rationale for Pharmacokinetic Evaluation
Preliminary results of the pivotal bioequivalence study (204994) showed that when 
administered in the fasted state, the bilayer tablet demonstrated bioequivalence to the 
single entity tablets for dolutegravir AUC(0-∞) & Cmax and 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. PK of the 
FDC components will be evaluated using a combination of intensive and sparse 
sampling.
11.1.1.
Exploratory Objectives

To assess the steady-state DTG and 3TC exposure in HIV-1 infected patients.

To characterize the DTG and 3TC steady-state PK of the DTG/3TC FDC in HIV-
1 infected patients. 
11.1.2.
Exploratory Endpoints

Steady state plasma PK parameters of DTG and 3TC will be assessed using 
intensive PK collected at week 4.

Population estimates of PK parameters (e.g. apparent clearance [CL/F], apparent 
volume of distribution [V/F]) using DTG and 3TC intensive and sparse plasma 
concentrations at Weeks, 4, 8, 12, 24, 36 and 48.
11.1.3.
Pharmacokinetic Sample Collection
For each timepoint two separate blood samples will be collected into di-potassium 
ethylenediaminetetraacetic acid (K2EDTA) tubes. Table 3 and Table 4 list the sampling 
schedule to be followed for the assessment of intensive and sparse PK, respectively. The 
sub-set of subjects undergoing intensive PK sampling at selected sites will not undergo 
Sparse PK sampling at Week4, however, these subjects will undergo Sparse PK sampling 
at other PK visits (Table 3 and Table 4).
Table 3
Intensive Pharmacokinetic Sampling Schedule in a Subset of 
Subjects
Study visit
Sample Times Relative to Dose
Week 4
Pre-dosea, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24b hours post-dose
a.
Pre-dose samples will be collected 20-28 hours after the prior dose AND approximately 15 minutes before the 
morning dose which will be taken under observation at the clinic. 
b.
Subjects in the intensive PK sampling group must return to the site the next morning immediately following the 
Week 4 visit for the 24 hour post-dose blood sample collection.


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Table 4
Sparse Pharmacokinetic Sampling Schedule 
Study 
Visit
PK sample collection time relative to 
dose
PK Sampling Group
Week 4
1 pre-dosea,b sample AND
1 sample 1 hour post-doseb
All subjectse except for subjects 
participating in the intensive PK group
Week 8
1 sample 1 to 4 hours post-dosec
All subjectse
Week 12
1 sample 4 to 12 hours post-dosed
Weeks 24, 
36 and 48
1 pre-dose samplea
a.
Pre-dose samples will be collected 20-28 hours after the prior dose AND approximately 15 minutes before the 
morning dose which will be taken under observation at the clinic.
b.
Both sample timepoints must be obtained from each subject
c.
The 1 to 4 hours sample may be drawn any time between 1 – 4 hours post-dose
d.
The 4 to 12 hours sample may be drawn any time between 4 – 12 hours post-dose
e.
All subjects are expected to participate in sparse PK
To allow flexibility in scheduling PK draws while maintaining quality and accuracy, the 
week 8 and week 12 samples can be drawn interchangeably (i.e. 1 to 4 hours post-dose 
drawn at week 12 and the 4 to 12 hours post-dose drawn at week 8) as long as both the 1 
to 4 hours post-dose and 4 to 12 hours post-dose samples are obtained for each subject. In 
addition, flexibility is allowed in collecting the post-dose sample anywhere from 1 to 4 
hours and 4 to 12 hours so that a range of sample time can be obtained. To achieve this, 
the subject may choose to remain in clinic until at least 1 hour after taking the DTG dose 
and may choose to return to the clinic 4 to 12 hours after taking the medication.
It is important to collect PK samples according to the following procedures:

To enhance the quality of the data, subjects undergoing intensive and/or sparse
PK assessments will be asked to complete a diary card with the following 
information which will be included in eCRF:
o
The date and time of the DTG/3TC FDC administration for 3 days prior to
the scheduled PK clinic visit;
o
Whether or not the doses were taken with a meal 
o
Whether or not the subject vomited within 4 hours of taking the study drug
In addition the following information should be recorded in the eCRF:
o
The actual date and time of the observed dose taken at the clinic visit;
o
The actual date and time of the PK samples collected

For the 3 days in advance of a PK clinic visit, the subject must be instructed to 
take the DTG/3TC FDC without regard to food at a time that corresponds with the 


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scheduled PK visit time to allow for a pre-dose sample collection as close to 24
hour after the previous dose. 

On the days of the either intensive PK or sparse pre-dose sample collection, the 
subjects should not take a dose of the DTG/3TC FDC until instructed at the clinic 
visit. 

The subjects participating in intensive PK sampling will be requested to present 
at the clinic fasted for at least 8 hours at the week 4 visit. These subjects should 
return to the clinic next day for the 24 hours post-dose sample collection, prior to 
taking a DTG/3TC FDC dose. The 24 hours post-dose sample may be collected 
without regard to food. 

The sparse PK samples will be collected without regard to food (however the 
fed/fasted status information will be collected and recorded on the eCRF)
Note: If a subject presents at the clinic for pre-dose PK sample collection having already 
taken the daily dose or having missed doses within the previous 3 days, it is 
recommended to reschedule PK sampling as early as possible within the defined PK visit 
window. It is recommended not to collect PK samples if date and time of dosing for the 
previous 3 days cannot reliably be confirmed. If PK cannot be rescheduled within the 
pre-defined visit of interest window (specified in the study procedure manual), no PK 
sample is to be collected for that visit.
11.1.4.
Bioanalysis of DTG and 3TC Samples
The bioanalysis of plasma DTG and 3TC samples will be performed by PPD using GSK 
validated LC/MS/MS assay. 
11.1.5.
Pharmacokinetic Populations
Sparse PK population is defined as all subjects who received at least 1 dose of DTG/3TC 
FDC and have evaluable sparse samples with drug concentrations reported.
Intensive PK population is defined as the subset of subjects enrolled into intensive PK 
sampling, who received at least 1 dose of DTG/3TC FDC and have evaluable drug 
concentrations reported.
The defining of evaluable drug concentrations and further details on the PK populations 
will be described in the RAP.
11.1.6.
Pharmacokinetic Analyses
The following intensive PK parameters will be summarized for 3TC and DTG: maximum 
observed plasma concentration (Cmax); time to maximum observed plasma concentration 
(tmax); observed plasma concentration at the end of a dosing interval (Ctau); observed 
pre-dose plasma concentration (C0); area under the concentration-time curve in one 
dosing interval (AUC(0-)). 


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11.1.7.
Population PK
If data permits, the sparse PK data will be pooled with the intensive PK data and 
potentially data from other studies to perform integrated PK analyses for DTG and 3TC 
to estimate steady-state AUC, Cmax and Cfor individual subjects. Further details of the 
PK analyses will be provided in the RAP. The population PK analyses may be reported 
separately. 


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13.
APPENDICES
13.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
ADR
Adverse drug reaction
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 (0-)
Area under the curve zero to infinity
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
CSR
Clinical Study Report
C-SSRS
Columbia Suicidality Severity Rating Scale
CI
Confidence interval
COBI
Cobicistat
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
DP
Diphosphate
DRV
Darunavir
DTG
Dolutegravir, TIVICAY


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E/C/F/TAF
Elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide
E/C/F/TDF
Elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate
ECG
Electrocardiogram
eCRF
Electronic case report form
eC-SSRS
Electronic Columbia Suicidality Severity Rating Scale
eDM
Electronic Data Management
EFV
Efavirenz
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Levels
ETR
Etravirine
EU
European Union
EVG
Elvitegravir
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FSFV
First subject first visit
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 henoglobin
HBsAb
Hepatitis B surface Antibody
HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
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
Hs-CRP
High-sensitivity C reactive protein
HSR
Hypersensitivity reaction
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDMC
Independent data monitoring committee
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IL-6
Interleukin-6
INI
Integrase inhibitor
INSTI
Integrase strand transfer inhibitor
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board


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ITT-E
Intent-to-treat exposed
IUD
Intrauterine device
IRT
Interactive response technology
IVRS/IWRS
Interactive Voice/Web Recognition System
LDL 
Low density lipoprotein
LOCF
Last Observation Carried Forward
Lp-PLA2
Lipoprotein-associated phospholipase A2
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
MSD=F
Missing, switch, or discontinuation equals failure
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
PRO
Protease
PRTD
Proximal Renal Tubule Dysfunction
PSRAE
Possible suicidality-related adverse event
QTc
Corrected QT interval 
RAL
Raltegravir
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic acid
RPV
Rilpivirine, Edurant
RT
Reverse transcriptase
RTV
Ritonavir
SAE
Serious adverse event
SJS
Stevens-Johnson syndrome
SRM
Study Reference Manual
STR
Single tablet regimen
SVW
Suspected Virologic Withdrawal
TAF
Tenofovir alafenamide 
TBR
TAF based regimen


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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
VAS
Visual Analog Scale
US
United States
VSLC
ViiV Safety and Labelling Committee
WBC
White blood cell
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Abbot Realtime HIV-1
EPZICOM/KIVEXA
Descovy
TIVICAY
Edurant
TRIUMEQ
EQ-5D-5L
ZIAGEN
GenoSure
Genvoya
Monogram Biosciences
Odefsey
PhenoSense
SAS
Truvada


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13.2.
Appendix 2: 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 13.9).  Additional 
information regarding detecting, documenting and reporting AEs and SAEs are available 
in Section 7.4.
Study drug 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 drugs will be allowed.  Study drugs 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 drugs 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 subject management and study drug interruptions based on the 
severity of the AE for specific toxicities.  All changes in study drug must be accurately 
recorded in the subject’s eCRF.
Grade 1 or Grade 2 Toxicity/Adverse Event
Subjects who develop a Grade 1 or Grade 2 AE or toxicity may continue study treatment 
at the discretion of the investigator.  Subjects 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
Subjects 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 treatment, dosing may continue after discussion with the medical 
monitor.
Subjects who develop a Grade 3 AE or toxicity that the investigator considers related or 
possibly related to the study drugs should have study treatment withheld and be 
rechecked each week until the AE returns to Grade 2.  Once the AE is Grade ≤2, study 
treatment may be restarted. 
Should the same Grade 3 AE recur within 28 days in the same subject, study treatment 
should be permanently discontinued and the subject withdrawn from study.  Subjects 
experiencing Grade 3 AEs requiring permanent discontinuation of study treatment 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 
drugs.


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Subjects 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 drug if the investigator has compelling evidence that the toxicity is 
not related to study treatment.
Exceptions are noted for lipid abnormalities in Section 13.2.1.7 and rash in Section
13.2.1.6.
Grade 4 Toxicity/Adverse Event
Subjects who develop a Grade 4 AE or toxicity should have study treatment discontinued.  
However, if the investigator has compelling evidence that the AE is not causally related 
to the study drugs, dosing may continue after discussion with and assent from the medical 
monitor.  Subjects should be rechecked each week until the AE returns to Grade 2.
Subjects experiencing Grade 4 AEs requiring permanent discontinuation of study 
treatment should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal and follow-up study evaluations as noted above.
Subjects 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 treatment.  Exceptions are noted for lipid abnormalities in Section
13.2.1.7.  An in-clinic Follow-Up visit will be conducted approximately 4 weeks after the 
last dose of study medication for subjects with ongoing AEs, and SAEs and also any 
laboratory abnormalities that are considered to be AEs or potentially harmful to the 
subject, at the last on-study visit.  
13.2.1.
Specific Toxicities/Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be 
related or possibly related to study treatment are provided below. 
Subjects who permanently discontinue study treatment 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 5.4).
13.2.1.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event aetiology during administration of study drug and the follow-
up period. For a complete listing of stopping and follow-up criteria refer to Section 5.4.
13.2.1.2.
Restarting Study Drug
Refer to Section 13.6 for details on drug restart following transient resolving liver events 
not related to study treatment.


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13.2.1.3.
Decline in Renal Function
Subjects 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/albumin 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.
Subjects 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 treatment 
should be discontinued and the subject withdrawn from the study (as dose adjustment is 
needed for NRTIs, which is not possible in a study of a fixed-dose combination tablet).
13.2.1.4.
Proteinuria
Subjects 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 and protein/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.
Subjects 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.
13.2.1.5.
Allergic reaction
Subjects may continue study drug for Grade 1 or 2 allergic reactions at the discretion of 
the Investigator.  The subject should be advised to contact the Investigator immediately if 
there is any worsening of symptoms or if further systemic signs or symptoms develop.  
Antihistamines, corticosteroids, or antipruritic agents may be prescribed. 
Subjects with Grade ≥3 allergic reactions that are considered to be possibly or probably 
related to the study drug should permanently discontinue study treatment and the subject 
should be withdrawn from the study.  Subjects should be treated as clinically appropriate 
and followed until resolution of the AE.


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13.2.1.6.
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 most current version of the DTG IB 
and any IB supplements [GSK Document Number RM2007/00683/11, GSK Document 
Number 2017N352880_00, GSK Document Number 2017N352880_01].
Subjects with an isolated Grade 1 rash may continue study drug at the Investigator’s 
discretion.  The subject 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.
Subjects may continue study drug for an isolated Grade 2 rash.  However, study drug
(and all other concurrent medication(s) suspected in the Investigators causality 
assessment) should be permanently discontinued for any Grade ≥2 rash that is associated 
with an increase in ALT.  The subject 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.
Subjects should permanently discontinue study drug [and all other concurrent 
medication(s) suspected in the Investigators causality assessment] for an isolated Grade 3 
or 4 rash, except where the aetiology of the rash has been definitively diagnosed as NOT 
attributable to study drug (see below), and the subject should be withdrawn from the 
study.  Subjects 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 13.9.
However, if the aetiology of the rash has been definitively diagnosed as being unrelated 
to study drug and due to a specific medical event or a concomitant infection or a 
concomitant non-study medication, routine management should be performed and 
documentation of the diagnosis provided. In this situation, the study drug should be 
continued. 
13.2.1.7.
Hypertriglyceridemia/Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events Table (Section 7.1).  Subjects who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive study drug.


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13.2.1.8.
Creatine Phosphokinase (CPK) Elevation
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2 to 4 
weeks to ensure the result is transient or due to exercise and will not require a change in 
study treatment.  A history regarding use of drugs known to cause increase of CPK (such 
as statins), physical activity or exercise preceding the CPK evaluation should be obtained.  
Grade 4 elevations in CPK should have a repeat assessment after the subject has 
abstained from exercise for >24 hours.  For persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the study drugs, study treatment should be 
discontinued and the subject withdrawn from the study.
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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13.3.
Appendix 3:  Pregnancy Information
13.3.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP) and Collection of 
Pregnancy Information
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilisation with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination, and/or 
semen analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
13.3.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, 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 subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to 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 also will forward this information to the Antiretroviral Pregnancy 
Registry.  The international registry is jointly sponsored by manufacturers or 
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 foetal status (presence 
or absence of anomalies) or indication for procedure.


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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.    

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to the 
Medical Monitor as described in Section 13.8. 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 subject who becomes pregnant (intrauterine) while participating in this 
study must be withdrawn from the study and must immediately discontinue study 
drug.
Reference
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 
20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2. 


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
1 1 2
1 3. 4.
A p p e n di x 4: C hil d- P u g h Cl a s sifi c ati o n
A s u bject is classifie d wit h 
 ( Class A) if t heir o verall s um of 
sc ores is 5- 6 p oi nts, 
 ( Class B) if t heir o verall s u m of sc ores 
is 7- 9 p oi nts, a n d 
 ( Class C) if t heir o verall s u m of sc ores is 1 0-
1 5 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 5 ).  F or s u bjects 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.
[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 . 1 9 7 3; 6 0: 6 4 6- 4 9.
C CI
C CI
C CI
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.


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13.5.
Appendix 5: Liver Safety - Required Actions and Follow up 
Assessments
Table 6
Liver Chemistry Stopping Criteria:  Required Actions and Follow up 
Assessments
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 weekly for 2 weeks
Symptomatic3
ALT  3xULN (if baseline ALT is ULN)  with symptoms (new or worsening) 
believed to be related to  liver injury or hypersensitivity
ALT  3xbaseline (if baseline ALT is > ULN) with symptoms (new or worsening) 
believed to be related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to the Medical Monitor
within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments

Complete the liver imaging and/or liver 
biopsy eCRFs if these tests are performed

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart subject with study treatment 
unless allowed per protocol and ViiV Safety 
and Labelling Committee  approval is 
granted (refer to Appendix 6)

If restart not allowed or not granted, 
permanently discontinue study treatment and 
may continue subject in the study for any 
protocol specified follow up assessments
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 4

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 subjects 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 


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MONITORING:

Make every reasonable attempt to have 
subjects return to clinic within 24 hours for 
repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments.

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
within 60 hours after last dose4

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 
2xULN

Obtain complete blood count with 
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 CRF 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 form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject 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) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), 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 subjects 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.
PK sample may not be required for subjects known to be receiving placebo or non- ViiV/GSK standard-of-care  
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be 


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collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  
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; 37:1779-84.
Table 7
Liver Chemistry Increased Monitoring Criteria With Continued 
Therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.

Notify the Medical Monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolution or stabilisation (ALT 
< 5xULN on 2 consecutive evaluations) 
If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above


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13.6.
Appendix 6:  Liver Safety - Study Treatment Restart 
Guidelines
VSLC GUIDELINES FOR DRUG RESTART AFTER STOPPING FOR 
LIVER CRITERIA
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 
associated with human leukocyte antigen (HLA) marker of liver injury, when liver 
chemistries improve to within 1.5x baseline and ALT<3xULN) (Table 8, 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 drug 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 subject stable or improving on 
study drug, who exhibits liver chemistry elevation meeting subject stopping criteria, 
which is transient, non-drug-related, and liver chemistries improve to within 1.5x 
baseline and ALT< 3xULN. 

Medical monitor and Clinical Safety Physician to review the subject’s diagnosis, 
restart risk factors and complete checklist (Table 8).

The LOC medical director (ViiV Healthcare and GSK where applicable) should be 
informed that study drug restart is under consideration and of the final decision, 
whether or not to proceed.


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Table 8
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 subject stable or improving on study drug?
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 drug has an HLA genetic marker associated with liver injury (e.g., 
lapatinib, abacavir, amoxicillin/clavulanate)
Previous drug history

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 subject must be 
recorded by GCSP Physician and sent to the VSLC Secretary.

VSLC must approve drug re-initiation and dosing regimen


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Figure 4
VSLC process for drug restart approval or disapproval
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.

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. 


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
1 1 9
Pri n ci p al I n v e sti g at or A cti o n s:

T he PI  m ust o btai n Et hics C o m mittee or Instit uti o nal Re vie w B oar d a p pr o val of dr u g 
restart, as re q uire d. 

If dr u g re-i nitiati o n V S L C-a p pr o ve d, t he patie nt m ust pr o vi de i nf or me d c o nse nt wit h 
a clear descri pti o n of p ossi ble be nefits a n d ris ks of dr u g a d mi nistrati o n i ncl u di n g 
rec urre nt, m ore se vere li ver i nj ur y or p ossi ble deat h.

T he patie nt’s i nf or me d c o nse nt m us t be rec or de d i n t he st u d y c hart, a n d t he dr u g 
a d mi nistere d at a gree d d ose, as c o m m u nicate d b y Me dical m o nit or.

Li ver c he mistries m ust be f oll o we d o nce wee kly f or ‘rest art’ c ases f or o ne m o nt h or 
f or as l o n g as cli nicall y i n dicate d f oll o wi n g dr u g re-i nitiati o n.  If s u bject e x hi bits 
pr ot oc ol -defi ne d li ver c he mistr y  ele vati o ns, st u d y dr u g s h o ul d be disc o nti n ue d as 
pr ot oc ol s pecifie d.
V S L C a n d t he I R B/I E C m ust be i nf or me d of t he p atie nt’s o utc o me f oll o wi n g dr u g 
rest art.
R e st art s af et y  o ut c o m e s:





R ef er e n c e s
A n dra de RJ, R o bles M, L uce na MI.  R e c halle n ge i n dr u g -i n d uce d li ver i nj ur y: t he 
attracti ve hazar d.  E x pert O pi n Dr u g Saf. 2 0 0 9; 8: 7 0 9- 7 1 4.
H u nt C M.  Mit oc h o n drial a n d i m m u n oaller gic i nj ur y  i ncrease ris k of p ositi ve dr u g 
rec halle n ge after dr u g-i n d uce d li ver i nj ur y: A sys te matic re vie w.  He patol. 2 0 1 0; 
5 2: 2 2 1 6 - 2 2 2 2.
Pa pa y  JI, Cli nes D, Rafi R, et al.  Dr u g-i n d uce d li ver i nj ur y f oll o wi n g p ositi ve dr u g 
rec halle n ge.  Re g ul T o x P har m. 2 0 0 9; 5 4: 8 4- 9 0. 
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.


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13.7.
Appendix 7: 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 

Cryptococcosis, extrapulmonary 


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
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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13.8.
Appendix 8: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
13.8.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 


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condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
13.8.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a) Results in death
b) Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c) Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d) Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


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and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e) Is a congenital anomaly/birth defect
f)
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g) Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
13.8.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF 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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13.8.4.
Sentinel Events
Sentinel Event Definition:
A sentinel event is a ViiV/GSK -defined SAE that is not necessarily drug-related but has 
been associated historically with adverse reactions for other drugs and is therefore worthy 
of heightened pharmacovigilance. Medical monitor review of all SAEs for possible 
sentinel events is mandated at ViiV/GSK. The medical monitor may request additional 
clinical information on an urgent basis if a possible sentinel event is identified on SAE 
review. The current ViiV/GSK-defined sentinel events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe neutropenia 

Anaphylaxis and anaphylactoid reactions 

Hepatotoxicity

Acute renal failure

Seizure

Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN)
13.8.5.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to ViiV/GSK in lieu of completion of the  AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by ViiV/GSK.  In this instance, all subject identifiers, with the exception 
of the subject number, will be blinded on the copies of the medical records prior to 
submission to ViiV/GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.


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13.8.6.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the categories in the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE Grading 
Table”) in Section 13.9:

Grade1 / 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 one of the pre-defined outcomes as 
described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A “reasonable possibility” is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to ViiV/GSK.  However, it is very 
important that the investigator always make an assessment of causality for 
every event prior to the initial transmission of the SAE data to ViiV/GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by ViiV/GSK 
to elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to ViiV/GSK within the 
designated reporting time frames.
13.8.7.
Reporting of SAEs and other events to ViiV/GSK/PPD
Reporting of SAEs and other events to ViiV/GSK/PPD

Primary mechanism for reporting SAEs to ViiV/GSK/PPD will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and scan and email it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool 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 subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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13.9.
Appendix 9: 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
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)
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


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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
Lipohypertrophy5
Detectable by
study participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference with 
usual social & 
functional
activities
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and
abdomen


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Gastrointestinal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Anorexia
Loss of appetite 
without
decreased oral
intake
Loss of appetite 
associated with 
decreased oral
intake without
significant weight
loss
Loss of appetite 
associated with 
significant
weight loss
Life-threatening 
consequences OR
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total
Ascites
No symptoms
Symptoms
AND
Intervention 
indicated (e.g.,
diuretics,
therapeutic 
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
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 
intermittent 
episodes of
unformed stools 
OR Increase of ≤ 3 
stools over
baseline
per 24-hour period
Persistent episodes 
of unformed to 
watery stools OR
Increase of 4 to  6 
stools over
baseline per 24-
hour period
Increase of ≥ 7 
stools per 24-
hour period OR
IV fluid 
replacement 
indicated
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
< 1 year of age
Liquid stools 
(more unformed
than usual) but
usual number of
stools
Liquid stools with 
increased number
of stools OR Mild 
dehydration
Liquid stools with 
moderate 
dehydration
Life-threatening 
consequences (e.g., 
liquid stools resulting
in severe dehydration, 
hypotensive shock)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 
intervention 
indicated
Transfusion  
indicated
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
Mucositis or 
Stomatitis
Report only
one and 
specify 
location
Mucosal erythema
Patchy 
pseudomembranes 
or ulcerations
Confluent
pseudomembranes 
or ulcerations OR
Mucosal bleeding 
with minor trauma
Life-threatening 
consequences (e.g., 
aspiration, choking)
OR Tissue necrosis 
OR Diffuse 
spontaneous mucosal
bl
di
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 
indicatedP
Life-
threatening 
consequences 
Proctitis
Rectal discomfort 
with no
intervention 
indicated
Symptoms causing 
greater than
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
Symptoms causing 
inability to
perform usual
social & functional
activities OR
Operative 
intervention
Life-threatening 
consequences 
(e.g., perforation)
Rectal Discharge
Visible discharge
Discharge 
requiring the use 
of pads
NA
NA


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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
fluids)
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
Musculoskeletal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Arthralgia
Joint pain
causing no or
minimal 
interference
with usual
social & 
functional
activities
Joint pain causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Joint pain
causing 
inability to
perform usual
social & 
functional
activities
Disabling joint pain 
causing inability to 
perform basic self-care 
functions
Arthritis
Stiffness or
joint swelling
causing no or
minimal 
interference
with usual
social & 
functional
activities
Stiffness or joint 
swelling causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Stiffness or
joint swelling
causing 
inability to
perform usual
social & 
functional
activities
Disabling joint stiffness 
or swelling causing 
inability to perform
basic self-care functions
Myalgia
(generalized)
Muscle pain 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Muscle pain
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Muscle pain
causing inability
to perform usual
social & 
functional
activities
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions
Osteonecrosis
NA
No symptoms 
but with
radiographic 
findings AND
No operative 
intervention 
indicated
Bone pain with 
radiographic 
findings OR
Operative 
intervention
indicated
Disabling bone pain 
with radiographic 
findings causing 
inability to perform
basic self-care functions


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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
Neurologic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute CNS Ischemia
NA
NA
Transient
ischemic attack
Cerebral vascular 
accident (e.g.,
stroke with
neurological deficit)
Altered Mental
Status (for
Dementia, see 
Cognitive,
Behavioral, or 
Attentional
Disturbance below)
Changes 
causing no or
minimal 
interference
with usual
social & 
functional
activities
Mild lethargy or 
somnolence 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Confusion,
memory 
impairment,
lethargy, or 
somnolence 
causing inability
to perform usual
social & 
functional 
activities
Delirium OR
Obtundation OR
Coma


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Ataxia
Symptoms 
causing no or
minimal 
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
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


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Neuromuscular 
Weakness 
(includes 
myopathy and 
neuropathy)
Specify type, if
applicable
Minimal muscle 
weakness 
causing no or
minimal 
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
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)


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


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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
Suicidal Ideation or
Attempt
Report only one
Preoccupied
with thoughts 
of death AND
No wish to kill
oneself
Preoccupied
with thoughts 
of death AND
Wish to kill 
oneself with no 
specific plan or 
intent
Thoughts of
killing oneself
with partial
or complete 
plans but no
attempt to do so 
OR
Hospitalization
indicated
Suicide attempted


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Respiratory
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute 
Bronchospasm
Forced
expiratory 
volume in 1
second or peak
flow reduced to
≥ 70 to < 80%
OR Mild
symptoms
with intervention
not indicated
Forced
expiratory 
volume in 1
second or peak
flow 50 to
< 70% OR
Symptoms with
intervention
indicated OR
Symptoms 
causing greater
than minimal 
interference with
usual social &
functional activities
Forced
expiratory 
volume in 1
second or peak
flow 25 to
< 50% OR
Symptoms 
causing
inability to
perform usual
social & 
functional
activities
Forced expiratory 
volume in 1 second
or peak flow < 25%
OR Life-threatening 
respiratory or 
hemodynamic 
compromise OR
Intubation
Dyspnea or 
Respiratory
Distress
Report only one
Dyspnea on 
exertion with no
or minimal 
interference with 
usual social &
functional
activities OR
Wheezing OR
Minimal increase 
in
respiratory rate
for age
Dyspnea on
exertion causing
greater than 
minimal
interference with
usual social & 
functional
activities OR Nasal
flaring OR
Intercostal
retractions OR
Pulse oximetry
90 to < 95%
Dyspnea at rest 
causing inability
to perform usual
social
& functional
activities OR
Pulse oximetry
< 90%
Respiratory failure 
with ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation)
Sensory
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Hearing Loss
≥ 12 years of age
NA
Hearing aid
or 
intervention
not indicated
Hearing aid or 
intervention
indicated
Profound bilateral 
hearing loss (> 80 dB 
at
2 kHz and above) OR
Non-serviceable 
hearing
(i.e., >50 dB
audiogram and <50%
speech 
discrimination)


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PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
< 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)
Vertigo
Vertigo causing
no or minimal 
interference
with usual
social & 
functional
activities
Vertigo causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Vertigo
causing 
inability to
perform 
usual social
& functional
activities
Disabling vertigo 
causing inability to 
perform basic self-
care functions
Visual Changes
(assessed from baseline)
Visual
changes 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Visual changes 
causing greater
than minimal
interference with
usual social & 
functional
activities
Visual
changes 
causing
inability to 
perform usual
social
& functional
activities
Disabling visual loss 
in affected eye(s)


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Systemic
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute Allergic
Reaction
Localized
urticaria (wheals)
with no medical
intervention 
indicated
Localized
urticaria with
intervention 
indicated OR
Mild 
angioedema
with no
intervention 
indicated
Generalized
urticaria OR
Angioedema
with intervention
indicated OR
Symptoms of
mild
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
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


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


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Urinary
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Urinary Tract
Obstruction
NA
Signs or
symptoms of
urinary tract 
obstruction
without 
hydronephrosis 
or renal
dysfunction
Signs or
symptoms of 
urinary tract 
obstruction with 
hydronephrosis 
or renal
dysfunction
Obstruction
causing life-
threatening 
consequences
Site Reactions to Injections and Infusions
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain
or
Tenderness
Report only one
Pain or
tenderness 
causing no or 
minimal
limitation of
use of limb
Pain or tenderness 
causing greater
than minimal
limitation of use 
of limb
Pain or
tenderness 
causing inability
to perform usual
social
& functional
activities
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR
Hospitalization 
indicated
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)


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


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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
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


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


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


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


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Hematology
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Absolute CD4+
Count, Low
(cell/mm3; cells/L)
> 5 years of age
(not HIV infected)
300 to < 400
300 to < 400
200 to <  300
200 to < 300
100 to < 200
100  to < 200
< 100
< 100
Absolute 
Lymphocyte
Count, Low
(cell/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


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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
57 days of age to
< 13 years of
age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of
age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72
22 to 35 days of
age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of
age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59
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 


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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
Urinalysis
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Glycosuria
(random 
collection tested
by dipstick)
Trace to 1+ or
≤ 250 mg
2+ or ˃ 250 to
≤ 500 mg
> 2+ or > 500 mg
NA
Hematuria (not
to be reported
based on dipstick
findings or on 
blood believed to
be of menstrual
origin)
6 to < 10 RBCs
per high power
field
≥ 10 RBCs per
high power field
Gross, with or 
without clots 
OR With RBC
casts OR
Intervention 
indicated
Life-threatening 
consequences
Proteinuria
(random 
collection tested
by dipstick)
1+
2+
3+  or higher
NA
Appendix A: Total Bilirubin Table for Term and Preterm Neonates
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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


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


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13.10.
Appendix 10: Protocol Recommendation for Assessment of 
Waist Circumference, Hip Circumference and Weight 
(Adapted from WHO STEPS Surveillance Manual, 2017) and 
for Resting Blood Pressure
[WHO, 2017]
13.10.1.
Waist Circumference
Equipment 
To take waist circumference measurements you will need a:

Constant tension tape (for example, Figure Finder or Myo Tape Body Tape 
Measure);
o
Tape measures will be provided for the study

Chair or coat stand for participants to place their clothes.
Privacy
A private area is necessary for this measurement. This could be a separate room, or an 
area that has been screened off from other people.
Preparing the participant
This measurement should be taken without clothing, meaning, directly over the skin.
If this is not possible, the measurement may be taken over light clothing (for example, a 
hospital gown, an undergarment or thin t-shirt). Thick or bulky clothing must be 
removed.  Body shaping garments are not allowed to be worn during this measurement.
How to take the measurement
We recommend having the same study staff performing the measurement across visits for 
individual study participants.
This measurement should be taken:

at the end of a normal expiration;

with the arms relaxed at the sides;

at the midpoint between the lower margin of the last palpable rib and the top of the 
iliac crest (hip bone).


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Figure 5
Location of Midpoint for Waist Circumference Measurement 
Procedure
Follow the steps below to measure the waist circumference of a participant:
1.
Standing to the side of the participant, locate the last palpable rib and the top of the 
hip bone. You may ask the participant to assist you in locating these points on their 
body.
2.
Wrap the tension tape around the participant and position the tape at the midpoint of 
the last palpable rib and the top of the hip bone, making sure to wrap the tape over 
the same spot on the opposite side.
Note: Check that the tape is horizontal across the back and front of the participant 
and as parallel with the floor as possible.
3.
Ask the participant to:

stand with their feet together with weight evenly distributed across both feet;

hold the arms in a relaxed position at the sides;

breathe normally for a few breaths, then make a normal expiration.


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4.
Measure waist circumference and read the measurement at the level of the tape to the 
nearest 0.1 cm, making sure to keep the measuring tape snug but not tight enough to 
cause compression of the skin.
5.
Record the measurement, in centimetres to one decimal place, within the eCRF.
Note: Measure once and record.
13.10.2.
Hip Circumference
Equipment
To take hip circumference measurements you will need a:

Constant tension tape (for example, Figure Finder or Myo Tape Body Tape 
Measure);
o
Tape measures will be provided for the study

Chair or coat stand for participants to place their clothes.
Privacy
A private area is necessary for this measurement. This could be a separate room, or an 
area that has been screened off from other people. Hip measurements are taken 
immediately after waist circumferences.
Preparing the participant
This measurement should be taken without clothing, that is, directly over the skin.
If this is not possible, the measurement may be taken over light clothing (for example, a 
hospital gown, an undergarment). Thick or bulky clothing must be removed.  Body 
shaping garments are not allowed to be worn during this measurement.
How to take the measurement
We recommend having the same study staff performing the measurement across visits for 
individual study participants.
This measurement should be taken:

with the arms relaxed at the sides

at the maximum circumference over the buttocks.
Procedure
Follow the steps below to take hip circumference measurements.
1.
Stand to the side of the participant and wrap the tension tape around them.


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2.
Position the measuring tape around the maximum circumference of the buttocks.
3.
Ask the participant to:

Stand with their feet together with weight evenly distributed over both feet;

Hold their arms relaxed at the sides.
4.
Check that the tape position is horizontal all around the body and snug without 
constricting.
5.
Measure hip circumference and read the measurement at the level of the tape to the 
nearest 0.1 cm.
6.
Record the measurement, in centimetres to one decimal place, within the eCRF. 
Note: Measure once and record.
13.10.3.
Weight
Equipment
To measure weight, you will need a weighing scale, (such as a SECA scale or the Tanita 
HS301 Solar Scale). Alternatively, a BMI scale measuring both height and weight (e. g. 
Growth Management Scale) can be used.
Ensure the scale has been regularly calibrated according to the manufacturer instructions 
and that calibration documentations are filed and available to the study CRA as required.
We recommend using the same scale across visits for individual study participants.
We recommend having the same study staff performing the measurement across visits for 
individual study participants.
We recommend that the time of day a participant’s weight is measured is consistent for 
every participant at the site within the study. (ex. If measured at 10 a.m. at initial 
measurement, attempt to have the participant measured at 10 a.m. at subsequent visits).
Set up requirements
Make sure the scales are placed on a firm, flat surface. Do not place the scales on:

carpet

a sloping surface

a rough, uneven surface.
Set up scales 
Follow the steps below before measuring the weight of a participant:
1.
Make sure the scale is on a firm, flat surface.
2.
Turn on the scale and wait until the display shows 0.0.


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Procedures
Follow the steps below to measure the weight of a participant:
1.
Ask the participant to remove their footwear (shoes, slippers, sandals, etc). They 
should also take off any heavy belts and remove all objects out of their pockets 
(example:  mobile phones, wallets, coins).
2.
Ask the participant to step onto scale with one foot on each side of the scale.
3.
Ask the participant to:

stand still

face forward

place arms on the side and

wait until asked to step off.
4.
Record the weight in kilograms to one decimal place in the eCRF.
References
World Health Organization (WHO). STEPS Surveillance Manual. The WHO STEPwise 
approach to noncommunicable disease risk factor surveillance, 2017; 3-5-9 to 3-5-13.
13.10.4.
Resting Blood Pressure
General instructions

Ensure that healthcare professionals taking blood pressure measurements have 
adequate initial training and periodic review of their performance.

Healthcare providers must ensure that devices for measuring blood pressure are 
properly validated, maintained and regularly recalibrated according to manufacturers' 
instructions.

When measuring blood pressure in the clinic or in the study site, standardise the 
environment and provide a relaxed, temperate setting, with the person quiet and 
seated, and their arm outstretched and supported. Use an appropriate cuff size for the 
person's arm.

Measure the blood pressure in one arm (after 5 minutes rest in semi-supine* position 
or seated).  
*Semi-supine position: Laying /sitting back (at 45angle or variations) in a relaxed 
position with feet touching a flat surface.


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13.11.
Appendix 11:  Country Specific Requirements
13.11.1.
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 Treatment for similar Phase III trials being conducted with 
dolutegravir.
The date of last study treatment administration in the UK will be determined by the 
completion of the Week 200 visit for the last UK subject enrolled.  The last subject was
enrolled by June 2018, and hence the last study treatment administration will occur by Q3
2022. (Note: For subjects in the UK, the study and provision of IP is anticipated to 
conclude by Q3 2022, at which time the dual regimen of DTG plus 3TC would be 
available as it is anticipated to be approved in Q3/Q4 2020).
13.11.2.
Japan
All drug will be provided centrally.  In Japan, only subjects receiving Descovy +DTG as 
their TBR are eligible for the study.   


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13.12.
Appendix 12 Protocol Changes
13.12.1.
Amendment 01 (2017-MAY-16): A global amendment applicable to 
all participating countries
Summary of Key Changes in Protocol Amendment 01 and Rationale

Tenofovir alafenamide (TAF) was corrected by removal of the word “fumarate”. 

Clarification was provided in the overall design to specify that subjects 
randomized to TBR will switch to DTG + 3TC at Week 52 if HIV-1 RNA <50 
c/mL at Week 48 (or upon retest by Week 52). 

Biomarkers of inflammation and mitochondrial function were removed as 
exploratory endpoints.  

A Week 96 endpoint was added to the measurement of biomarkers of telomerase 
function in a subset of subjects.

Cardiovascular biomarker measurements were removed as exploratory endpoints. 

Inclusion Criterion #5 was edited for clarity.

New section added as Sec 6.2, Protocol Permitted Substitutions, clarifying a 
switch from a PI boosted with RTV to the same PI boosted with cobisistat is 
allowed, and vice versa.

The text defining the TBR comparators as investigational medicinal product was 
removed; TBR comparators will be provided in designated, specific countries 
only, as needed. 

The Time and Events Table was modified to clarify that whole blood samples 
may be utilized for virology and for telomere length measurements, and 
cryopreserved PBMCs will be used to evaluate telomerase activity.

Updated version of Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (v2.1), March 2017, was provided in Section 12.9.

Changes were made to the protocol text to reflect the addition of Country Specific 
requirements for Japan. 

Minor revisions were made to the text to correct errors and improve accuracy.


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List of Specific Changes 
Section 1.  Rationale (also updated in Sec. 12.1 Appendix 1 Abbreviations and 
Trademarks):
Previous text:
Study 204862 is being conducted to establish if human immunodeficiency virus type 1 
(HIV-1) infected adult subjects with current virologic suppression on a ≥3-drug tenofovir 
alafenamide fumarate (TAF) based regimen (TBR)  remain suppressed upon switching 
to a two-drug regimen of dolutegravir (DTG) 50 mg + lamivudine (3TC) 300 mg.  
Current text:
Study 204862 is being conducted to establish if human immunodeficiency virus type 1 
(HIV-1) infected adult subjects with current virologic suppression on a ≥3-drug tenofovir 
alafenamide (TAF) based regimen (TBR)  remain suppressed upon switching to a two-
drug regimen of dolutegravir (DTG) 50 mg + lamivudine (3TC) 300 mg.

Section 1.  Overall Design (also updated in Section 4.1):
Previous Text:
Approximately 766 HIV-1 infected adults who are on a stable TBR will be randomized 
1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for up to 100 weeks, or to 
continue their TBR for 52 weeks, at which time and if HIV1 RNA <50 c/mL at Week 48 
these subjects will switch to DTG + 3TC up to Week 100.
Current Text:
Approximately 766 HIV-1 infected adults who are on a stable TBR will be randomized 
1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for up to 100 weeks, or to 
continue their TBR for 52 weeks, at which time and if HIV1 RNA <50 c/mL at Week 48 
(or upon re-test by Week 52), these subjects will switch to DTG + 3TC up to Week 100.

Section 1.  Synopsis, Overall Design:
Deleted paragraph (this was duplicate text):
All subjects who successfully complete up to 100 weeks of treatment will have the 
opportunity to continue receiving these agents until either DTG + 3TC Fixed dose 
Combination (FDC) is locally approved and commercially available, they no longer 
derive clinical benefit, they meet a protocol-defined reason for discontinuation, or until 
development of DTG plus 3TC dual regimen is terminated.


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
Section 2.1.  Study Rationale: 
Previous Text:
Compared to tenofovir disoproxil fumarate (TDF)-based regimens, tenofovir alafenamide 
fumarate (TAF) based regimen (TBRs) are associated with short-term improvements in 
renal and bone biomarkers in both treatment-naive and treatment-experienced persons 
[Genvoya, 2016].  
Current Text:
Compared to tenofovir disoproxil fumarate (TDF)-based regimens, tenofovir alafenamide 
(TAF) based regimens (TBRs) are associated with short-term improvements in renal and 
bone biomarkers in both treatment-naive and treatment-experienced persons [Genvoya,
2016].

Section 3.  Objectives and Endpoints:
Previous Text:
To evaluate biomarkers of inflammation, 
mitochondrial function and telomerase activity
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
inflammation, mitochondrial function and
telomerase activity at Week 48
Current Text:
To evaluate biomarkers of telomerase 
function in a subset of subjects treated with 
DTG + 3TC compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48 and 96
Previous Text:
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count at Week 96

Incidence and severity of AEs and 
laboratory abnormalities over 96 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 96 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 96


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
Change from Baseline in renal, bone and 
cardiovascular biomarkers at Week 96
Current Text:
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count at Week 96

Incidence and severity of AEs and 
laboratory abnormalities over 96 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 96 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 96

Change from Baseline in renal and bone, 
biomarkers at Week 96
Previous Text:
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count at Week 96

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal, bone and 
cardiovascular biomarkers at Week 96


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Current Text:
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count at Week 96

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 96

Section 4.1.  Overall Design:
Previous Text:
All subjects who successfully complete up to 100 weeks of treatment will have the 
opportunity to continue receiving these agents until either DTG + 3TC FDC is locally 
approved and commercially available, they no longer derive clinical benefit, they meet a 
protocol-defined reason for discontinuation, or until development of DTG + 3TC dual 
regimen is terminated. 
Current Text:
All subjects who successfully complete up to 100 weeks of treatment will have the 
opportunity to continue receiving DTG + 3TC FDC once daily in a Continuation Phase, 
as outlined in Section 4.2.4.   
Section 5.1.  Inclusion Criteria #5:


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Previous Text:
Must be on uninterrupted ART for at least 6 months prior to screening. Only the 
following regimens are allowed:
Subjects on a TAF-based regimen for at least 6 months, or 
Subjects who switched from TDF (as part of first-line regimen) to TAF, without any 
changes to the other drugs in their regimen, and have been on the TAF-based regimen for 
at least 3 months immediately prior to Screening. The switch must have occurred due to 
tolerability/safety, access to medications, or convenience/simplification, and must NOT 
have been done for suspected or established treatment failure.
Current Text:
  
Must be on uninterrupted ART for at least 6 months prior to screening. Only the 
following regimens are allowed:
Subjects on a TAF-based regimen for at least 6 months as the initial regimen, or 
Subjects who switched from a TDF first regimen to TAF, without any changes to the 
other drugs in their regimen, and have been on the TAF-based regimen for at least 3 
months immediately prior to Screening, i.e., the only switch made is from TDF to TAF.  
This switch must have occurred due to tolerability/safety, access to medications, or 
convenience/simplification, and must NOT have been done for suspected or established 
treatment failure.  A switch from a PI boosted with RTV to the same PI boosted with 
cobicistat is allowed, and vice versa.

Section 6.1.  Investigational Product and Other Study Treatment: 
Removed text: “The TBR comparators will be considered investigational medicinal 
product medicinal product: a pharmaceutical form of an active substance being tested or 
used as a reference in a clinical trial.”

Section 6.2.  Protocol Permitted Substitutions:
New Section added for clarification on use of pharmacokinetic boosters. 

New text added:  A switch from a PI boosted with RTV to the same PI boosted with 
cobicistat is allowed.  A switch from a PI boosted with cobicistat to the same PI 
boosted with RTV is allowed.   Section 7.1.  Table 2 Time and Events Table:

Footnote ‘o’ regarding plasma samples revised for clarity.  


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
‘Whole Blood’ entry was separated into two rows: ‘Whole Blood (Virology)’ and 
‘Whole Blood (Telomere length)’ to distinguish the samples by the intended use. 
In addition the word ‘PBMCs’ was removed. 

‘PBMCs’ entry was changed to ‘Cryopreserved PBMCs’ to specify that the 
PBMC sample must be cryopreserved for the evaluation of telomerase activity. 

Footnote ‘w’ was revised to clarify that whole blood samples (instead of PBMCs) 
may be used for virologic analyses as described in the protocol. Sample collection 
timepoints are indicated in the T&E table and were removed from the footnote. 

An additional footnote ‘x’ was created for the new entry Whole Blood (Telomere 
length) specifying that the sample will be used for telomere length evaluations. 

Footnote ‘y’ (previously footnote ‘x’) specifies that PBMCs (instead of plasma) 
will be collected, cryopreserved, and stored for a subset of sites. Additional 
revisions were made to clarify that these samples will be used for the 
measurement of telomerase activity only.

Footnote ‘z’ (previously footnote ‘y’) was renamed due to the creation of the 
above footnote ‘x’. 

Section 7.3.1.3.   Exploratory Efficacy Endpoints:
Additional text regarding exploratory efficacy endpoints was added:
Additional exploratory efficacy endpoints for subjects treated with DTG + 3TC since the 
Early Switch Phase, and for subjects switching in the Late Switch Phase include:

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte count at Week 96

Incidence of disease progression (HIV associated conditions, AIDS and death) 
through Week 96.

Section 7.5.  Other Biomarkers:
Previous text:
In a subset of subjects and at sites that can collect these samples, PBMCs and plasma will 
be collected, cryopreserved and stored at baseline and at Weeks 48 and 96. PBMCs and 
plasma will be analyzed for various markers of inflammation, mitochondrial and 
telomerase activity/function. Changes from baseline in these measurements will be 
compared between the DTG + 3TC and TBR arms.
Current text: 

Whole blood will be used for measurement of telomere length.


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
In a subset of sites, PBMCs will be collected, cryopreserved and stored for 
measurement of telomerase activity. 
Previous text: 
Since the intention is to utilize these biomarkers 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 25 hydroxy-vitamin D.
Current text: 
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 25 
hydroxy-vitamin D.

Section 12.9.  Appendix 9: 
Updated the Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events from Version 2.0 (November 2014) to Version 2.1 (March 2017). 

Section 12.10.  Appendix 10: 
Additional Level 2 headers in this Section, and added new Section 12.10.2: 

12.10.2 Japan
All drug will be provided centrally.  For subjects receiving Descovy as their TBR in 
Japan, the baseline third agent choice must be DTG.
13.12.2.
Protocol changes for Amendment 02 (2017-JUN-13) from 
Amendment 01 (2017-MAY-16): A global amendment applicable to 
all participating countries
Summary of Key Changes in Protocol Amendment 02

Clarification was provided that a switching from a PI boosted with ritonavir to the 
same PI boosted with cobicistat and vice versa is allowed during the study 
(Section 1). These agents are expected to have similar boosting effect and no 
impact on overall efficacy of the regimen.

Text related to the retesting of subjects with HIV-1 RNA <50 c/mL at Week 48 
was removed because only subjects with HIV-1 RNA 50 c/mL at Week 48 will 
be retested (Section 4.2.2).

The screening criteria related to hepatitis B status were corrected in the risk 
assessment table (Section 4.6.1).


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
Relevant text throughout the protocol was edited to make it clear that the review 
of genotypic resistance testing results (for both NRTI and DTG resistance 
mutations) by ViiV Virology is required after screening and before randomization 
(see Section 4.6.1, Section 5.2, Section 7.1 and Section 7.2.1). The prior text 
implied that this review was optional and/or that it only applied to DTG 
resistance-associated mutations.

The exclusion criteria were updated to make it clear that any evidence of major 
NRTI mutation or presence of any DTG resistance-associated mutations must be 
provided to ViiV after screening and before randomization (Section 5.2). The 
prior text implied that only DTG resistance-associated mutations be provided. The 
same clarification was made in footnote ‘e’ of the Time and Events Table 
(Section 7.1) and in the Screening Assessments section (Section 7.2.1).

The inclusion criteria for pregnancy testing were updated to be consistent with the 
Time and Events Table. Specifically, a local serum hCG test is allowed at 
randomization if results can be obtained 24 hours prior to randomization (Section 
5.1).

The missing connector words, ‘or anticipated need’, were added to the exclusion 
criteria related to HCV therapy (Section 5.2).

Text was updated to allow the use of local labs in exceptional circumstances, only 
if central lab results cannot be generated (plasma HIV-1 RNA levels are excluded 
from this allowance and must come from a central lab). In this case, the local lab 
results must be reviewed by the Medical Monitor (Section 5.3). Based on prior 
experience with studies in similar regions, ViiV Healthcare will allow this 
exception for study feasibility purposes. This same change was made to the 
Clinical Safety Laboratory Assessments text (Section 7.4.6).

The blinding section was updated to reflect the open-label design of the study 
(Section 6.5). Prior text had conflicting language indicating that some aspects of 
the study were blinded. An additional reference to blinding was removed from 
Appendix 2 (see Section 12.2.1.3). 

The Screening Assessments text related to syphilis treatment was clarified 
because the prior text was unclear (Section 7.2.1).

The Vital Signs section was corrected to be consistent with the planned 
assessments outlined in the Time and Events Table (Section 7.4.4).

Methods for GFR estimates were updated in Table 1 (required safety labs). 
Specifically, GFR will be estimated using the CKD-EPI-cystatin C equation in 
addition to the CKD-EPI-creatinine equation (Section 7.4.6).

The Analysis Data Sets text (Section 9.3.2) was updated to clarify that a switch 
from a PI boosted with ritonavir to the same PI boosted with cobicistat (and vice 
versa) is permitted per protocol and will not be considered as a change in 
background ART hence, will not incur a penalty in the Snapshot algorithm. These 


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agents are expected to have similar boosting effect and no impact on overall 
efficacy of the regimen.

Appendix 5 (Liver Safety – Required Actions and Follow-up Assessments): The 
appendix was updated to be consistent with ViiV Healthcare’s required 
assessments which are appropriate for this patient population. The prior appendix 
was based on a general GSK set of assessments and was not appropriate.

Appendix 6 (Liver Safety – Study Treatment Restart Guidelines): The appendix 
was updated to be consistent with ViiV Healthcare’s guidelines which are 
appropriate for this patient population. The prior appendix was based on a general 
GSK set of assessments and was not appropriate.

Appendix 8 (Definition of and Procedures for Recording, Evaluating, Follow-Up 
and Reporting of Adverse Events): The appendix was updated to be consistent 
with ViiV Healthcare’s definitions and procedures. The prior appendix was based 
on a general GSK template and was not appropriate.

Throughout the protocol, references to GSK were changed to ViiV, PPD, 
ViiV/GSK, or ViiV/GSK/PPD in order to indicate the appropriate roles and 
responsibilities of each entity.

Additional minor revisions were made to the text to correct errors and improve 
accuracy.
13.12.3.
Protocol changes for Amendment 03 (2017-AUG-24) from 
Amendment 02 (2017-JUN-13): A global amendment applicable to 
all participating countries
Summary of Key Changes in Protocol Amendment 03 and Rationale

Reduction in Sample size from a total of 766 randomized subjects to 550 
randomized subjects based on reassessment of the statistical assumptions and the 
use of a more accurate expected value for the primary endpoint of the 
investigational arm.

Addition of assessment of CD8+ lymphocyte cell counts at Baseline, Week 24, 
Week 48 and Week 96. Based on external expert advice.

Addition of assessment of inflammation biomarkers at Baseline, Week 48 and 
Week 96 as a new exploratory endpoint. Based on external expert advice.

Specification of the minimum 25 years retention from the issue of the final 
Clinical Study Report (CSR) or equivalent summary for the Investigator Site Files 
to align with the most recent Sponsor standard operating procedure.


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
1 7 2
List of S pecific C h a n ges 
Title P a ge.  A u t h ors
Pre vi o us te xt:
C urre nt te xt:
Secti o n 1.  O bjecti ve(s)/ E n d p oi nts:
Pre vi o us te xt:
T o ev al u at e t h e i m m u n e eff ects of D T G + 3 T C 
o nc e d aily c o m p ar e d t o c o nti n u ati o n of T B R

C h a n g e fr o m B as eli n e i n C D 4 + c ell c o u nt at 
W e eks 2 4 a n d 4 8

I nci d e nc e of dis e as e pr o gr essi o n ( HI V-
ass oci at e d c o n diti o ns, AI D S, a n d d e at h) 
t hr o u g h W e eks 2 4 a n d 4 8
C urre nt te xt:
T o ev al u at e t h e i m m u n e eff ects of D T G + 3 T C 
o nc e d aily c o m p ar e d t o c o nti n u ati o n of T B R

C h a n g e fr o m B as eli n e i n C D 4 + c ell c o u nt 
a n d i n C D 4 +/ C D 8 + c ell c o u nt s r ati o at 
W e eks 2 4 a n d 4 8

I nci d e nc e of dis e as e pr o gr essi o n ( HI V-
ass oci at e d c o n diti o ns, AI D S, a n d d e at h) 
t hr o u g h W e eks 2 4 a n d 4 8
Secti o n 1.  O ver all Desi g n:
Pre vi o us te xt:
A p pr o xi matel y  7 6 6 HI V- 1 i nfecte d a d ults w h o are o n a sta ble T B R will be ra n d o mize d 
1: 1 t o s witc h t o D T G + 3 T C o nce dail y ( D T G + 3 T C ar m) f or u p t o 1 0 0 wee ks, or t o 
c o nti n ue t heir T B R f or 5 2 wee ks, at w hic h ti me a n d if HI V 1 R N A < 5 0 c/ m L  at Wee k 4 8 
( or u p o n retest b y Wee k 5 2), t hese s u bjects will s witc h t o D T G + 3 T C u p t o Wee k 1 0 0.  
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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The sample size is such that the study has 90% power to demonstrate non-inferiority 
using a 4% margin, assuming a true 3 % virologic failure rate at Week 48 and using a
2.5% one-sided alpha level.
Current text:
Approximately 550 HIV-1 infected adults who are on a stable TBR will be randomized 
1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for up to 100 weeks, or to 
continue their TBR for 52 weeks, at which time and if HIV1 RNA <50 c/mL at Week 48 
(or upon retest by Week 52), these subjects will switch to DTG + 3TC up to Week 100.
The sample size is such that the study has 90% power to demonstrate non-inferiority 
using a 4% margin, assuming a true 2 % virologic failure rate at Week 48 and using a
2.5% one-sided alpha level.
Section 1.  Type and Number of Subjects:
Previous text:
Assuming 30% screen failure rate, approximately 1100 HIV-1-infected adult subjects 
will be screened to achieve 766 randomized subjects for a total of 383 evaluable subjects 
per treatment group.
Current text:
Assuming 30% screen failure rate, approximately 800 HIV-1-infected adult subjects will 
be screened to achieve 550 randomized subjects for a total of 275 evaluable subjects per 
treatment group.
Section 2.2.  Brief Background:
Previous text:
One such study was the OLE study which was an open label study in virologically 
suppressed HIV-1 infected individuals (HIV-1 RNA < 50 copies/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 dual regimen of LPV/r + 3TC or FTC [Arribas, 2015].  The primary endpoint was 
the proportion of patients free of therapeutic failure at 48 weeks. In a modified Intent to 
Treat (m-ITT) analysis, dual therapy with LPV/r + 3TC or FTC demonstrated non-
inferior efficacy and comparable safety to LPV/r + 2 NRTIs, as maintenance therapy in 
virologically suppressed patients (91.5% vs. 90.9% respectively; 95% Confidence 
Interval (CI): -0.6% to 8.1%).
Current text:
One such study was the OLE study which was an open label study in virologically 
suppressed HIV-1 infected individuals (HIV-1 RNA < 50 copies/mL) receiving a 
lopinavir (LPV)/r plus 3TC or emtricitabine (FTC) containing 3-drug regimen who were 


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randomized to continue their current triple based regimen or have their therapy simplified 
to a dual regimen of LPV/r + 3TC [Arribas, 2015].  The primary endpoint was the 
proportion of patients free of therapeutic failure at 48 weeks. In a modified Intent to Treat 
(m-ITT) analysis, dual therapy with LPV/r + 3TC demonstrated non-inferior efficacy and 
comparable safety to LPV/r + 2 NRTIs, as maintenance therapy in virologically 
suppressed patients (91.5% vs. 90.9% respectively; 95% Confidence Interval (CI): -0.6% 
to 8.1%).
Section 3. Objective(s) and Endpoint (s):
Previous text:
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
Change from Baseline in CD4+ cell count at 
Weeks 24 and 48
Incidence of disease progression (HIV-
associated conditions, AIDS, and death) 
through Weeks 24 and 48
Current text:
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
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
Previous text:
Exploratory
To evaluate the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4) on 
antiviral and immunological responses to DTG 
+ 3TC compared to TBR 
Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with snapshot 
virologic failure at Weeks 24 and 48
Change from Baseline in CD4+ cell counts at 
Weeks 24 and 48 by patient subgroups
To asses willingness to switch for subjects 
treated with DTG + 3TC compared to TBR
Reasons for Willingness to Switch at Day 1
To evaluate biomarkers of telomerase function 
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48 and 96
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 


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
Change from Baseline in CD4+ lymphocyte 
count at Week 96

Incidence and severity of AEs and 
laboratory abnormalities over 96 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 96 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 96

Change from Baseline in renal and bone 
biomarkers at Week 96
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count at Week 96

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 96
Current text:
Exploratory
To evaluate the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4) on 
antiviral and immunological responses to DTG 
+ 3TC compared to TBR 
Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with snapshot 
virologic failure at Weeks 24 and 48
Change from Baseline in CD4+ cell counts at 
Weeks 24 and 48 by patient subgroups
To asses willingness to switch for subjects 
treated with DTG + 3TC compared to TBR
Reasons for Willingness to Switch at Day 1
To evaluate biomarkers of telomerase function 
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48 and 96


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To evaluate inflammation biomarkers in a 
subset of subjects treated with DTG+ 3TC 
compared to TBR
Change from Baseline in inflammation  
biomarkers at Weeks 48
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio
at Week 96

Incidence and severity of AEs and 
laboratory abnormalities over 96 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 96 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 96

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation and telomerase function at 
week 96 
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio
at Week 96

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation and telomerase function at 
week 96


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Section 4.1. Overall Design
Previous text:
Approximately 766 HIV-1 infected adults who are on a stable TBR will be randomized 
1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for up to 100 weeks, or to 
continue their TBR for 52 weeks, at which time and if HIV-1 RNA <50 c/mL at Week 48 
(or upon retest by Week 52), these subjects will switch to DTG + 3TC up to Week 100.
Current text:
Approximately 550 HIV-1 infected adults who are on a stable TBR will be randomized 
1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for up to 100 weeks, or to 
continue their TBR for 52 weeks, at which time and if HIV-1 RNA <50 c/mL at Week 48 
(or upon retest by Week 52), these subjects will switch to DTG + 3TC up to Week 100.
Section 4.3. Type and Number of Subjects
Previous text:
The target population to be enrolled is HIV-1 infected adults who are virologically 
suppressed on a TBR (either as a first- or second-line regimen) and with no evidence or 
history of ARV drug-resistance.
Current text:
The target population to be enrolled is HIV-1 infected adults who are virologically 
suppressed on a TBR (As a first-line regimen with specific allowed switches as defined 
in inclusion criterion 5) and with no evidence or history of ARV drug-resistance.  
Previous text:
Assuming 30% screen failure rate, approximately 1100 HIV-1-infected adult subjects 
will be screened to achieve 766 randomized subjects for a total of 383 evaluable subjects 
per treatment group.
Current text:
Assuming 30% screen failure rate, approximately 800 HIV-1-infected adult subjects will 
be screened to achieve 550 randomized subjects for a total of 275 evaluable subjects per 
treatment group.
Section 5.1. Inclusion Criteria
Inclusion criterion 6:
Previous text: Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Section 12.3) from 30 days prior to the first dose of 


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study medication and until from 30 days prior to the first dose of study medication
and until the last dose of study medication and completion of the follow-up visit. 
Current text:
Reproductive potential and agrees to follow one of the options listed in the Modified List 
of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP) (see Section 12.3) from 30 days prior to the first dose of study 
medication and until the last dose of study medication and completion of the follow-up 
visit. 
Section 5.2. Exclusion CriteriaExclusion criterion 14
Previous text:
Use of any regimen consisting of single or dual ART (including peri-partum treatment 
with nevirapine).
Current text;
Use of any regimen consisting of single or dual ART.
Exclusion criterion 15
Previous text:
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, must be provided to ViiV after screening and before randomization for review by 
ViiV Virology.  Refer to the most recent version of IAS Guidelines, SPM, and Section 
7.2.1 (Screening Assessments) for more information.
Current text:
Any evidence of major NRTI mutation or presence of any major INSTI
resistance-associated mutation [Wensing, 2017] in any available prior resistance 
genotype assay test result, if known, must be provided to ViiV after screening and before 
randomization for review by ViiV Virology.  Refer to the most recent version of IAS 
Guidelines, SPM, and Section 7.2.1 (Screening Assessments) for more information.
Section 7.1. Time and Events Table:
New assessment row:
Added a row of vital sign procedure of body weight and calculated BMI at all visits.
Lymphocyte subset:
Previous text:


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Lymphocyte subset
Current text:
Lymphocyte subset (CD4+ at all visits and CD8+ at Baseline, and Weeks 24, 48 and 
96 only)
Added a row under Laboratory Assessment:
Previous text:
None
Current text:
Inflammation biomarkers (blood)aa with assessement at Baseline, Week 48, Week 96 and 
Withdrawal. Footnote aa specifies the biomarkers as follows:  Blood sample for 
inflammation biomarker assessments: IL-6, hs-CRP, d dimer, sCD14, sCD163.
Footnote q was edited and added to the withdrawal visit assessment of the renal and 
bone markers analytes. 
Previous text:
Collect fasting lipids and glucose if the Withdrawal visit occurs at Week 48 or 96.
Current text:
Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 24,
48 or 96
Additional footnote was added to the withdrawal visit assessment of the Whole 
blood (telomere Length), Cryopreserved PBMCs and Inflammation biomarkers.
Previous text:
None.
Current text:
Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 48 or 
96
Section 7.3.1. Efficacy Evaluations
Lymphocyte subsets:
Previous text:


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Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage, and absolute CD4+ lymphocyte counts) according to the 
Time and Events Table (Section 7.1).
Current text:
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage, and absolute CD4+ and CD8+ lymphocyte counts) 
according to the Time and Events Table (Section 7.1).
Section 7.3.1.2. Secondary Efficacy Endpoints
Previous text:
None
Current text:
Change from Baseline in CD8+ lymphocyte count and CD4+/CD8+ cell counts ratio 
at Weeks 24 and 48
Section 7.3.1.3. Exploratory Efficacy Endpoints
Previous text:
Change from Baseline in CD4+ lymphocyte count at Week 96
Current text:
Change from Baseline in CD4+ and CD8+ lymphocyte count and CD4+/CD8+ cell 
counts ratio at Week 96
Section 7.4.4. Vital Signs
Previous text:
At the Screening visit, vital signs will be measured in semi-supine position after 5 
minutes rest and will include height, weight, systolic and diastolic blood pressure and 
Body Mass Index (BMI).
Current text:
At the Screening visit, vital signs will be measured in semi-supine position after 5 
minutes rest and will include height, weight, systolic and diastolic blood pressure and 
Body Mass Index (BMI). Body weight and BMI will also be assessed at each visit 
according to the Time and Events Table (Section 7.1).


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Section 7.4.6. Table 1, Other Tests:
Previous text:
CD4+ lymphocyte counts
Current text:
CD4+ lymphocyte counts and percent
CD8+ lymphocyte counts, percent and CD4+/CD8+ cell counts ratio at Baseline and 
Weeks 24, 48 and 96.
Previous text:
None
Current addition:
Inflammation biomarkers including IL-6, hs CRP, d dimer, sCD14 and sCD163g.
Updated footnote g with definition of the inflammation biomarkers abbreviations: Il-6 = 
interleukin-6, hs-CRP = high-sensitivity C reactive protein, sCD = soluble CD.
Section 7.5. Biomarkers:
Previous text:
Blood and urine are being collected to perform renal and bone biomarker assessments.  In 
addition to measurements of serum creatinine, estimated GFR, and urinary excretion of 
albumin, protein, creatinine and phosphate, additional renal biomarkers include:
Renal biomarkers:

Cystatin C (blood), 

Retinol Binding Protein (RBP, blood/urine) 

Beta-2-Microglobulin (B2M, blood/urine).  
Bone biomarkers:

Bone-specific alkaline phosphatase

Procollagen type 1 N-propeptide 

Type 1 collagen cross-linked C-telopeptide 

Osteocalcin 

25 hydroxy-Vitamin D 
Other Biomarkers: 

Whole blood will be used for measurement of telomere length.  
In a subset of sites, PBMCs will be collected, cryopreserved and stored for measurement 
of telomerase activity.
Current text:


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Blood and urine are being collected to perform renal and bone biomarker assessments.  In 
addition to measurements of serum creatinine, estimated GFR, and urinary excretion of 
albumin, protein, creatinine and phosphate, additional renal biomarkers include:
Renal biomarkers:

Cystatin C (blood), 

Retinol Binding Protein (RBP, blood/urine) 

Beta-2-Microglobulin (B2M, blood/urine).  
Bone biomarkers:

Bone-specific alkaline phosphatase

Procollagen type 1 N-propeptide 

Type 1 collagen cross-linked C-telopeptide 

Osteocalcin 

25 hydroxy-Vitamin D 
Blood is being collected to perform assessments of biomarkers of inflammation and 
telomere function.
Inflammation biomarkers:

Interleukin-6 (IL-6) 

High-sensitivity C reactive protein (hs-CRP)

D-dimer

Soluble CD14 (sCD14)

Soluble CD163 (sCD163)
Telomere function:

Whole blood will be used for measurement of telomere length.  
In a subset of sites, PBMCs will be collected, cryopreserved and stored for measurement 
of telomerase activity.
Section 9.2. Sample Size Considerations.
Previous text:
Assuming a true 3% virologic failure rate in each arm, a non-inferiority margin of 4%, 
and a 2.5% one-sided significance level, this study requires 383 subjects per treatment 
arm.
This would provide 90% power to show non-inferiority for the proportion of subjects 
with virologic failure according to the FDA snapshot algorithm at 48 weeks post-switch. 
If we observed a 3% virologic failure rate for the non-switch subjects then non-inferiority 
would be declared if the observed treatment difference was less than 1.4 percentage 
points.
9.2.1.1. Rationale for non-inferiority margin


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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. Per the FDA 
document, typical rates of virological failure seen in switch studies range from 1 to 3 
percent and a margin of 4% for virologic failure rate is considered tolerable. Assuming 
2% virologic failure rate in both treatment arms, a 4% non-inferiority margin is 
considered comparable to a 10% to 12% non-inferiority margin using response rate as 
endpoint. A margin of 4% was e chosen for the present study assuming 3% failure rate in 
both arms, which is more stringent than assuming 2% failure rate in both arms
[CDER, 2015]. 
9.2.1.2. Response rate assumptions
Table 2 shows Snapshot response rates and Snapshot virologic failure rates in previous 
switch studies in HIV-1 infected ART-experienced subjects. Taken together, these data 
suggest that a reasonable assumption for the true failure rate for the current ART control 
arm and the switch arm is 3%.
Table 2 Snapshot Response rates in previous switch studies
Week 48
Study
Treatment Arm
HIV-1 RNA <50 Virologic Failure 
SPIRITa,b
RPV/FTC/TDF
89%
8/317 (2.5%)
STRATEGY-PIc
QUAD
94%
2/290 (<1%)
PI + FTC/TDF
87%
2/139 (1%)
STRATEGY-NNRTId
QUAD
93%
3/290 (1%)
NNRTI + FTC/TDF
88%
1/143 (<1%)
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%)
Week 24
STRIIVINGl
DTG + ABC/3TC STR
85%
1%
Current ART 
88%
1%
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 dual 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.
EVG/Cobistat/TDF/FTC, EFV/TDF/FTC, ATV/Cobistat/TDF/FTC, or RTV/ATV/TDF/FTC 
k.
[Gallant, 2016]


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l.
[TRottier, 2015]
9.2.2. Sample Size Sensitivity
Figure 3 shows sensitivity of the required sample size to the true response rate for the 
DTG + 3TC arm assuming a 3% failure rate in the current ART non-switch arm and a 4% 
margin.  
Figure 3 Sample size sensitivity for the Snapshot Virologic Failure
Power=90%, NI margin=4%, control arm failure rate=3%
N=383 per arm, NI 
margin=4%, control arm failure rate=3%
Current text:
9.2.1. Sample Size Assumptions
Assuming a true 2% virologic failure rate in each arm, a non-inferiority margin of 4%, 
and a 2.5% one-sided significance level, this study requires 275 subjects per treatment 
arm.
This would provide 92% power to show non-inferiority for the proportion of subjects 
with virologic failure according to the FDA snapshot algorithm at 48 weeks post-switch. 
If we observed a 2% virologic failure rate for the non-switch subjects then non-inferiority 
would be declared if the observed treatment difference was less than or equal to 1.24
percentage points.


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9.2.1.1. 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. Per the FDA 
document, typical rates of virological failure seen in switch studies range from 1 to 3 
percent and a margin of 4% for virologic failure rate is considered tolerable. Assuming 
2% virologic failure rate in both treatment arms, a 4% non-inferiority margin is 
considered comparable to a 10% to 12% non-inferiority margin using response rate as 
endpoint. A margin of 4% was therefore chosen for the present study assuming 2% 
failure rate in both arms [CDER, 2015].
9.2.1.2. Response and Virological 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 HIV-1 infected ART-
experienced subjects. Taken together, these data suggest that a reasonable assumption for 
the true failure rate for the current ART control arm and the switch arm is 2%.
Table 2 Snapshot Response and Virological Failure rates in previous switch studies
Week 48
Study
Treatment Arm
Response Rate 
(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%)
SWORD 1 & 2ll
CAR
95%
6/511 (1%)
DTG+RPV
95%
3/513 (<1%)
Week 24
STRIIVINGm
DTG + ABC/3TC STR
85%
1%
Current ART 
88%
1%
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]


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d.
[Pozniak, 2014]
e.
[Perez-Molina, 2015]
f.
The percentage of snapshot virologic failure is not available; however, 4% in the dual 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.
EVG/Cobistat/TDF/FTC, EFV/TDF/FTC, ATV/Cobistat/TDF/FTC, or RTV/ATV/TDF/FTC 
k.
[Gallant, 2016]
l.
[Libre, 2017]
m.
[Trottier, 2015]
9.2.2. Sample Size Sensitivity
Figure 3 shows sensitivity of the required sample size to the true response rate for the 
DTG + 3TC arm assuming a 2% failure rate in the current ART non-switch arm and a 4% 
margin.  
Figure 3 Sample size sensitivity for the Snapshot Virologic Failure
Power=90%, NI margin=4%, control arm failure rate=2%
N=275 per 
arm, NI margin=4%, control arm failure rate=2%
Section 9.3.2 Analysis Data Sets
Previous text:
A last observation carried forward (LOCF) dataset, in which missing values will be 
carried forward from previous (non-missing) value during the treatment 
assessments, might be used in the analysis of health outcomes data. Further details 
will be provided in the RAP.


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Current text:
Further details will be provided in the RAP.
Section 9.4.1. Efficacy Analyses
Previous text:
For the primary comparison, adjusted estimates of the difference in the rate of 
responders between the two arms will be presented along with CIs based on a stratified 
analysis using Cochran-Mantel-Haenszel (CMH) weights.
Current text:
For the primary comparison, adjusted estimates of the difference in the rate of virologic 
failures between the two arms will be presented along with CIs based on a stratified 
analysis using Cochran-Mantel-Haenszel (CMH) weights.
Previous text:
Changes from baseline in CD4+ lymphocyte count and resistance data will be 
summarized overall and by baseline third agent class.
Current text:
Changes from baseline in CD4+ lymphocyte count and in CD4+/CD8+ lymphocyte 
counts ratio and resistance data will be summarized overall and by baseline third agent 
class.
Section 9.4.2. Safety Analyses
Previous text:
Statistical analysis of selected biomarkers and fasting lipids may be performed overall 
and by subgroup.  Change from baseline in renal and bone biomarkers will be 
summarized by treatment and visit.  Further details will be detailed in the RAP.
Current text:
Statistical analysis of selected biomarkers and fasting lipids may be performed overall 
and by subgroup.  Change from baseline in renal, inflammation and bone biomarkers 
will be summarized by treatment and visit.  Change from baseline in Telomerase 
function will be summarized by treatment and visit.  Further details will be detailed in 
the RAP.
Section 10.6. Records Retention:
Previous text:


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ViiV/GSK will inform the investigator of the time period for retaining these records 
to comply with all applicable regulatory requirements.  The minimum retention 
time will meet the strictest standard applicable to that site for the study, as dictated 
by any institutional requirements or local laws or regulations, ViiV/GSK 
standards/procedures, and/or institutional requirements.
Current text:
The Investigator’s Site Files must be retained for 25 years from the date of the final 
CSR. ViiV Healthcare, GSK or PPD will inform the investigator of the retention 
period due date at the time when this CSR (or equivalent) is issued to the site, 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.
Section 11. References
Previous text:
None
Current text:
Libre JM, Hung C-C, Brinson C, et. al. Phase III SWORD 1&2: Switch to 
DTG+RPV maintains virologic suppression through 48 wks. 2017 CROI, Seattle. 
Abstract 44LB.
Section 12.2.1.4.  Proteinuria:
Previous text:
Subjects with an abnormal urine microalbumin/creatinine ratio (>0.3 mg/mg, >300 mg/g, 
or >34 mg/mmol) that represents a change from Baseline and no associated increase in
creatinine, should have a repeat spot urine microalbumin/creatinine ratio performed 
within 2-4 weeks.  If confirmed, then consideration should be given to additional 
evaluation after consultation with the study medical monitor. Additional evaluation may 
include a 24-hour urine protein and creatinine measurement and nephrology referral.
Current text:
Subjects 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 and 
protein/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.


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13.12.4.
Protocol changes for Amendment 04 (2017-DEC-07) from 
Amendment 03 (2017-AUG-24): A global amendment applicable to 
all participating countries
Summary of Key Changes in Protocol Amendment 04 and Rationale

Addition of a pharmacokinetics (PK) sub-study with sparse PK sampling and 
intensive PK sampling in a subset of subject in the DTG/3TC FDC arm to assess 
the PK parameters of DTG and 3TC of the DTG/3TC FDC in HIV-1 infected 
individuals as exploratory endpoints. This addition is based on Preliminary results 
of the pivotal bioequivalence study (204994) comparing the DTG/3TC FDC 
compared to the single entity tablets.

Deletion of the secondary objective and endpoint assessing the safety and 
tolerability of DTG + 3TC once daily in those with creatinine clearance of 
between 30 – 49 mL/min/1.73m2 compared to those with creatinine clearance of ≥ 
50 mL/min/1.73m2 because the exclusion criterion 18 has been updated to the 
higher threshold of creatinine clearance of ≥ 50 mL/min/1.73m2.

Inclusion of additional biomarkers for collection and analysis.

Change of exclusion criterion 18 to a threshold of creatinine clearance of ≥ 50 
mL/min/1.73m2 based on the approved 3TC prescribing information at the time of 
this amendment. The rational and corresponding references for lowering this 
threshold were deleted as no longer relevant.

Correction of the Time and event table footnote for plasma for storage samples to 
confirm the collection of these samples at the Screening visit; this was an error in 
the table.

Correction of the rational for not making adjustment for multiplicity because of an 
error in the original text.

Because of the addition of the PK substudy as Section 11, prior Section numbers 
from number 11 have been update by an increment of 1.

For clarification purposes, the AE severity gradings in Appendix 8, Section 13.8.6 
(Evaluating AEs and SAEs) were updated to be consistent with Appendix 9, 
Section 13.9. (Division of AIDS table for Grading Severity of Adult and Pediatric 
Adverse Events).  This change has no impact on the investigator’s evaluation of 
adverse events.

Text was edited in Appendix 10, Section 13.10.2. to clarify wording for the 
country specific requirement for Japan.


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
1 9 0
List of S pecific C h a n ges: U nless st ate d ot her wise, ne w te xt is re prese nte d i n b ol d 
f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
Title P a ge.  A ut h ors
Pre vi o us te xt:
C urre nt te xt:
Secti o n 1.  O bjecti ve(s)/ E n d p oi nts a n d Secti o n 3. O bjecti ve(s)/ E n d p oi nts:
Pre vi o us te xt:
O bj e cti v e
E n d p oi nt
S e c o n d ar y
T o ev al u at e t h e s af ety a n d t ol er a bility of D T G + 
3 T C o nc e d aily i n t h os e wit h cr e ati ni n e 
cl e ar a nc e of b et w e e n 3 0 – 4 9 m L/ mi n/ 1. 7 3 m 2
c o m p ar e d t o t h os e wit h cr e ati ni n e cl e ar a nc e of 
≥ 5 0 m L/ mi n/ 1. 7 3 m 2

I nci d e nc e a n d s ev erity of A Es a n d l a b or at ory 
a b n or m aliti es t hr o u g h 2 4 a n d 4 8 w e eks

Pr o p orti o n of s u bj ects w h o disc o nti n u e 
tr e at m e nt d u e t o A Es t hr o u g h 2 4 a n d 4 8 
w e eks 
C urre nt te xt:
O bj e cti v e
E n d p oi nt
S e c o n d ar y
T o ev al u at e t h e s af ety a n d t ol er a bility of D T G + 
3 T C o nc e d aily i n t h os e wit h cr e ati ni n e 
cl e ar a nc e of b et w e e n 3 0 – 4 9 m L/ mi n/ 1. 7 3 m 2
c o m p ar e d t o t h os e wit h cr e ati ni n e cl e ar a nc e of 
≥ 5 0 m L/ mi n/ 1. 7 3 m 2

I nci d e nc e a n d s ev erity of A Es a n d l a b or at ory 
a b n or m aliti es t hr o u g h 2 4 a n d 4 8 w e eks

Pr o p orti o n of s u bj ects w h o disc o nti n u e 
tr e at m e nt d u e t o A Es t hr o u g h 2 4 a n d 4 8 
w e eks 
Secti o n 1.  O ver all Desi g n a n d Secti o n 4. 1 O ver all Desi g n:
Pre vi o us te xt:
N o ne.
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


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Current text:
A pharmacokinetic (PK) substudy in the DTG+3TC arm will be conducted to 
evaluate DTG and 3TC concentrations using a sparse PK sampling approach at 
designated visits (See Section 11). In addition, intensive PK samples will be collected 
from a subgroup of subjects (approximately 30) enrolled at selected sites with the 
capability to perform intensive PK sampling.
Section3. Objective(s)/Endpoints:
Previous text:
None:
Current text:
Exploratory
To assess the steady-state DTG and 3TC 
exposure in HIV-1 infected patients
Steady state plasma PK parameters of DTG 
and 3TC will be assessed using intensive PK 
collected at week 4.
To characterize the DTG and 3TC steady-
state PK of the DTG/3TC FDC in HIV-1 
infected patients
Population estimates of DTG and 3TC PK 
parameters (e.g. apparent clearance [CL/F], 
apparent volume of distribution [V/F]) using 
DTG and 3TC intensive and sparse plasma 
concentrations at Weeks, 4, 8, 12, 24, 36 and 
48
Section3. Objective(s)/Endpoints:
Previous text:
Exploratory
To evaluate the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4) on 
antiviral and immunological responses to DTG 
+ 3TC compared to TBR 
Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with snapshot 
virologic failure at Weeks 24 and 48
Change from Baseline in CD4+ cell counts at 
Weeks 24 and 48 by patient subgroups
To asses willingness to switch for subjects 
treated with DTG + 3TC compared to TBR
Reasons for Willingness to Switch at Day 1
To evaluate biomarkers of telomerase function 
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48 and 96
To evaluate inflammation biomarkers in a 
subset of subjects treated with DTG+ 3TC 
compared to TBR
Change from Baseline in inflammation 
biomarkers at Weeks 48


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To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 96

Incidence and severity of AEs and 
laboratory abnormalities over 96 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 96 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 96

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation and telomerase function at 
week 96
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 96

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation and telomerase function at 
week 96


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Current text:
Exploratory
To evaluate the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4) on 
antiviral and immunological responses to DTG 
+ 3TC compared to TBR 
Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with snapshot 
virologic failure at Weeks 24 and 48
Change from Baseline in CD4+ cell counts at 
Weeks 24 and 48 by patient subgroups
To asses willingness to switch for subjects 
treated with DTG + 3TC compared to TBR
Reasons for Willingness to Switch at Day 1
To evaluate biomarkers of telomerase function 
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48 and 96
To evaluate inflammation biomarkers and 
insulin resistance in a subset of subjects 
treated with DTG+ 3TC compared to TBR
Change from Baseline in inflammation 
biomarkers and homeostasis model of 
assessment-insulin resistance (HOMA-IR) at 
Weeks 48
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 96

Incidence and severity of AEs and 
laboratory abnormalities over 96 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 96 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 96

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at week 96
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 96

Incidence and severity of AEs and 


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laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at week 96
Section 4.2.4 Continuation Phase (Post Week 100)
Previous text:
Assessments during the Continuation Phase are limited and will consist of safety 
laboratory assessments, including CD4+ lymphocyte counts that would be considered 
part of standard of care therapy for HIV-infected individuals.
Current text:
Assessments during the Continuation Phase are limited and will include plasma HIV-1 
RNA and collection of AEs and SAEs.  consist of safety laboratory assessments, 
including CD4+ lymphocyte counts that would be considered part of standard of care 
therapy for HIV-infected individuals.
Section 4.4 Design Justification:
Previous text:
This study also will 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 patients with 
moderate to severe renal impairment due to decreased clearance, and the current label 
recommends halving the dose to 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 
inclusion of HIV-infected persons with creatinine clearance of ≥30 mL/min/1.73m2 to 
confirm these earlier observations.


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Current text:
This study also will 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 patients with moderate to severe renal impairment due to decreased 
clearance, and the current label recommends halving the dose to 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 inclusion of HIV-
infected persons with creatinine clearance of ≥30 mL/min/1.73m2 to confirm these 
earlier observations.
Section 4.5 Dose Justification:
Previous text:
None.
Current text:
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 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. PK of the FDC 
components will be evaluated using a combination of intensive and sparse sampling.
Section 4.6.1 Risk Assessment:
Previous text:
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 blockade 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 patients with 
Specific/detailed toxicity management 
guidance is provided for subjects who 
develop a decline in renal function 
(Section12.2.1.3).
Creatinine clearance is calculated in all 
patients prior to initiating therapy and renal 
function (creatinine clearance and serum 
phosphate) will be monitored at all 
subsequent study visits.


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renal dysfunction.  3TC is not 
recommended to treat patients with a 
creatinine clearance <50 mL/min.
Subjects with creatinine clearance <30 
mL/min are excluded from participation in 
this study.
Safety events, including laboratory toxicities 
will be monitored closely in subjects with 
creatinine clearance between 
30-49 mL/min, as outlined in the Time and 
Events table.
Current text:
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 blockade 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 patients with 
renal dysfunction.  3TC is not 
recommended to treat patients with a 
creatinine clearance <50 mL/min.
Specific/detailed toxicity management 
guidance is provided for subjects who 
develop a decline in renal function 
(Section13.2.1.3).
Creatinine clearance is calculated in all 
patients prior to initiating therapy and renal 
function (creatinine clearance and serum 
phosphate) will be monitored at all 
subsequent study visits.
Subjects with creatinine clearance <50
mL/min are excluded from participation in 
this study.
Safety events, including laboratory toxicities 
will be monitored closely in subjects with 
creatinine clearance between 
30-49 mL/min, as outlined in the Time and 
Events table.
Section 5.1 Inclusion Criteria, clarification of criterion 1:
Inclusion criterion 1:
Previous text:
Aged 18 years or older (or ≥18 where required by local regulatory agencies), at the time 
of signing the informed consent
Current text:
Aged 18 years or older (or ≥18 older where required by local regulatory agencies), at the 
time of signing the informed consent


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Section 5.2 Exclusion Criteria, update of exclusion criterion 18:
Exclusion criterion 18:
Previous text:
Creatinine clearance of <30 mL/min/1.73m2 via CKD-EPI method
Current text
Creatinine clearance of <350 mL/min/1.73m2 via CKD-EPI method
Section 6.1 Investigational Product and Other Study Treatment
Previous text:
Study Treatment
(Open Label Randomised Phase, Day 1 to Week 100)
Product name:
DTG + 3TC FDC
Formulation description:
Clinical Trial Material
Dosage form:
Tablet
Unit dose strength(s)/Dosage level(s):
50mg/300mg
Route of Administration:
Oral
Dosing instructions:
Take one tablet daily.
Physical description:
White, oval, film-coated tablets.  The tablets are packed in 
high density polyethylene (HDPE) bottles with induction seals, 
and child-resistant closures.  Each 60mL bottle contains 30 
tablets.
Current text:
Study Treatment
(Open Label Randomised Phase, Day 1 to Week 100)
Product name:
DTG + 3TC FDC
Formulation description:
Clinical Trial Material
Dosage form:
Tablet
Unit dose strength(s)/Dosage level(s):
50mg/300mg
Route of Administration:
Oral
Dosing instructions:
Take one tablet daily.
Physical description:
White, oval, film-coated tablets with ‘SV 137’ debossed on 
one face.  The tablets are packed in high density polyethylene 
(HDPE) bottles with induction seals, 2gm desiccant, and 
child-resistant closures.  Each 60mL bottle contains 30 tablets.
Section 7.1. Time and Event Table:
Addition of insulin and HbA1c to biomarkers 


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Previous text:
Renal and bone marker analytes (blood/urine)v
Current text:
Insulin, HbA1c, renal and bone marker analytes (blood/urine)v
Section 7.1. Time and Event Table:
Correction of Footnote o:
Previous text:
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 subjects meet Suspected 
and Confirmed Virologic Withdrawal criteria.
Current text:
Plasma samples for storage will be collected at each visit starting at Day 1 Screening,
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 subjects meet 
Suspected and Confirmed Virologic Withdrawal criteria.
Addition to Footnote v:
Previous text:
Blood sample for renal and bone biomarker assessments
Current text:
Blood sample for insulin, Hb1Ac, renal and bone biomarker assessments
PK assessments:
Previous text:
None
Current text:


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Procedures
Screening Visita
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
Every 12 
weeks after 
Week 100
4
8
12
24
36
48
52
Switch 
Visitb
6
0
7
2
8
4
9
6
1
0
0
Pharmacokineticc
c
Intensive PK 
sample collection 
at selected sites 
for subset of ~30 
subjects 
(Fasting)cc
Xdd
Dispense PK 
diary Card to 
intensive PK sub-
set
X
Sparse PK 
sample 
collectioncc
Xee
X
X
X
X
X
Dispense PK 
Diary Card to 
Sparse PK 
subjects
X
X
X
X
X
X
Additional footnotes:
cc:PK sampling in subjects from the DTG/3TC FDC arm only, as detailed in Section 
11.
dd: Intensive PK sampling in a subset of subjects from the DTG/3TC FDC arm at 
select sites at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours post-dose. On the 
intensive PK day, patients are required to fast from 8 hours prior to dosing and then 
through 4 hours post-dose. Detailed in Section 11.
ee: At Week 4, subjects who performed intensive PK do not perform Sparse PK 
sampling.
Section 7.4.6 Clinical Safety Laboratory Assessments
Addition to Table 1 of Protocol Required Safety Laboratory Assessments
Previous text: 
None
Current text:


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HbA1c, Insulin, HOMA-IR
Addition to Table 1 footnote: HbA1c = glycated haemoglobin, HOMA-IR = 
homeostasis model of assessment – insulin resistance
Section 7.5 Biomarkers
HbA1c, insulin, HOMA-IR, and D-dimer were added to the list of biomarkers.
Previous text:
Blood is being collected to perform assessments of biomarkers of inflammation and 
telomere function.
Current text:
Blood is being collected to perform assessments of biomarkers of insulin resistance, 
inflammation and telomere function.
Insulin, HbA1c, and HOMA-IR
Additional Section 7.8. Pharmacokinetic Assessments:
Previous text:
None
Current text:
A PK substudy will be performed (see Section 11 for details).
Section 9.3.4. Interim Analysis:
Previous text:
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.
Current text:
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.


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Additional Section 9.4.5. Pharmacokinetic Analysis:
Previous text:
None
Current text:
See Section 11 for details.
Additional Section 11. PHARMACOKINETIC SUBSTUDY:
Previous text:
None.
Current text:
11. PHARMACOKINETIC SUBSTUDY
11.1.1. Rationale for Pharmacokinetic Evaluation
Preliminary results of the pivotal bioequivalence study (204994) showed that when 
administered in the fasted state, the bilayer tablet demonstrated bioequivalence to 
the single entity tablets for dolutegravir AUC(0-∞) & Cmax and 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. PK of the FDC components will be evaluated using a combination of 
intensive and sparse sampling. 
11.1.2. Exploratory Objectives
•
To assess the steady-state DTG and 3TC exposure in HIV-1 infected patients.
•
To characterize the DTG and 3TC steady-state PK of the DTG/3TC FDC in 
HIV-1 infected patients. 
11.1.3. Exploratory Endpoints
•
Steady state plasma PK parameters of DTG and 3TC will be assessed using 
intensive PK collected at week 4.
•
Population estimates of PK parameters (e.g. apparent clearance [CL/F], 
apparent volume of distribution [V/F]) using DTG and 3TC intensive and sparse 
plasma concentrations at Weeks, 4, 8, 12, 24, 36 and 48. 
11.1.4. Pharmacokinetic Sample Collection
For each timepoint two separate blood samples will be collected into di-potassium 
ethylenediaminetetraacetic acid (K2EDTA) tubes.  Table 3 and Table 4 list the 


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sampling schedule to be followed for the assessment of intensive and sparse PK, 
respectively. The sub-set of subjects undergoing intensive PK sampling at selected 
sites will not undergo Sparse PK sampling at Week4, however, these subjects will 
undergo Sparse PK sampling at other PK visits (Table 3 and Table 4).
Table 3 Intensive Pharmacokinetic Sampling Schedule in a Subset of Subjects
Study visit
Sample Times Relative to Dose
Week 4
Pre-dosea, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24b hours post-dose
a.
Pre-dose samples will be collected 20-28 hours after the prior dose AND approximately 15 
minutes before the morning dose which will be taken under observation at the clinic. 
b.
Subjects in the intensive PK sampling group must return to the site the next morning 
immediately following the Week 4 visit for the 24 hour post-dose blood sample collection. 
Table 4
Sparse Pharmacokinetic Sampling Schedule 
Study 
Visit
PK sample collection time relative to 
dose
PK Sampling Group
Week 4
1 pre-dosea,b sample AND
1 sample 1 hour post-doseb
All subjectse except for subjects 
participating in the intensive PK 
group
Week 8
1 sample 1 to 4 hours post-dosec
All subjectse
Week 12
1 sample 4 to 12 hours post-dosed
Weeks 
24, 36 
and 48
1 pre-dose samplea
a.
Pre-dose samples will be collected 20-28 hours after the prior dose AND approximately 15 
minutes before the morning dose which will be taken under observation at the clinic.
b.
Both sample timepoints must be obtained from each subject
c.
The 1 to 4 hours sample may be drawn any time between 1 – 4 hours post-dose
d.
The 4 to 12 hours sample may be drawn any time between 4 – 12 hours post-dose
e.
All subjects are expected to participate in sparse PK
To allow flexibility in scheduling PK draws while maintaining quality and accuracy, 
the week 8 and week 12 samples can be drawn interchangeably (i.e. 1 to 4 hours 
post-dose drawn at week 12 and the 4 to 12 hours post-dose drawn at week 8) as 
long as both the 1 to 4 hours post-dose and 4 to 12 hours post-dose samples are 
obtained for each subject. In addition, flexibility is allowed in collecting the post-
dose sample anywhere from 1 to 4 hours and 4 to 12 hours so that a range of sample 
time can be obtained. To achieve this, the subject may choose to remain in clinic 
until at least 1 hour after taking the DTG dose and may choose to return to the 
clinic 4 to 12 hours after taking the medication.
It is important to collect PK samples according to the following procedures:


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•
To enhance the quality of the data, subjects undergoing intensive and/or 
sparse PK assessments will be asked to complete a diary card with the following 
information which will be included in eCRF:
o
The date and time of the DTG/3TC FDC administration for 3 days prior to 
the scheduled PK clinic visit;
o
Whether or not the doses were taken with a meal 
o
Whether or not the subject vomited within 4 hours of taking the study drug
In addition the following information should be recorded in the eCRF:
o
The actual date and time of the observed dose taken at the clinic visit;
o
The actual date and time of the PK samples collected
•
For the 3 days in advance of a PK clinic visit, the subject must be instructed 
to take the DTG/3TC FDC without regard to food at a time that corresponds with 
the scheduled PK visit time to allow for a pre-dose sample collection as close to 24 
hour after the previous dose. 
•
On the days of the either intensive PK or sparse pre-dose sample collection, 
the subjects should not take a dose of the DTG/3TC FDC until instructed at the 
clinic visit. 
•
The subjects participating in intensive PK sampling will be requested to 
present at the clinic fasted for at least 8 hours at the week 4 visit. These subjects 
should return to the clinic next day for the 24 hours post-dose sample collection, 
prior to taking a DTG/3TC FDC dose. The 24 hours post-dose sample may be 
collected without regard to food. 
•
The sparse PK samples will be collected without regard to food (however the 
fed/fasted status information will be collected and recorded on the eCRF)
Note: If a subject presents at the clinic for pre-dose PK sample collection having 
already taken the daily dose or having missed doses within the previous 3 days, it is 
recommended to reschedule PK sampling as early as possible within the defined PK 
visit window. It is recommended not to collect PK samples if date and time of dosing 
for the previous 3 days cannot reliably be confirmed. If PK cannot be rescheduled 
within the pre-defined visit of interest window (specified in the study procedure 
manual), no PK sample is to be collected for that visit.
11.1.5. Bioanalysis of DTG and 3TC Samples
The bioanalysis of plasma DTG and 3TC samples will be performed by PPD using 
GSK validated LC/MS/MS assay. 
11.1.6. Pharmacokinetic Populations


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Sparse PK population is defined as all subjects who received at least 1 dose of 
DTG/3TC FDC and have evaluable sparse samples with drug concentrations 
reported.
Intensive PK population is defined as the subset of subjects enrolled into intensive 
PK sampling, who received at least 1 dose of DTG/3TC FDC and have evaluable 
drug concentrations reported.
The defining of evaluable drug concentrations and further details on the PK 
populations will be described in the RAP. 
11.1.7. Pharmacokinetic Analyses
The following intensive PK parameters will be summarized for 3TC and DTG: 
maximum observed plasma concentration (Cmax); time to maximum observed 
plasma concentration (tmax); observed plasma concentration at the end of a dosing 
interval (Ctau); observed pre-dose plasma concentration (C0); area under the 
concentration-time curve in one dosing interval (AUC(0-)).
11.1.8. Population PK
If data permits, the sparse PK data will be pooled with the intensive PK data and 
potentially data from other studies to perform integrated PK analyses for DTG and 
3TC to estimate steady-state AUC, Cmax and Cfor individual subjects. Further 
details of the PK analyses will be provided in the RAP. The population PK analyses 
may be reported separately.
Section 12. REFERENCES:
Previous text:
Dolutegravir (Tivicay) Product Insert.  Available at:  
http://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Inf
ormation/Tivicay/pdf/TIVICAY-PI-PIL.PDF.   June 2016.  Accessed February 8, 2017.
Epivir/Lamivudine Product Insert.  Available at:  
http://www.viivhealthcare.com/media/32160/us_epivir.pdf.  January, 2013.  Accessed 
February 8, 2017.
GlaxoWellcome Document Number: GIO/94/005. A Randomized, Controlled 
Lamivudine (3TC) Double-blind Trial to Compare the Safety and Efficacy of Zidovudine 
(ZDV) Monotherapy versus Lamivudine Plus ZDV in Combination in Treating HIV-1 
Infected Patients Who Are ZDV Therapy with a CD4 Cell Counts between 100-400 
cells/mm3 (Protocol No: NUCB3002). May 18, 1995.
GlaxoWellcome Document Number: UCR/95/003. A Randomized 3TC, ddC Double-
blind (ZDV Open-labeled) Multicenter Trial to Evaluate the Safety and Efficacy of 3TC 


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(low dose) Administered Concurrently with Zidovudine (ZDV) Versus 3TC (high dose) 
Administered Concurrently with ZDV Versus Dideoxycytidine (ddC) Administered 
Concurrently with ZDV in the Treatment of HIV-1 Infected ZDV-experienced (~24 
Weeks) Patients with CD4 Cell Counts of 100-300/mm3 (Protocol No: NUCA3002). May 
17, 1995.
Current text:
Dolutegravir (Tivicay) Product Information.  November 2017. 
Epivir (Lamivudine) Product Information.  September 2017. 
GlaxoWellcome Document Number: GIO/94/005. A Randomized, Controlled 
Lamivudine (3TC) Double-blind Trial to Compare the Safety and Efficacy of Zidovudine 
(ZDV) Monotherapy versus Lamivudine Plus ZDV in Combination in Treating HIV-1 
Infected Patients Who Are ZDV Therapy with a CD4 Cell Counts between 100-400 
cells/mm3 (Protocol No: NUCB3002). May 18, 1995.
GlaxoWellcome Document Number: UCR/95/003. A Randomized 3TC, ddC Double-
blind (ZDV Open-labeled) Multicenter Trial to Evaluate the Safety and Efficacy of 3TC 
(low dose) Administered Concurrently with Zidovudine (ZDV) Versus 3TC (high dose) 
Administered Concurrently with ZDV Versus Dideoxycytidine (ddC) Administered 
Concurrently with ZDV in the Treatment of HIV-1 Infected ZDV-experienced (~24 
Weeks) Patients with CD4 Cell Counts of 100-300/mm3 (Protocol No: NUCA3002). May 
17, 1995.
Section 13.2.1.5. Allergic Reaction
Previous text:
Subjects may continue study drug for Grade 1 or 2 allergic reactions at the discretion of 
the Investigator.  The subject 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.
Current text:
Subjects may continue study drug for Grade 1 or 2 allergic reactions at the discretion of 
the Investigator.  The subject 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.
Section 13.8.6. Evaluating AEs and SAEs
Previous text:
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:


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
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities.

Severe:  An event that prevents normal everyday activities. An AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Current text:
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the categories in the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE 
Grading Table”) in Section 13.9:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities.

Severe:  An event that prevents normal everyday activities. An AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

Grade1 / 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 one of the pre-defined outcomes as 
described in the definition of an SAE.
Section 13.10.2. Japan:
Previous text:
All drug will be provided centrally.  For subjects receiving Descovy as their TBR in 
Japan, the baseline third agent must be DTG.
Current text:


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
2 0 7
All dr u g will be pr o vi de d ce ntrall y.  F or s u bjects I n J a p a n, o nl y s u bjects recei vi n g 
Desc o v y + D T G as t heir T B R i n Ja pa n, t he baseli ne t hir d a ge nt m ust be D T G are eli gi ble 
f or t he st u d y.   
1 3. 1 2. 5.
Pr ot o c ol c h a n g e s f or A m e n d m e nt 0 5 ( 1 4 -J U N -2 0 1 8 ) fr o m 
A m e n d m e nt 0 4 ( 2 0 1 7 -D E C -0 7): A gl o b al a m e n d m e nt a p pli c a bl e t o 
all p arti ci p ati n g c o u ntri e s
S u m m ar y of Ke y C h a n ges i n Pr ot oc ol A me n d me nt 0 5 a n d R ati o n ale
C ha n ges were ma de t o t he pr ot oc ol t o ma na ge a n d miti gate ris ks f oll o wi n g i de ntificati o n 
of a p ote ntial safet y  iss ue relate d t o ne ural t u be defects i n i nfa nts b or n t o w o me n wit h 
e x p os ure t o d ol ute gra vir at t he ti me of c o nce pti o n.  C ha n ges were als o ma de t o i ncl u de 
u p date d te xt t o a d dress a hi g her n u m ber of partici pa nts scree ne d t ha n pla n ne d, t o u p date 
refere nces t o t he D T G I B t o reflect t he m ost c urre nt versi o ns a n d t o a d d clarificati o n a n d 
c orrect mi n or t yp os.  

T he Ris k Assess me nt ta ble ( Secti o n 4. 6. 1 ) was u p date d t o i ncl u de la n g ua ge re gar di n g 
ris k a n d miti gati o n of ne ural t u be defects.

T he wit h dra wal criteria ( Secti o n 5. 4 ) were u p date d t o i ncl u de a re mi n der t hat fe males 
of re pr o d ucti ve p ote ntial w h o c ha n ge t heir mi n ds a n d desire t o be pre g na nt , or w h o 
state t he y n o l o n ger are willi n g t o c o m pl y wit h t he a p pr o ve d pre g na nc y a v oi da nce 
met h o ds, s h o ul d als o be wit h dra w n fr o m t he st u d y.

T he Ti me a n d E ve nts ta ble ( Secti o n 7. 1 ). was u p date d t o i ncl u de a re mi n der f or 
i n vesti gat ors t o c hec k at e ver y visit t hat fe males of re pr o d ucti ve p ote ntial are 
a v oi di n g pre g na nc y.

T he m o difie d list of hi g hl y  effecti ve met h o ds f or a v oi di n g pre g na nc y i n F R P ( Secti o n
1 3. 3. 1 ) was u p date d t o e xcl u de the d o u ble barrier met h o d of c o ntrace pti o n, w hic h 
d oes n ot meet u p date d G S K/ Vii V criteria f or a hi g hl y effecti ve met h o d.

T he T y pe a n d N u m ber of S u bjects ( Secti o n 4. 3) a n d Sa m ple Size Ass u m pti o ns 
( Secti o n 9. 2. 1) were u p date d t o a d dress a hi g her n u m ber of partici pa nts scree ne d t ha n 
pla n ne d.
List of S pecific C h a n ges. U nless st ate d ot her wise, ne w te xt is re prese nte d i n b ol d 
f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
Title P a ge.  A ut h ors:
Pre vi o us te xt:
P P D
P P D


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
2 0 8
C urre nt te xt:
Pr ot oc ol S y n o psis f or St u d y 2 0 4 8 6 2, T y pe a n d N u m ber of S u bjects:
A d de d t he f oll o wi n g te xt: T he st u d y cl ose d scree ni n g o n 1 8 M a y 2 0 1 8 wit h a t ot al of 
9 3 3 scree ne d s u bjects a n d b ase d o n c urre nt r a n d o mis ati o n n u m bers a n d c urre nt 
scree n f ail ure r ate a t ot al of a p pr o xi m atel y 7 5 0 s u bjects are e x pecte d t o be 
r a n d o mise d.
Secti o n 3 O bjecti ves a n d E n d p oi nts:
T o e val uate i nfla m mati o n bi o mar kers a n d 
i ns uli n resista nce i n a s u bset of s u bjects 
treate d wit h D T G + 3 T C c o m pare d t o T B R
C ha n ge fr o m Baseli ne i n i nfla m mati o n 
bi o mar kers a n d h o me ostasis m o del of 
assess me nt -i ns uli n resista nce ( H O M A-I R) 
at Wee ks 4 8 a n d 9 6
Secti o n 4. 3 T y pe a n d N u m ber of S u bjects :
A d de d t he f oll o wi n g te xt: T he st u d y cl ose d scree ni n g o n 1 8 M a y 2 0 1 8 wit h a t ot al of 
9 3 3 scree ne d s u bjects a n d b ase d o n c urre nt r a n d o mis ati o n n u m bers a n d c urre nt 
scree n f ail ure r ate a t ot al of a p pr o xi m atel y 7 5 0 s u bjects are e x pecte d t o be 
r a n d o mise d .
Secti o n 4. 6. 1 Ris k Assess me nt :
A d de d t he f oll o wi n g te xt:
D T G: 
Ne ur al 
t u be 
defects
I n o ne o n g oi n g birt h o utc o me 
s ur veill a nce st u d y i n B ots w a n a, 
e arl y res ults fr o m a n u n pl a n ne d 
i nteri m a n al ysis s h o w t h at 4/ 4 2 6
( 0. 9 %) of w o me n w h o were 
t a ki n g D T G w he n t he y bec a me 
pre g n a nt h a d b a bies wit h ne ur al 
t u be defects c o m p are d t o a 
b ac k gr o u n d r ate of 0. 1 %.
1.
A fe m ale s u bject is eli gi ble 
t o p artici p ate if s he is n ot 
pre g n a nt, n ot l act ati n g, 
a n d, if s he is a fe m ale of 
re pr o d ucti ve p ote nti al, 
a grees t o f oll o w o ne of t he 
o pti o ns liste d i n t he 
M o difie d List of Hi g hl y 
Effecti ve Met h o ds f or 
A v oi di n g Pre g n a nc y i n 
Fe m ales of Re pr o d ucti ve 
P ote nti al ( F R P) (see 
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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Appendix 3, Section
13.3.1) 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 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.
Section 5.1 Inclusion Criteria:
Updated inclusion criterion 6: b. Reproductive potential and agrees to follow one of the 
options listed in the Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) (see Section 13.3) from 30 
days prior to the first dose of study medication and for at least 2 weeks after the 
last dose of study medication. and until the last dose of study medication and 
completion of the follow-up visit.
Section 5.4 Withdrawal and Stopping Criteria:
Previous text: 

Pregnancy (intrauterine), regardless of termination status of pregnancy.


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Current text:

Pregnancy (intrauterine), regardless of termination status of pregnancy. (Section 
7.4.2).  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. 
Section 7.1 Time and Events Table:
Inserted footnote t: Remind females of reproductive potential of the need to avoid 
pregnancy while in study and adherence to the study’s contraception requirements.
Due to the addition of this footnote, the sequence of footnotes has changed.
Section 7.3.1 Efficacy Evaluations:
HIV-associated conditions will be recorded as per the Time and Events Table (Section 
7.1).  HIV associated conditions will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection in Adults (see Section 13.7).  When assessing 
CDC stage at screening consider only the latest available CD4 T-cell count, 
including CD4 T-cell count at screening. If a stage-3–defining opportunistic illness 
has been diagnosed up to screening, then the stage is 3 regardless of CD4 T-cell 
count test results.
For Baseline CDC classification at Day 1 use latest CD4 T-cell count, including CD4 
T-cell count at baseline. If a stage-3–defining opportunistic illness has been 
diagnosed between screening and Day 1, then the stage is 3 regardless of CD4 T-cell 
count test results.
Section 9.2.1 Sample Size Assumptions:
Previous text:
If we observed a 2% virologic failure rate for the non-switch subjects then non-inferiority 
would be declared if the observed treatment difference was less than or equal to 1.24
percentage points.
Current text:
If we observed a 2% virologic failure rate for the non-switch subjects then non-inferiority 
would be declared if the observed treatment difference was less than or equal to 1.3
percentage points.
Added the following text: While the targeted study size was 550 randomised subjects 
(from a target of 800 screened subjects), the study was over-enrolled based on an 
unexpected surge in recruitment in the last week of screening. Based on an 


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estimated screen failure rate of 20%, a total of 750 subjects are expected to be 
randomized.
In this case where 750 subjects are randomized, this will provide 97.5% power to 
show non-inferiority with the current assumptions, and non-inferiority can be 
declared if the actual observed treatment difference in the trial is less than or equal 
to 1.6%. 
Section 12 References:
References to the DTG IB have been updated to add DTG IB version 11, supplement 01 
and 02 as follows:
GlaxoSmithKline Document Number 2017N352880_00: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 01, 11 December 2017.
GlaxoSmithKline Document Number 2017N352880_01: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 02, June 2018.
In text references to the DTG IB were also updated to include the link for GSK 
Document Numbers for IB version 11, and version 11, supplement 01 and 02.
Section 13.3.1 Modified list of highly effective methods for avoiding pregnancy in 
females of reproductive potential (FRP) and Collection of Pregnancy Information:
Removed the following text: Male condom combined with a vaginal spermicide (foam, 
gel, film, cream, or suppository) [Hatcher, 2007].
Removed the corresponding reference: Hatcher RA, Trussell J, Nelson AL, Cates W Jr, 
Stewart F, Kowal D, editors.  Contraceptive Technology. 19th edition. New York: Ardent 
Media, 2007:28.
13.12.6.
Protocol changes for Amendment 06 (29-AUG-2018) from 
Amendment 05 (14-JUN-2018)
Summary of Key Changes in Protocol Amendment 06 and Rationale
Changes were made to the protocol to update the study design to extend the Randomized 
Early Switch Phase through to 148 weeks instead of Week 52, delaying the late switch to 
Week 148 with long term follow-up through to completion of the study at Week 200.  
The rationale for this change is to collect and assess long-term comparative efficacy and 
safety data for DTG + 3TC FDC vs. a TAF-based regimen.  
List of Specific Changes. Unless stated otherwise, new text is represented in bold 
font, and deleted text in strikethrough font.


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
2 1 2
Title P a ge. A ut h ors:
Pre vi o us te xt:
C urre n t te xt: 
Me dic al M o nit or/ S p o ns or I nf or m ati o n P a ge
Pre vi o us te xt:
S p o ns or L e gal Re gistere d A d dress:
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
S p o ns or C o ntact A d dress:
Vii V Healt hcare 
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: + 1 9 1 9 4 3 8 2 1 0 0
C urre nt te xt:
S p o ns or N a me a n d Le gal 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 :
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
P P D
P P D


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ViiV Healthcare 
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: + 1 919 438 2100
Previous text:
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is supporting ViiV 
Healthcare in the conduct of this study.
Current text:
This study is sponsored by ViiV Healthcare. GlaxoSmithKline and PPD are supporting 
ViiV Healthcare in the conduct of this study.
Protocol Synopsis for Study 201862:
Previous text:
This study also will characterize the long-term antiviral activity, tolerability and safety of 
DTG + 3TC through Week 100.
Current text:
This study also will characterize the long-term antiviral activity, tolerability and safety of 
DTG + 3TC compared to TBR through Week 144 and characterize the long-term 
antiviral activity, tolerability and safety of DTG + 3TC through Week 200.
Previous text:
Objective
Endpoint
Primary
To demonstrate the non-inferior antiviral 
activity of switching to DTG +3TC once daily 
compared to continuation of TBR over 48 
weeks in HIV-1 infected, ART therapy (ART)-
experienced, virologically suppressed subjects
Virologic failure endpoint as per FDA snapshot 
category at Week 48
Secondary
To demonstrate the antiviral activity of 
switching to DTG +3TC once daily compared to 
continuation of TBR over 48 weeks 
Proportion of subjects with plasma HIV-1 RNA 
<50 copies c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 24 weeks 
Virologic failure 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


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Objective
Endpoint
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
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 once daily compared to TBR over time
Incidence and severity of AEs and laboratory 
abnormalities through 24 and 48 weeks
Cumulative incidence of AEs by time to first 
occurrence
Proportion of subjects who discontinue 
treatment due to AEs through 24 and 48
weeks
To evaluate the effects of DTG + 3TC once 
daily on fasting lipids over time compared to 
TBR
Change from Baseline in fasting lipids at Weeks 
24 and 48
To assess viral resistance in subjects meeting 
Virologic Withdrawal Criteria
Incidence of observed genotypic and phenotypic 
resistance to ARVs for subjects meeting 
Virologic Withdrawal Criteria 
To evaluate renal (in urine and blood) and 
bone (in blood) biomarkers in subjects treated 
with DTG + 3TC compared to TBR
Change from Baseline in renal and bone 
biomarkers at Weeks 24 and 48
To assess health related quality of life for 
subjects treated with DTG + 3TC compared to 
TBR
Change from Baseline in health status using EQ-
5D-5L at Weeks 24 and 48 (or Withdrawal from 
the study)
Current text:
Objective
Endpoint
Primary
To demonstrate the non-inferior antiviral 
activity of switching to DTG +3TC once daily 
compared to continuation of TBR over 48 
weeks in HIV-1 infected, ART therapy (ART)-
experienced, virologically suppressed subjects
Virologic failure endpoint as per FDA snapshot 
category at Week 48
Secondary
To demonstrate the antiviral activity of 
switching to DTG +3TC once daily compared to 
continuation of TBR over 48 weeks 
Proportion of subjects with plasma HIV-1 RNA 
<50 copies c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 24 weeks, 96 
weeks and 144 weeks
Virologic failure endpoint as per FDA 
snapshot category at Weeks 24, 96 and 144
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL at Weeks 24, 96 and 144 using the 
Snapshot algorithm for the ITT-E population


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Objective
Endpoint
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
over 24, 48, 96 and 144 weeks
Change from Baseline in CD4+ cell count and 
in CD4+/CD8+ cell counts ratio at Weeks 
24,48, 96 and 144
Incidence of disease progression (HIV-
associated conditions, AIDS, and death) 
through Weeks 24, 48, 96 and 144
To evaluate the safety and tolerability of DTG + 
3TC once daily compared to TBR over time
Incidence and severity of AEs and laboratory 
abnormalities through 144 weeks
Proportion of subjects who discontinue 
treatment due to AEs through 144 weeks
To evaluate the effects of DTG + 3TC once 
daily on fasting lipids over time compared to 
TBR
Change from Baseline in fasting lipids at Weeks 
24, 48, 96 and 144
To assess viral resistance in subjects meeting 
Virologic Withdrawal Criteria
Incidence of observed genotypic and phenotypic 
resistance to ARVs for subjects meeting 
Virologic Withdrawal Criteria 
To evaluate renal (in urine and blood) and 
bone (in blood) biomarkers in subjects treated 
with DTG + 3TC compared to TBR
Change from Baseline in renal and bone 
biomarkers at Weeks 24, 48, 96 and 144
To assess health related quality of life for 
subjects treated with DTG + 3TC compared to 
TBR
Change from Baseline in health status using EQ-
5D-5L at Weeks 24, 48, 96 and 144 (or 
Withdrawal from the study)
Previous text:
This is a 100-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of replacing a 
TBR with a two-drug regimen of DTG + 3TC in HIV-infected adults who are 
virologically suppressed and stable on a TBR.  The study will include a Screening Phase 
(up to 28 days), a Randomized Early Switch Phase (Day 1 up to Week 52), a Randomized 
Late Switch Phase (Week 52 up to Week 100), and a Continuation Phase (post Week 
100).  Approximately 550 HIV-1 infected adults who are on a stable TBR will be 
randomized 1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for up to 100
weeks, or to continue their TBR for 52 weeks, at which time and if HIV1 RNA <50 c/mL 
at Week 48 (or upon retest by Week 52), these subjects will switch to DTG + 3TC up to 
Week 100. For subjects randomized to the TBR, provisions will be in place, as needed 
and after discussion with the study team, to assist patients in obtaining their TBR during 
the study.
The primary endpoint for the study is the proportion of participants who meet the 
Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat Exposed (ITT-E) 
population.  The Week 48 primary analysis will take place after the last subject has had 
their Week 48 viral load assessed, including any retests.  Subjects randomized to DTG + 
3TC will receive DTG + 3TC up to Week 100.  Subjects randomized to TBR will have a 
Week 52 switch visit, allowing approximately 4 weeks for subjects who have a viral load 


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≥50 c/mL at Week 48 to have a retest prior to switch.  The study will continue for at least 
100 weeks.
Current text:
This is a 200-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of replacing a 
TBR with a two-drug regimen of DTG + 3TC in HIV-infected adults who are 
virologically suppressed and stable on a TBR.  The study will include a Screening Phase 
(up to 28 days), a Randomized Early Switch Phase (Day 1 up to Week 148), a 
Randomized Late Switch Phase (Week 148 up to Week 200) and a Continuation Phase 
(post Week 200) if DTG + 3TC fixed dose combination (FDC) is not yet approved 
and available locally.  Approximately 550 HIV-1 infected adults who are on a stable 
TBR will be randomized 1:1 to switch to DTG + 3TC once daily (DTG + 3TC arm) for 
up to 200 weeks, or to continue their TBR for 148 weeks, at which time and if HIV-1 
RNA <50 c/mL at Week 144 (or upon retest by Week 148), these subjects will switch to 
DTG + 3TC up to Week 200. For subjects randomized to the TBR, provisions will be in 
place, as needed and after discussion with the study team, to assist patients in obtaining 
their TBR during the study. For subjects who switch to DTG + 3TC at Week 148, a 
separate Late Switch Phase Time and Events Table is provided in Section 7.1.2 as 
these participants will be monitored closely for the first 24 weeks post-switch. 
Subjects who remain on DTG + 3TC will follow a separate Late Switch Phase Time 
and Events Table in Section 7.1.3.
The primary endpoint for the study is the proportion of participants who meet the 
Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat Exposed (ITT-E) 
population.  The Week 48 primary analysis will take place after the last subject has had 
their Week 48 viral load assessed, including any retests.  Subjects randomized to DTG + 
3TC will receive DTG + 3TC up to Week 200.  Subjects randomized to TBR will have a 
Week 148 switch visit, allowing approximately 4 weeks for subjects who have a viral 
load ≥50 c/mL at Week 144 to have a retest prior to switch.  The study will continue for 
at least 200 weeks.
Previous text:
The study will include a Screening Phase (up to 28 days), a Randomized Early Switch 
Phase (Day 1 up to Week 52), a Randomized Late Switch Phase (Week 52 up to Week 
100) and a Continuation Phase (post Week 100).  Subjects randomized to DTG + 3TC 
will receive DTG + 3TC up to Week 100.  Subjects randomized to TBR will continue to 
take their current regimen up to Week 52, at which time and if HIV-1 RNA <50 c/mL at 
Week 48 (or upon retest by Week 52), these subjects will switch to DTG + 3TC up to 
Week 100.  Randomization will be stratified by baseline third agent class (protease 
inhibitor [PI], integrase inhibitor [INI], or non-nucleoside reverse transcriptase inhibitor
[NNRTI]).
The primary analysis at Week 48 will take place after the last subject completes 52 weeks 
on therapy, to allow for the collection of a confirmatory viral load measurement in 
subjects presenting with HIV-1 RNA 50 c/mL at the Week 48 visit.  The secondary 


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analysis at Week 24 will take place after the last subject completes 28 weeks on therapy, 
to allow for the collection of a confirmatory viral load measurement in subjects 
presenting with HIV-1 RNA 50 c/mL at the Week 24 visit.  
All subjects who successfully complete 100 weeks of treatment will continue to have 
access to DTG + 3TC fixed-dose combination (FDC) in a Continuation Phase until:
DTG and 3TC are each locally approved for use as part of a dual regimen, and 
each of the single entities of DTG and 3TC are available to subjects (e.g., through 
public health services or through their usual health insurance payer), or
the actual FDC tablet, if required by local regulations, is available, or
the subject no longer derives clinical benefit, or 
the subject meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC dual regimen is terminated.
The purpose of the Continuation Phase is to ensure provision of DTG and 3TC. 
Assessments during the Continuation Phase are limited.  
Current text:
The study will include a Screening Phase (up to 28 days), a Randomized Early Switch 
Phase (Day 1 up to Week 148), a Randomized Late Switch Phase (Week 148 up to Week 
200) and a Continuation Phase (post Week 200) if DTG + 3TC FDC is not yet 
approved and available locally.  Subjects randomized to DTG + 3TC will receive DTG 
+ 3TC up to Week 200.  Subjects randomized to TBR will continue to take their current 
regimen up to Week 144, at which time and if HIV-1 RNA <50 c/mL at Week 144 (or 
upon retest by Week 148), these subjects will switch to DTG + 3TC up to Week 200.  
Randomization will be stratified by baseline third agent class (protease inhibitor [PI], 
integrase inhibitor [INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]).
The primary analysis at Week 48 will take place after the last subject completes up to 52 
weeks on therapy, to allow for the collection of a confirmatory viral load measurement in 
subjects presenting with HIV-1 RNA 50 c/mL at the Week 48 visit.  The secondary 
analysis at Week 24 will take place after the last subject completes up to 28 weeks on 
therapy, to allow for the collection of a confirmatory viral load measurement in subjects 
presenting with HIV-1 RNA 50 c/mL at the Week 24 visit.  Further secondary 
analyses will take place at Week 96, 144 and 196. 
All subjects who successfully complete 200 weeks of treatment will complete the study 
and transition to locally approved and available DTG + 3TC fixed-dose combination 
(FDC) and be managed as per standard of care at their study site. Prior to 
completion of the Week 200 visit, sites will need to have confirmation that DTG + 
3TC FDC is locally available for study subjects.  If DTG + 3TC FDC is not yet 
approved and available locally, ViiV Healthcare will continue to provide study drug 
in a Continuation Phase until: 


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DTG + 3TC FDC is locally approved for use as a 2-drug regimen, and available 
to subjects (e.g., through public health services or through their usual health 
insurance payer), or
the subject no longer derives clinical benefit, or 
the subject meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC dual regimen is terminated.
Assessments during the Continuation Phase are limited and will include plasma HIV-1 
RNA and collection of AEs/SAEs.  
Previous text:
The study closed screening on 18 May 2018 with a total of 933 screened subjects and 
based on current randomisation numbers and current screen failure rate a total of 
approximately 750 subjects are expected to be randomised.
Current text:
The study closed screening on 18 May 2018 with a total of 933 screened subjects and a 
total of 743 subjects were randomised.
Section 2.1 Study Rationale:
Previous text: However, this longer life expectancy has been accompanied by higher rates 
of non-acquired immuno-deficiency syndrome (AIDS)-defining events (NADEs) such as 
cardiovascular disease, liver disease and cancer.
Current text: However, this longer life expectancy has been accompanied by higher rates 
of non-acquired immunodeficiency syndrome (AIDS)-defining events (NADEs) such as 
cardiovascular disease, liver disease and cancer.
Previous text:
Finally, if a 2-drug ART regimen is shown to be as effective and safe as conventional 
3-drug regimens, the lower cost associated with taking one less drug for the lifetime of an 
HIV-infected person will have substantial individual and societal individual benefits.
The overall objective of the DTG + 3TC clinical development program is to develop a 
single tablet, fixed-dose, two-drug combination therapy regimen that offers a high level 
of tolerability and a high barrier to the emergence of viral resistance.  A DTG + 3TC 
two-drug strategy may be effective in maintaining virologic suppression among treatment 
experienced subjects, while preserving future HIV-1 treatment options.
Study 204862 is being conducted to establish if human immunodeficiency virus type 1 
(HIV-1) infected adult subjects with current virologic suppression on a TBR remain 
suppressed upon switching to a two-drug regimen with DTG + 3TC. This study will 
provide important information regarding efficacy, safety, and health-related quality of 
life.  This trial is designed to demonstrate the non-inferior antiviral activity of switching 


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to DTG + 3TC once daily compared to continuation of a TBR over 48 weeks.  This study 
will also characterize the long-term antiviral activity, tolerability and safety of DTG + 
3TC through Week 100.
One of the potential risks of a 2-drug regimen is the increase in virologic failure 
associated with the emergence of drug resistance.  DTG, with its higher barrier to 
resistance, may reduce the risk of treatment-emergent resistance in patients taking a 
2-drug regimen.  The pivotal Phase 3 studies of DTG in naïve subjects have shown the 
absence of treatment-emergent INI or NRTI resistance mutations through 144+ weeks of 
treatment [Walmsley, 2013].  The absence of treatment emergent mutations to DTG or 
background agents in ART-naïve individuals, the potency of both DTG and 3TC, and the 
well-tolerated safety profile of both drugs provides a strong rationale for the development 
of the DTG + 3TC STR as an important treatment option for patients.
Current text:
Finally, if a 2-drug ART regimen is shown to be as effective and safe as conventional 
3-drug regimens, the lower cost associated with taking one less drug for the lifetime of an 
HIV-infected person will have substantial individual and societal individual benefits.
One of the potential risks of a 2-drug regimen is the increase in virologic failure 
associated with the emergence of drug resistance.  DTG, with its higher barrier to 
resistance, may reduce the risk of treatment-emergent resistance in patients taking a 
2-drug regimen.  The pivotal Phase 3 studies of DTG in naïve subjects have shown 
the absence of treatment-emergent INI or NRTI resistance mutations through 144+ 
weeks of treatment [Walmsley, 2013].  The absence of treatment emergent 
mutations to DTG or background agents in ART-naïve individuals, the potency of 
both DTG and 3TC, and the well-tolerated safety profile of both drugs provides a 
strong rationale for the development of the DTG + 3TC STR as an important 
treatment option for patients.
The overall objective of the DTG + 3TC clinical development program is to develop a 
single tablet, fixed-dose, two-drug combination therapy regimen that is as effective as 3-
drug ART in treating HIV-1 infection, is safe and well tolerated in the long-term, and 
has a high barrier to the emergence of viral resistance.  A DTG + 3TC two-drug strategy 
may be effective in maintaining virologic suppression among treatment experienced 
subjects, while improving long-term safety and tolerability, and preserving future 
HIV-1 treatment options.
Study 204862 is being conducted to establish if human immunodeficiency virus type 1 
(HIV-1) infected adult subjects with current virologic suppression on a TBR remain 
suppressed upon switching to a two-drug regimen with DTG + 3TC. This trial is 
designed to demonstrate the non-inferior antiviral activity of switching to DTG + 3TC 
once daily compared to continuation of a TBR over 48 weeks.  To better understand 
the long-term differences in antiviral efficacy, safety and tolerability between 
DTG + 3TC and TAF-based regimens, the comparative phase of the study will be 
extended to 148 weeks. The originally planned Week 52 Switch Visit in the TBR 
arm will be moved to Week 148 to allow for 2 additional years of comparative 


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follow-up. This study will also characterize the long-term antiviral activity, 
tolerability and safety of DTG + 3TC through Week 200.
Previous text:
This study will also characterize the long-term antiviral activity, tolerability and safety of 
DTG + 3TC through Week 100.
Current text:
This study will also characterize the long-term antiviral activity, tolerability and safety of 
DTG + 3TC compared to TBR through Week 144 and the long-term antiviral 
activity, tolerability and safety of DTG + 3TC through Week 200.
Section 2.2 Brief Background:
Added text: GEMINI-1 and GEMINI-2 are two identical global, double-blind, 
multicentre Phase III studies evaluating the efficacy and safety of DTG + 3TC once 
daily in treatment-naïve HIV-1-infected adults with Screening HIV-1 ≤500,000 
c/mL.  At 48 weeks, dual therapy with DTG + 3TC demonstrated non-inferior 
efficacy to DTG + TDF/FTC (in the primary endpoint: proportion of subjects with 
plasma HIV-1 RNA<50 c/ml by FDA Snapshot in the pooled ITT-E population 
[DTG/3TC n=716. DTG/TDF/FTC n= 717] 91% vs. 93% respectively, adjusted 
difference (95% CI) -1.7 (-4.4, 1.1).  Across both studies, 6 participants on DTG + 
3TC and 4 participants on DTG + TDF/FTC met protocol-defined virologic 
withdrawal criteria and none had treatment-emergent INSTI or NRTI resistance 
mutations.  Overall, the rates of AEs were similar between arms, with low rates of 
withdrawals due to AEs for both arms [Cahn, 2018].
Section 3 Objectives and Endpoints:
Previous text:
Objective
Endpoint
Primary
To demonstrate the non-inferior antiviral 
activity of switching to DTG +3TC once daily 
compared to continuation of TBR over 48 
weeks in HIV-1 infected, ART therapy (ART)-
experienced, virologically suppressed subjects
Virologic failure endpoint as per FDA snapshot 
category at Week 48
Secondary
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 48 weeks 
Proportion of subjects with plasma HIV-1 RNA 
<50 copies c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 24 weeks 
Virologic failure 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 


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Objective
Endpoint
algorithm for the ITT-E population
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
Change from Baseline in CD4+ cell count and 
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
To evaluate the safety and tolerability of DTG + 
3TC once daily compared to TBR over time
Incidence and severity of AEs and laboratory 
abnormalities through 24 and 48 weeks
Cumulative incidence of AEs by time to first 
occurrence
Proportion of subjects who discontinue 
treatment due to AEs through 24 and 48
weeks
To evaluate the effects of DTG + 3TC once 
daily on fasting lipids over time compared to 
TBR
Change from Baseline in fasting lipids at Weeks 
24 and 48
To assess viral resistance in subjects meeting 
Virologic Withdrawal Criteria
Incidence of observed genotypic and phenotypic 
resistance to ARVs for subjects meeting 
Virologic Withdrawal Criteria 
To evaluate renal (in urine and blood) and 
bone (in blood) biomarkers in subjects treated 
with DTG + 3TC compared to TBR
Change from Baseline in renal and bone 
biomarkers at Weeks 24 and 48
To assess health related quality of life for 
subjects treated with DTG + 3TC compared to 
TBR
Change from Baseline in health status using EQ-
5D-5L at Weeks 24 and 48 (or Withdrawal from 
the study)
Exploratory
To evaluate the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4) on 
antiviral and immunological responses to DTG 
+ 3TC compared to TBR 
Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with snapshot 
virologic failure at Weeks 24 and 48
Change from Baseline in CD4+ cell counts at 
Weeks 24 and 48 by patient subgroups
To assess willingness to switch for subjects 
treated with DTG + 3TC compared to TBR
Reasons for Willingness to Switch at Day 1
To evaluate biomarkers of telomerase function 
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48 and 96
To evaluate inflammation biomarkers and 
insulin resistance in a subset of subjects 
treated with DTG+ 3TC compared to TBR
Change from Baseline in inflammation 
biomarkers and homeostasis model of 
assessment-insulin resistance (HOMA-IR) at 
Weeks 48 and 96


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Objective
Endpoint
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 96

Incidence and severity of AEs and 
laboratory abnormalities over 96 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 96 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 96

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at week 96
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 96

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 96

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at week 96
To assess the steady-state DTG and 3TC 
exposure in HIV-1 infected patients
Steady state plasma PK parameters of DTG and 
3TC will be assessed using intensive PK 


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Objective
Endpoint
collected at week 4.
To characterize the DTG and 3TC steady-state 
PK of the DTG/3TC FDC in HIV-1 infected 
patients
Population estimates of DTG and 3TC PK 
parameters (e.g. apparent clearance [CL/F], 
apparent volume of distribution [V/F]) using DTG 
and 3TC intensive and sparse plasma 
concentrations at Weeks, 4, 8, 12, 24, 36 and 48
Current text:
Objective
Endpoint
Primary
To demonstrate the non-inferior antiviral 
activity of switching to DTG +3TC once daily 
compared to continuation of TBR over 48 
weeks in HIV-1 infected, ART therapy (ART)-
experienced, virologically suppressed subjects
Virologic failure endpoint as per FDA snapshot 
category at Week 48
Secondary
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 48 weeks 
Proportion of subjects with plasma HIV-1 RNA 
<50 copies c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 24, 96 and 144 
weeks 
Virologic failure endpoint as per FDA 
snapshot category at Weeks 24, 96 and 144
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL at Weeks 24, 96 and 144 using the 
Snapshot algorithm for the ITT-E population
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR
over 24, 48, 96 and 144 weeks
Change from Baseline in CD4+ cell count and 
in CD4+/CD8+ cell count ratio at Weeks 24, 
48, 96 and 144
Incidence of disease progression (HIV-
associated conditions, AIDS, and death) 
through Weeks 24, 48, 96 and 144
To evaluate the safety and tolerability of DTG + 
3TC once daily compared to TBR over time
Incidence and severity of AEs and laboratory 
abnormalities through 144 weeks
Proportion of subjects who discontinue 
treatment due to AEs through 144 weeks
To evaluate the effects of DTG + 3TC once 
daily on fasting lipids over time compared to 
TBR
Change from Baseline in fasting lipids at Weeks 
24, 48, 96 and 144
To assess viral resistance in subjects meeting 
Virologic Withdrawal Criteria
Incidence of observed genotypic and phenotypic 
resistance to ARVs for subjects meeting 
Virologic Withdrawal Criteria 


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Objective
Endpoint
To evaluate renal (in urine and blood) and 
bone (in blood) biomarkers in subjects treated 
with DTG + 3TC compared to TBR
Change from Baseline in renal and bone 
biomarkers at Weeks 24, 48, 96 and 144
To assess health related quality of life for 
subjects treated with DTG + 3TC compared to 
TBR
Change from Baseline in health status using EQ-
5D-5L at Weeks 24, 48, 96 and 144 (or 
Withdrawal from the study)


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Objective
Endpoint
Exploratory
To evaluate the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4) on 
antiviral and immunological responses to DTG 
+ 3TC compared to TBR 
Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with plasma 
HIV-1 RNA <50 c/mL using the Snapshot 
algorithm at Weeks 24, 48, 96 and 144
Change from Baseline in CD4+ cell counts at 
Weeks 24, 48, 96 and 144 by patient 
subgroups
To assess willingness to switch for subjects 
treated with DTG + 3TC compared to TBR
Reasons for Willingness to Switch at Day 1
To evaluate biomarkers of telomerase function 
in a subset of subjects treated with DTG + 3TC 
compared to TBR.
Change from baseline in biomarkers of 
telomerase function at Weeks 48, 96 and 144
To evaluate inflammation biomarkers and 
insulin resistance in a subset of subjects 
treated with DTG+ 3TC compared to TBR
Change from Baseline in inflammation 
biomarkers and homeostasis model of 
assessment-insulin resistance (HOMA-IR) at 
Weeks 48, 96 and 144
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability of 
DTG + 3TC once daily in subjects treated with 
DTG + 3TC since the Early Switch Phase
For subjects in the DTG + 3TC arm since Early 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 196

Incidence and severity of AEs and 
laboratory abnormalities over 196 weeks

Proportion of subjects who discontinue 
treatment due to AEs over 196 weeks

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 196

Change from Baseline in renal and bone 
biomarkers at Week 196

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at week 196
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC for 
subjects switching in the Late Switch Phase
For subjects switching to DTG + 3TC in the Late 
Switch Phase:

Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ lymphocyte 
count and in CD4+/CD8+ cell count ratio at 
Week 196


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Objective
Endpoint

Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase

Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase

Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase

Change from Baseline in renal and bone 
biomarkers at Week 196

Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at week 196
To assess the steady-state DTG and 3TC 
exposure in HIV-1 infected patients
Steady state plasma PK parameters of DTG and 
3TC will be assessed using intensive PK 
collected at week 4.
To characterize the DTG and 3TC steady-state 
PK of the DTG/3TC FDC in HIV-1 infected 
patients
Population estimates of DTG and 3TC PK 
parameters (e.g. apparent clearance [CL/F], 
apparent volume of distribution [V/F]) using DTG 
and 3TC intensive and sparse plasma 
concentrations at Weeks, 4, 8, 12, 24, 36 and 48
Section 4.1 Study Design: 
Previous text:
This is a 100-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of replacing a 
TBR with a two-drug regimen of DTG + 3TC in HIV-infected adults who are 
virologically suppressed and stable on a TBR.  The study will include a Screening Phase 
(up to 28 days), an Early Switch Phase (Day 1 up to Week 52), a Late Switch Phase 
(Week 52 up to Week 100), and a Continuation Phase (post Week 100).  Approximately 
550 HIV-1 infected adults who are on a stable TBR will be randomized 1:1 to switch to 
DTG + 3TC once daily (DTG + 3TC arm) for up to 100 weeks, or to continue their TBR 
for 52 weeks, at which time and if HIV-1 RNA <50 c/mL at Week 48 (or upon retest by 
Week 52), these subjects will switch to DTG + 3TC up to Week 100. For subjects 
randomized to the TBR, provisions will be in place, as needed and after discussion with 
the study team, to assist patients in obtaining their TBR during the study.
The primary endpoint for the study is the proportion of participants who meet the 
Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat Exposed (ITT-E) 
population.  The Week 48 primary analysis will take place after the last subject has had 
their Week 48 viral load assessed, including any retests. Subjects randomized to DTG + 
3TC will receive DTG + 3TC up to Week 100.  Subjects randomized to TBR will have a 


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Week 52 switch visit, allowing approximately 4 weeks for subjects who have a viral load 
≥50 c/mL at Week 48 to have a retest prior to switch.  The study will continue for at least 
100 weeks.
All subjects who successfully complete up to 100 weeks of treatment will have the 
opportunity to continue receiving DTG + 3TC FDC once daily in a Continuation Phase as 
outlined in Section 4.2.4.   
Current text:
This is a 200-week, Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group study to assess the non-inferior antiviral activity and safety of replacing a 
TBR with a two-drug regimen of DTG + 3TC in HIV-infected adults who are 
virologically suppressed and stable on a TBR.  The study will include a Screening Phase 
(up to 28 days), an Early Switch Phase (Day 1 up to Week 148) a Late Switch Phase 
(Week 148 up to Week 200) and a Continuation Phase (post Week 200) if DTG + 3TC 
FDC is not yet approved and available locally.  Approximately 550 HIV-1 infected 
adults who are on a stable TBR will be randomized 1:1 to switch to DTG + 3TC once 
daily (DTG + 3TC arm) for up to 200 weeks, or to continue their TBR for 148 weeks, at 
which time and if HIV-1 RNA <50 c/mL at Week 144 (or upon retest by Week 148), these 
subjects will switch to DTG + 3TC up to Week 200. For subjects randomized to the 
TBR, provisions will be in place, as needed and after discussion with the study team, to 
assist patients in obtaining their TBR during the study.  For subjects who switch to 
DTG + 3TC at Week 148, a separate Late Switch Phase Time and Events Table is 
provided in Section 7.1.2 as these participants will be monitored closely for the first 
24 weeks post-switch. Subjects who remain on DTG + 3TC will follow a separate 
Late Switch Phase Time and Events Table in Section 7.1.3.
The primary endpoint for the study is the proportion of participants who meet the 
Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat Exposed (ITT-E) 
population.  The Week 48 primary analysis will take place after the last subject has had 
their Week 48 viral load assessed, including any retests. Subjects randomized to DTG + 
3TC will receive DTG + 3TC up to Week 200.  Subjects randomized to TBR will have a 
Week 148 switch visit, allowing approximately 4 weeks for subjects who have a viral 
load ≥50 c/mL at Week 144 to have a retest prior to switch.  The study will continue for 
at least 200 weeks.
All subjects who successfully complete 200 weeks of treatment will complete the 
study and transition to locally approved and available DTG + 3TC fixed-dose 
combination (FDC) and be managed as per standard of care at their study site.
Prior to completion of the Week 200 visit, sites will need to have confirmation that 
DTG + 3TC FDC is locally available for study subjects.  If DTG + 3TC FDC is not 
yet approved and available locally, ViiV Healthcare will continue to provide study 
drug in a Continuation Phase as outlined in Section 4.2.4.
Previous text:


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Current text:
Section 4.2.2. Early Switch Phase
Previous text:
Early Switch Phase (Day 1 up to Week 52)
Subjects who fulfil all eligibility requirements will be randomly assigned 1:1 to receive 
DTG + 3TC FDC once daily up to Week 100, or continue their TBR up to Week 52.  The 
DTG + 3TC and TBR will be administered in an open-label fashion throughout the study.  
For subjects randomized to the TBR, provisions will be in place, as needed and after 
discussion with the study team, to assist patients in obtaining their TBR during the study.
Following the Week 48 visit, subjects will stay on DTG + 3TC or their TBR for another 4 
weeks so that the result from the Week 48 HIV-1 RNA testing is known.  All subjects 
with a viral load 50 c/mL must have plasma HIV-1 RNA levels re-assessed within 
approximately 2-4 weeks.  This will allow any subject in the TBR arm with a viral load 
50 c/mL at Week 48 to have their viral load confirmed by a second measurement 
performed within approximately 2-4 weeks while still on their TBR regimen.  
The primary analysis will take place after the last subject completes 52 weeks on therapy, 
to allow for the collection of a confirmatory viral load measurement in subjects 
presenting with HIV-1 RNA 50 c/mL at the Week 48 visit.  If the retest HIV-1 RNA is 
<50 c/mL, then the subject will be considered to have met the criteria for virologic 
responder by Food Drugs and Administration (FDA)’s Snapshot algorithm at Week 48; 
such subjects in the TBR arm will be considered eligible to switch to DTG + 3TC at 


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Week 52.  If the retest HIV-1 RNA is 50 c/mL, then the subject will be considered to be 
a virologic non-responder at Week 48 by Snapshot; such subjects in the TBR arm will be 
considered ineligible to switch to DTG + 3TC.  Subjects who are ineligible to switch will 
be withdrawn from the study.  Thus, the treatment extension up to Week 52 will allow for 
as complete an assessment as possible of treatment response in the primary endpoint 
analysis at Week 48 within the Snapshot window.
The secondary analyses at Week 24 will take place after the last subject completes 28 
weeks on therapy, as needed, to allow for the collection of a confirmatory viral load 
measurement in subjects presenting with HIV-1 RNA 50 c/mL at Week 24.
Current text:
Early Switch Phase (Day 1 up to Week 148)
Subjects who fulfil all eligibility requirements will be randomly assigned 1:1 to receive 
DTG + 3TC FDC once daily up to Week 200, or continue their TBR up to Week 148.  
The DTG + 3TC and TBR will be administered in an open-label fashion throughout the 
study.  For subjects randomized to the TBR, provisions will be in place, as needed and 
after discussion with the study team, to assist patients in obtaining their TBR during the 
study. 
Following the Week 144 visit, subjects will stay on DTG + 3TC or their TBR for another 
4 weeks so that the result from the Week 144 HIV-1 RNA testing is known.  All subjects 
with a viral load 50 c/mL must have plasma HIV-1 RNA levels re-assessed within 
approximately 2-4 weeks.  This will allow any subject in the TBR arm with a viral load 
50 c/mL at Week 144 to have their viral load confirmed by a second measurement 
performed within approximately 2-4 weeks while still on their TBR regimen.  
The primary analysis will take place after the last subject completes up to 52 weeks on 
therapy, to allow for the collection of a confirmatory viral load measurement in subjects 
presenting with HIV-1 RNA 50 c/mL at the Week 48 visit.  If the retest HIV-1 RNA is 
<50 c/mL, then the subject will be considered to have met the criteria for virologic 
responder by Food Drugs and Administration (FDA)’s Snapshot algorithm at Week 48.  
If the retest HIV-1 RNA is 50 c/mL, then the subject will be considered to be a virologic 
non-responder at Week 48 by Snapshot.
The secondary analysis at Week 24 will take place after the last subject completes up to
28 weeks on therapy, as needed, to allow for the collection of a confirmatory viral load 
measurement in subjects presenting with HIV-1 RNA 50 c/mL at Week 24.
The secondary analysis at Week 96 will take place after the last subject completes 
up to 100 weeks on therapy, as needed, to allow for the collection of a confirmatory 
viral load measurement in subjects presenting with HIV-1 RNA 50 c/mL at Week 
96.
The secondary analysis at Week 144 will take place after the last subject completes 
up to 148 weeks on therapy, as needed, to allow for the collection of a confirmatory 


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viral load measurement prior to Week 148 switch visit in subjects presenting with 
HIV-1 RNA 50 c/mL at Week 144.  If the retest HIV-1 RNA is <50 c/mL, subjects 
in the TBR arm will be considered eligible to switch to DTG + 3TC at Week 148.  If 
the retest HIV-1 RNA is 50 c/mL, the subjects in the TBR arm will be considered 
ineligible to switch to DTG + 3TC.  Subjects who are ineligible to switch will be 
withdrawn from the study.  Thus, the treatment extension up to Week 148 will allow 
for as complete an assessment as possible of treatment response in the analysis at 
Week 144 within the Snapshot window.
Section 4.2.3 Late Switch Phase
Previous text:
Late Switch Phase (Week 52 to Week 100)
At Week 48, subjects randomly assigned to DTG + 3TC and with HIV-1 RNA <50 c/mL 
will continue on that treatment through Week 100.  At Week 52, subjects randomly 
assigned to continue their TBR and with HIV-1 RNA <50 c/mL at Week 48 will switch 
to DTG + 3TC once daily and be followed up to Week 100.  
The analyses at Week 96 will take place after the last subject completes 100 weeks on 
therapy, as needed, to allow for the collection of a confirmatory viral load measurement 
in subjects presenting with HIV-1 RNA 50 c/mL at Week 96.
Current text:
Late Switch Phase (Week 148 to Week 200)
At Week 144, subjects randomly assigned to DTG + 3TC and with HIV-1 RNA <50 
c/mL will continue on that treatment through Week 200.  At Week 148, subjects 
randomly assigned to continue their TBR and with HIV-1 RNA <50 c/mL at Week 144 
(or upon retest) will switch to DTG + 3TC once daily and be followed up to Week 200. 
For subjects who switch to DTG + 3TC at Week 148, a separate Late Switch Phase 
Time and Events Table is provided in Section 7.1.2 as these participants will be 
monitored closely for the first 24 weeks post-switch. Subjects who remain on DTG + 
3TC will follow a separate Late Switch Phase Time and Events Table in Section 
7.1.3.
The analysis at Week 196 will take place after the last subject completes 200 weeks on 
therapy, as needed, to allow for the collection of a confirmatory viral load measurement 
in subjects presenting with HIV-1 RNA 50 c/mL at Week 196.
Section 4.2.4 Continuation Phase (Post Week 200)
Previous text:
All subjects who successfully complete 100 weeks of treatment will have the opportunity 
to receive DTG + 3TC FDC once daily in a Continuation Phase until:


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DTG and 3TC are each locally approved for use as part of a dual regimen, and 
each of the single entities of DTG and 3TC are available to subjects (e.g., through 
public health services or through their usual health insurance payer), or
the actual FDC tablet, if required by local regulations, is available, or
the subject no longer derives clinical benefit, or 
the subject meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC dual regimen is terminated.
The purpose of the Continuation Phase is to ensure provision of DTG and 3TC.  
Assessments during the Continuation Phase are limited and will include plasma HIV-1 
RNA and collection of AEs/SAEs. 
Current text:
At the end of the study at Week 200, subjects will transition to locally approved and 
available DTG + 3TC FDC and be managed as per standard of care at their study 
site.  Prior to completion of the Week 200 visit, sites will need to have confirmation 
that DTG + 3TC FDC is locally available for study subjects.  If DTG + 3TC FDC is 
not yet approved and available locally, ViiV Healthcare will continue to provide 
study drug in a Continuation Phase until:
DTG + 3TC FDC is locally approved for use as a 2-drug regimen, and available 
to subjects (e.g., through public health services or through their usual health 
insurance payer), or
the subject no longer derives clinical benefit, or 
the subject meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC dual regimen is terminated.
Assessments during the Continuation Phase are limited and will include plasma HIV-1 
RNA and collection of AEs/SAEs. 
Section 4.3 Type and Number of Subjects
Previous text:  The study closed screening on 18 May 2018 with a total of 933 screened 
subjects and based on current randomisation numbers and current screen failure rate a 
total of approximately 750 subjects are expected to be randomised.
Current text: The study closed screening on 18 May 2018 with a total of 933 screened 
subjects and a total of 743 subjects were randomized.
Section 4.4 Design Justification:
Previous text:
In this study, subjects will be randomized 1:1 to switch to DTG + 3TC from a TBR at 
Day 1 or stay on their TBR for up to 52 weeks.  The primary endpoint will be evaluated 
at Week 48 using a 4% non-inferiority (NI) margin.  This study is evaluating the rate of 


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Snapshot algorithm measured virological failure in already suppressed subjects to test the 
hypothesis that maintenance of the suppression of HIV-1 replication by DTG + 3TC will 
be non-inferior to that observed in the TBR arm of the study through Week 48.  To assess 
the durability of HIV-1 RNA suppression by DTG + 3TC, subjects will remain on DTG + 
3TC through Week 100.
Current text:
In this study, subjects will be randomized 1:1 to switch to DTG + 3TC from a TBR at 
Day 1 or stay on their TBR for up to 148 weeks.  The primary endpoint will be evaluated 
at Week 48 using a 4% non-inferiority (NI) margin.  This study is evaluating the rate of 
Snapshot algorithm measured virological failure in already suppressed subjects to test the 
hypothesis that maintenance of the suppression of HIV-1 replication by DTG + 3TC will 
be non-inferior to that observed in the TBR arm of the study through Week 48.  To assess 
the durability of HIV-1 RNA suppression by DTG + 3TC, subjects will remain on DTG + 
3TC through Week 200.
After Week 96, study visits will be extended to every 6 months (instead of 12 weekly 
visits) except in countries where visits are required every 3 months per standard of 
care.  For subjects who switch to DTG + 3TC at Week 148, a separate Late Switch 
Phase Time and Events Table is provided in Section 7.1.2 as these participants will 
be monitored closely for the first 24 weeks post-switch. Subjects who remain on 
DTG + 3TC will follow a separate Late Switch Phase Time and Events Table in 
Section 7.1.3.
This amended design will allow a longer period of comparison of antiviral efficacy, 
safety and tolerability between DTG + 3TC and TAF-based regimens.  Long-term 
comparison of outcomes between regimens is important in a disease where 
treatment is provided life-long.
Section 4.6.1 Risk Assessment:
Previous text:
DTG: Neural 
tube defects
In one ongoing birth outcome surveillance 
study in Botswana, early results from an 
unplanned interim analysis show that 4/426 
(0.9%) of women who were taking DTG 
when they became pregnant had babies 
with neural tube defects compared to a 
background rate of 0.1%.
1.
A female subject is eligible to 
participate if she is not pregnant, 
not lactating, and, if she is a 
female of reproductive potential, 
agrees to follow one of the options 
listed in the Modified List of Highly 
Effective Methods for Avoiding 
Pregnancy in Females of 
Reproductive Potential (FRP) (see 
Appendix 3, Section 13.3.1) 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 


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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
Current text:
DTG: Neural 
tube defects
In one ongoing birth outcome surveillance 
study in Botswana, early results from an 
unplanned interim analysis show that 4/426 
(0.9%) of women who were taking DTG 
when they became pregnant had babies 
with neural tube defects compared to a 
background rate of 0.1%.
1.
A female subject is eligible to 
participate if she is not pregnant, 
not lactating, and, if she is a 
female of reproductive potential, 
agrees to follow one of the options 
listed in the Modified List of Highly 
Effective Methods for Avoiding 
Pregnancy in Females of 
Reproductive Potential (FRP) (see 
Appendix 3, Section 13.3.1) 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 and using home-based 
urine pregnancy tests at
approximately 12 week intervals 
when study visits are extended to 
every 24 weeks.


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Section 5.4 Withdrawal and Stopping Criteria:
Previous text:

For subjects in the TBR arm during the Early Switch Phase, plasma HIV-1 RNA 
50 c/mL at Week 48 with a confirmatory retest (see Section 5.4)
Current text:

For subjects in the TBR arm during the Early Switch Phase, plasma HIV-1 RNA 
50 c/mL at Week 144 with a confirmatory retest (see Section 5.4)
Section 5.5 Subject and Study Completion:
Previous text:
Subjects are considered to have completed the study if they satisfy one of the following: 

Randomly assigned to either treatment group, completed the Randomized Phase at the 
Week 100 visit, and did not enter the Continuation Phase;

Randomly assigned to either treatment group, completed the Randomized Phase at the 
Week 100 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 dual regimen, and 
each of the single entities of DTG and 3TC are available through public health 
services or through the subject’s usual health insurance payer, or

the actual FDC tablet, if required by local regulations, is available, or

the subject no longer derives clinical benefit, or 

the subject meets a protocol-defined reason for discontinuation, or development 
of the DTG plus 3TC dual regimen is terminated.
Current text:
Subjects are considered to have completed the study if they satisfy one of the following: 

Randomly assigned to either treatment group and completed the Late Switch Phase 
at the Week 200 visit, and did not enter the Continuation Phase;

Randomly assigned to either treatment group, completed the Randomized Phase at the 
Week 200 visit, entered and completed the Continuation Phase, defined as remaining 
on study until:

DTG + 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

the subject no longer derives clinical benefit, or 

the subject meets a protocol-defined reason for discontinuation, or 

development of the DTG plus 3TC dual regimen is terminated.


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Section 6.1 Study treatment: Investigational Product and Other Study Treatment:
Previous text:
The investigational study drugs DTG and 3TC will be supplied by GSK/ViiV Healthcare 
as the fixed dose combination tablet DTG + 3TC. Subjects randomly assigned to continue 
their TBR for up to 52 weeks will not have drug provided as clinical trial material.  
Current text:
The investigational study drugs DTG and 3TC will be supplied by GSK/ViiV Healthcare 
as the fixed dose combination tablet DTG + 3TC. Subjects randomly assigned to continue 
their TBR for up to 148 weeks will not have drug provided as clinical trial material.
Previous text:
Study Treatment
(Open Label Randomised Phase, Day 1 to Week 100)
Current text:
Study Treatment
(Open Label Randomised Phase, Day 1 to Week 200)
Section 6.10 Treatment after the end of the Study:
Previous text:
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not ViiV is providing specific 
post-study treatment.
All subjects who successfully complete 100 weeks of treatment will continue to have 
access to DTG + 3TC FDC in the Continuation Phase until:

DTG and 3TC are each locally approved for use as part of a dual regimen, and 
each of the single entities of DTG and 3TC are available to subjects (e.g., 
through public health services or through their usual health insurance payer), or

the actual FDC tablet, if required by local regulations, is available, or

the subject no longer derives clinical benefit, or 

the subject meets a protocol-defined reason for discontinuation, or 

development of the DTG plus 3TC dual regimen is terminated.
The purpose of the Continuation Phase is to ensure provision of DTG + 3TC.  
Assessments during the Continuation Phase are limited (see Time and Events schedule, 
Section 7.1).
Current text: 


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The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition.  At the end of the study at Week 200, 
subjects will transition to locally approved and available DTG + 3TC FDC and be 
managed as per standard of care at their study site.  Prior to completion of the 
Week 200 visit, sites will need to have confirmation that DTG + 3TC FDC is locally 
available for study subjects.  If DTG + 3TC FDC is not yet approved and available 
locally, ViiV Healthcare will continue to provide study drug in a Continuation Phase 
until local availability.
Assessments during the Continuation Phase are limited (see Time and Events schedule, 
Section 7.1).
Section 6.11.2 Prohibited Medications and Non-Drug Therapies:
Previous text:

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited through Week 96 (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.   
Current text:

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited through Week 200 (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.   
Section 7.1 Time and Events Table:
Added level 3 headings: Early Switch Phase Time and Events Table (Screening to
Week 148); Late Switch Phase Time and Events Table: TBR subjects who switched 
to DTG + 3TC at Week 148; Late Switch Phase Time and Events Table: DTG + 
3TC arm
Added text: TBR subjects switching at Week 148 are followed up at 4, 12 and 24 
weeks post-switch after which 24 weekly visits are resumed.
Previous text: Please note updates to sequence of footnotes are not marked in the table in 
strikethrough text.


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Procedures
Screening 
Visita
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline 
/ Day 1
Week
Every 12 weeks 
after Week 100
4
8
12
24
36
48
52
Switch 
Visitb
60
72
84
96
100
Clinical and Other Assessments
Written informed consent
X
Inclusion/Exclusion criteriae
X
X
Demography
X
Prior ART history
X
Medical historyf
X
Current medical conditions
X
Cardiovascular risk 
assessment, including vital 
signsg
X
Body Weight (BMI will be 
calculated within the eCRF)
X
X
X
X
X
X
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 conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Columbia Suicidality Severity 
Rating Scale
Xh
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symptom Directed Physical 
Exami
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGj
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious adverse events
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Willingness to Switchl
Xl
EQ-5D-5Lm
X
X
X
X
X
X


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Procedures
Screening 
Visita
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline 
/ Day 1
Week
Every 12 weeks 
after Week 100
4
8
12
24
36
48
52
Switch 
Visitb
60
72
84
96
100
Laboratory Assessments
Quantitative plasma HIV-1 
RNAn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subset (CD4+ at 
all visits and CD8+ at 
Baseline, and Weeks 24, 48 
and 96 only) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for storageo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and glucosep
X
X
X
X
Xq
Urinalysis and spot urine for 
protein analysisr
X
X
X
X
X
X
Pregnancy tests,t
S
U/Su
S
S
S
S
S
S
U
S
S
S
S
S
S
S
HbsAg, anti-HBc, anti-HBs, 
and HBV DNAv
X
HCV antibody
X
RPR
X
Insulin, HbA1c and renal, and 
bone marker analytes 
(blood/urine)w
X
X
X
X
Xq
Whole Blood (Virology)x
X
X
X
X
Whole Blood (Telomere 
length)y
X
X
X
Xz
Cryopreserved PBMCsaa
X
X
X
Xz
Inflammation biomarkers 
(Blood) bb
X
X
X
Xw
Study Treatment
IVRS/IWRScc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedures
Screening 
Visita
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline 
/ Day 1
Week
Every 12 weeks 
after Week 100
4
8
12
24
36
48
52
Switch 
Visitb
60
72
84
96
100
Dispense study treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment 
accountability (pill counts)
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic dd
Intensive PK sample 
collection at selected sites for 
subset of ~30 subjects 
(Fasting)dd
Xee
Dispense PK Diary Card to 
intensive PK sub-set
X
Sparse PK sample 
collectiondd
X ff
X
X
X
X
X
Dispense PK Diary Card to 
Sparse PK subjects
X
X
X
X
X
X
anti-HBc = antibody to hepatitis B core antigen, anti-HBs = hepatitis B surface antibody, ART = antiretroviral therapy, CDC = Centers for Disease Control and Prevention, DNA = 
deoxyribonucleic acid, HbA1c = Glycated hemoglobin, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus type 1, IVRS = interactive 
voice recognition system, IWRS = interactive web recognition system, PBMC = peripheral blood mononuclear cell, RNA = ribonucleic acid, RPR = rapid plasma reagin
a.
As soon as all Screening results are available, randomization may occur.
b.
Subjects 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. 
Subjects should have received full doses of study treatment for at least 2 weeks at the time of HIV-1 RNA re-assessment. Subjects randomized to DTG + 3TC do not attend a 
Week 52 switch visit.  
c.
All subjects who complete through Week 100 will have the opportunity to enter the Continuation Phase. Subjects 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 with the exception of dispensing study treatment. 
d.
An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study medication for subjects with the following conditions at the last on-study visit:  ongoing AEs, 
serious adverse events (SAEs) regardless of attributability, any laboratory abnormalities considered to be AEs or potentially harmful to the subject.
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 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.


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g.
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.
h.
On Day 1, the electronic Columbia Suicidality Severity Rating Scale eC-SSRS, patient completed questionnaire) is to be administered prior to randomization. 
i.
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. 
j.
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes.
k.
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and administration of study 
drug at Day 1. 
l.
Willingness to Switch Survey must be done prior to randomization.
m.
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 96.
n.
See Virologic Withdrawal and Stopping Criteria Section of protocol (Section 5.4).
o.
Plasma samples for storage will be collected at each visit starting at Screening, 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 subjects meet 
Suspected and Confirmed Virologic Withdrawal criteria. 
p.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
q.
Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 24, 48 or 96.
r.
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
s.
Women of childbearing potential only. S=serum, U=urine. Pregnancy events will be captured starting at Day 1 following exposure to study drug.
t.
Remind females of reproductive potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements.
u.
Local serum pregnancy test on Day 1 is allowed if it can be done, and results obtained, within 24 hours prior to randomization
v.
HBV DNA testing will be performed for subjects with positive anti-HBc and negative HBsAg and negative anti-HBs (past and/or current evidence).  Subjects will have to return to 
the clinic to provide a sample for HBV DNA testing prior to randomisation.
w.
Blood sample for insulin, HbA1c, and renal and bone biomarker assessments: Renal: Cystatin C; Beta-2-Microglobulin; Retinol Binding Protein (RBP); Bone: bone specific 
alkaline phosphatase, procollagen type 1-N-propeptide, type 1 collagen cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin D. 
x.
Whole blood (Virology) may be used for virologic analyses as described in the protocol.  
y.
Whole blood will be used for telomere length evaluation at Day 1, Week 48, Week 96, and at the Withdrawal visit.
z.
Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 48 or 96
aa.
PBMCs will be collected, cryopreserved and stored in a subset of sites. These samples will be used for the measurement of telomerase activity.
bb. Blood sample for inflammation biomarker assessments: IL-6, hs-CRP, d dimer, sCD14, sCD163.
cc. At Screening, a subject number will be generated.
dd. PK sampling in subjects from the DTG/3TC FDC arm only, as detailed in Section 11.
ee. Intensive PK sampling in a subset of subjects from the DTG/3TC FDC arm at select sites at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours post-dose. On the intensive PK day, 
patients are required to fast from 8 hours prior to dosing and then through 4 hours post-dose. Detailed in Section 11.
ff.
At Week 4, subjects who performed intensive PK do not perform Sparse PK sampling.


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Current text: Please note updates to sequence of footnotes are not marked in the table in bold text.
Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108 
(optional)b
120
132 
(optional)b
144
148c
Clinical and Other Assessments
Written informed 
consent
X
Inclusion/Exclusion 
criteriae
X
X
Demography
X
Prior ART history
X
Medical historyf
X
Current medical 
conditions
X
Cardiovascular risk 
assessment, including 
vital signsg
X
Body Weight (BMI will 
be calculated within the 
eCRF)
X
X
X
X
X
X
X
X
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 
conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Columbia Suicidality 
Severity Rating Scale
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108 
(optional)b
120
132 
(optional)b
144
148c
Symptom Directed 
Physical Exami
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGj
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious adverse events
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Willingness to Switchl
Xl
EQ-5D-5m
X
X
X
X
X
X
X
Laboratory Assessments
Quantitative plasma 
HIV-1 RNAn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subset 
(CD4+ at all visits and 
CD8+ at Baseline, and 
Weeks 24, 48, 96, 144 
and 196 only) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for storageo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and 
glucosep
X
X
X
X
X
Xq
Urinalysis and spot 
urine for protein 
analysisr
X
X
X
X
X
X
X
Pregnancy tests,t,u
S
U/Sv
S
S
S
S
S
S
S
S
S
S
S
S
S
S
U
S
HbsAg, anti-HBc, anti-
HBs, and HBV DNAw
X


2015N242992_07
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Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108 
(optional)b
120
132 
(optional)b
144
148c
HCV antibody
X
RPR
X
Insulin, HbA1c and 
renal, and bone marker 
analytes (blood/urine)x
X
X
X
X
X
Xq
Whole Blood (Virology)y
X
X
X
X
X
Whole Blood (Telomere 
length)z
X
X
X
X
Xaa
Cryopreserved 
PBMCsbb
X
X
X
X
Xaa
Inflammation 
biomarkers (Blood)cc
X
X
X
X
Xaa
Study Treatment
IVRS/IWRSdd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study 
treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment 
accountability (pill 
counts)
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokineticee
Intensive PK sample 
collection at selected 
sites for subset of ~30 
subjects (Fasting)ee
Xff
Dispense PK Diary 
Card to intensive PK 
sub-set
X


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Procedures
Screening Visita
Open-label Randomised Early Switch Phase
Switch 
Visit
Withdrawal
Follow-upd
Baseline / 
Day 1
Week
4
8
12
24
36
48
60
72
84
96
108 
(optional)b
120
132 
(optional)b
144
148c
Sparse PK sample 
collectionee
Xgg
X
X
X
X
X
Dispense PK Diary 
Card to Sparse PK 
subjects
X
X
X
X
X
X
anti-HBc = antibody to hepatitis B core antigen, anti-HBs = hepatitis B surface antibody, ART = antiretroviral therapy, CDC = Centers for Disease Control and Prevention, DNA = 
deoxyribonucleic acid, HbA1c = Glycated hemoglobin, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus type 1, IVRS = interactive 
voice recognition system, IWRS = interactive web recognition system, PBMC = peripheral blood mononuclear cell, RNA = ribonucleic acid, RPR = rapid plasma reagin
Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
152
160
172
184 
(optional)b
196
200hh
Clinical and Other Assessments
Body Weight (BMI will be 
calculated within the eCRF)
X
X
X
X
X
X
X
X
X
HIV associated conditions
X
X
X
X
X
X
X
X
Columbia Suicidality Severity 
Rating Scale
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Symptom Directed Physical 
Exami
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Serious adverse events
X
X
X
X
X
X
X
X
X
EQ-5D-5Lm
X
X
Laboratory Assessments


2015N242992_07
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Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
152
160
172
184 
(optional)b
196
200hh
Quantitative plasma HIV-1 
RNAn
X
X
X
X
X
X
X
Lymphocyte subset (CD4+ at 
all visits and CD8+ at 
Baseline, and Weeks 24, 48, 
96, 144 and 196 only) 
X
X
X
X
X
X
Plasma for storageo
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Fasting lipids and glucosep
X
Xq
Urinalysis and spot urine for 
protein analysisr
X
X
X
Pregnancy tests,t,u
S
S
S
S
S
S
S
S
Insulin, HbA1c and renal, and 
bone marker analytes 
(blood/urine)x
X
Xq
Whole Blood (Virology)y
X
X
Whole Blood (Telomere 
length)z
X
Xaa
Cryopreserved PBMCsbb
X
Xaa
Inflammation biomarkers 
(Blood)cc
X
Xaa
Study Treatment
IVRS/IWRSdd
X
X
X
X
X
X
X
X
X
Dispense study treatment
X
X
X
X
X
Study treatment accountability 
(pill counts)
X
X
X
X
X
X
X


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Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
160 
(optional)b
172
184 
(optional)b
196
200hh
Clinical and Other Assessments
Body Weight (BMI will be calculated within 
the eCRF)
X
X
X
X
X
X
X
X
HIV associated conditions
X
X
X
X
X
X
X
Columbia Suicidality Severity Rating Scale
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
Symptom Directed Physical Exami
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Serious adverse events
X
X
X
X
X
X
X
X
EQ-5D-5Lm
X
X
Laboratory Assessments
Quantitative plasma HIV-1 RNAn
X
X
X
X
X
X
Lymphocyte subset (CD4+ at all visits and 
CD8+ at Baseline, and Weeks 24, 48, 96, 144 
and 196 only) 
X
X
X
X
X
Plasma for storageo
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Fasting lipids and glucosep
X
Xq
Urinalysis and spot urine for protein 
analysisr
X
X
X
Pregnancy tests,t,u
S
S
S
S
S
S
S
Insulin, HbA1c and renal, and bone marker 
analytes (blood/urine)x
X
Xq
Whole Blood (Virology)y
X
X
Whole Blood (Telomere length)z
X
Xaa
Cryopreserved PBMCsbb
X
Xaa
Inflammation biomarkers (Blood)cc
X
Xaa
Study Treatment
IVRS/IWRSdd
X
X
X
X
X
X
X
X


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Procedures
Late Switch Phase through End of Study
Continuation Phase
Withdrawal
Follow-up
Week
Every 24 weeks after Week 200b,ii
160 
(optional)b
172
184 
(optional)b
196
200hh
Dispense study treatment
X
X
X
Study treatment accountability (pill counts)
X
X
X
X
X
a.
As soon as all Screening results are available, randomization may occur.
b.
This optional study visit is ONLY to be conducted in countries that require visits every 3 months per standard of care.
c.
Subjects with plasma HIV-1 RNA 50 c/mL at Week 144 must have HIV-1 RNA level re-assessed by a second measurement performed 2-4 weeks later. Subjects should have 
received full doses of study treatment for at least 2 weeks at the time of HIV-1 RNA re-assessment. Subjects randomized to DTG + 3TC do not attend a Week 148 switch visit.  
d.
An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study medication for subjects with the following conditions at the last on-study visit:  ongoing AEs, 
serious adverse events (SAEs) regardless of attributability, any laboratory abnormalities considered to be AEs or potentially harmful to the subject. Only the laboratory tests 
necessary to evaluate the AE/SAE/laboratory abnormality should be collected.
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 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.
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.
h.
On Day 1, the electronic Columbia Suicidality Severity Rating Scale eC-SSRS, patient completed questionnaire) is to be administered prior to randomization. 
i.
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. 
j.
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes.
k.
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and administration of study 
drug at Day 1. 
l.
Willingness to Switch Survey must be done prior to randomization.
m.
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 196.
n.
See Virologic Withdrawal and Stopping Criteria Section of protocol (Section 5.4).
o.
Plasma samples for storage will be collected at each visit starting at Screening, 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 subjects meet 
Suspected and Confirmed Virologic Withdrawal criteria. 


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p.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
q.
Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 24, 48, 96, 144 or 196.
r.
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
s.
Women of childbearing potential only. S=serum, U=urine. Pregnancy events will be captured starting at Day 1 following exposure to study drug.
t.
Remind females of reproductive potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements.  
u.
Beginning after Week 96, if study visits are every 24 weeks, participants who are women of child bearing potential must also do a home-based urine pregnancy test 
approximately every 12 weeks between study visits at approximately Weeks 108, 132, 160 and 184 and during the Continuation Phase.  Site staff must contact the 
participants who are women of child bearing potential to remind them to complete the test and to verify and record pregnancy test results in the source documents.  
The site must also complete the pregnancy status eCRF if a pregnancy occurs and report the pregnancy to ViiV/GSK per Section 13.3.2.
v.
Local serum pregnancy test on Day 1 is allowed if it can be done, and results obtained, within 24 hours prior to randomization
w.
HBV DNA testing will be performed for subjects with positive anti-HBc and negative HBsAg and negative anti-HBs (past and/or current evidence).  Subjects will have to return to 
the clinic to provide a sample for HBV DNA testing prior to randomisation.
x.
Blood sample for insulin, HbA1c, and renal and bone biomarker assessments: Renal: Cystatin C; Beta-2-Microglobulin; Retinol Binding Protein (RBP); Bone: bone specific 
alkaline phosphatase, procollagen type 1-N-propeptide, type 1 collagen cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin D. 
y.
Whole blood (Virology) may be used for virologic analyses as described in the protocol.  
z.
Whole blood will be used for telomere length evaluation at Day 1, Week 48, Week 96, Week 144, Week 196 and at the Withdrawal visit.
aa. Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 48, 96, 144 or 196
bb. PBMCs will be collected, cryopreserved and stored in a subset of sites. These samples will be used for the measurement of telomerase activity.
cc. Blood sample for inflammation biomarker assessments: IL-6, hs-CRP, d dimer, sCD14, sCD163.
dd. At Screening, a subject number will be generated.
ee. PK sampling in subjects from the DTG/3TC FDC arm only, as detailed in Section 11.
ff.
Intensive PK sampling in a subset of subjects from the DTG/3TC FDC arm at select sites at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours post-dose. On the intensive PK day, 
patients are required to fast from 8 hours prior to dosing and then through 4 hours post-dose. Detailed in Section 11.
gg. At Week 4, subjects who performed intensive PK do not perform Sparse PK sampling.
hh. Subjects must return to the clinic for a Week 200 End of Study visit when transitioning to commercial supplies or to an alternate ART regimen, if appropriate. Do not 
dispense study treatment at this study completion visit unless the participant is entering the Continuation Phase.
ii.
Only in case of non-availability of DTG + 3TC FDC.  Subjects 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 with the exception of dispensing study treatment.


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Section 7.3.1.2 Secondary Efficacy Endpoints:
Previous text:

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Weeks 24 and 48 using 
the Snapshot algorithm for the ITT-E population

Percentage of subjects with viral failure endpoint as per FDA snapshot category at 
Weeks 24 

Change from Baseline in CD4+ lymphocyte count at Weeks 24 and 48

Change from Baseline in CD8+ lymphocyte count and CD4+/CD8+ cell counts ratio 
at Weeks 24 and 48

Incidence of disease progression (HIV-associated conditions, AIDS and death).
Current text:

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Weeks 24,48, 96 and 
144 using the Snapshot algorithm for the ITT-E population

Percentage of subjects with viral failure endpoint as per FDA snapshot category at 
Weeks 24, 96 and 144 

Change from Baseline in CD4+ lymphocyte count at Weeks 24, 48, 96 and 144

Change from Baseline in CD8+ lymphocyte count and CD4+/CD8+ cell counts ratio 
at Weeks 24, 48, 96, and 144

Incidence of disease progression (HIV-associated conditions, AIDS and death).
Section 7.3.1.3 Exploratory Efficacy Endpoints:
Previous text:

Proportion of subjects with virologic failure endpoint as per FDA snapshot category
by patient subgroup(s) (e.g., by age, gender, Baseline CD4+) at Week 24, 48 and 96 
using the Snapshot algorithm for the ITT-E population

Change from Baseline in CD4+ cell counts at Weeks 24, 48 and 96 by patient 
subgroups
Additional exploratory efficacy endpoints for subjects treated with DTG + 3TC since the 
Early Switch Phase, and for subjects switching in the Late Switch Phase include:

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 96 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ and CD8+ lymphocyte count and CD4+/CD8+ cell 
counts ratio at Week 96

Incidence of disease progression (HIV associated conditions, AIDS and death) 
through Week 96.
Current text:


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
Proportion of subjects with plasma HIV-1 RNA <50 c/mL by patient subgroup(s) 
(e.g., by age, gender, Baseline CD4+) at Week 24, 48, 96 and 144 using the Snapshot 
algorithm for the ITT-E population

Change from Baseline in CD4+ cell counts at Weeks 24, 48, 96, 144 and 196 by 
patient subgroups
Additional exploratory efficacy endpoints for subjects treated with DTG + 3TC since the 
Early Switch Phase, and for subjects switching in the Late Switch Phase include:

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E population 

Change from Baseline in CD4+ and CD8+ lymphocyte count and CD4+/CD8+ cell 
counts ratio at Week 196

Incidence of disease progression (HIV associated conditions, AIDS and death) 
through Week 196.
Section 7.4.2 Pregnancy
Added text: Beginning after Week 96, if study visits are 24 weeks apart, the 
participants who are women of child bearing potential must also do a home-based 
urine pregnancy test approximately every 12 weeks between study visits at 
approximately Weeks 108, 132, 160 and 184. Site staff must contact the participants 
who are women of child bearing potential to remind them to complete the test and 
to verify and record pregnancy test results in the source documents. Site staff must 
complete the pregnancy status eCRF if a pregnancy occurs.  
Section 7.4.6 Table 1: Protocol Required Safety Laboratory Assessments:
Previous text:
CD8+ lymphocyte counts, percent and CD4+/CD8+ cell count ratio at Baseline and 
Weeks 24, 48 and 96
Current text:
CD8+ lymphocyte counts, percent and CD4+/CD8+ cell count ratio at Baseline and Weeks 24, 
48, 96, 144 and 196
Section 9.2.1 Sample Size Assumptions:
Previous text:
While the targeted study size was 550 randomised subjects (from a target of 800 screened 
subjects), the study was over-enrolled based on an unexpected surge in recruitment in the 
last week of screening. Based on an estimated screen failure rate of 20%, a total of 750
subjects are expected to be randomized.


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In this case where 750 subjects are randomized, this will provide 97.5% power to show 
non-inferiority with the current assumptions, and non-inferiority can be declared if the 
actual observed treatment difference in the trial is less than or equal to 1.6%.
Current text:
While the targeted study size was 550 randomised subjects (from a target of 800 screened 
subjects), the study was over-enrolled based on an unexpected surge in recruitment in the 
last week of screening, resulting in a total of 743 subjects randomized. 
This final sample size will provide 97.3% power to show non-inferiority with the current 
assumptions, and non-inferiority can be declared if the actual observed treatment 
difference in the trial is less than or equal to 1.6%. 
Section 9.3.2 Analysis Data Sets
Previous text:
A secondary analysis set of data is based on subjects’ responses at <50 c/mL calculated 
according to a Missing, Switch or Discontinuation = Failure (MSDF) algorithm, as 
codified by the FDA’s snapshot algorithm. This algorithm treats all subjects 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 subjects who switch their concomitant 
ART prior to the visit of interest, since no switches (with the exception below) are 
allowed in the protocol. 
Current text:
A secondary analysis set of data is based on subjects’ responses at <50 c/mL calculated 
according to the FDA snapshot algorithm. This algorithm treats all subjects 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 subjects who switch their concomitant ART 
prior to the visit of interest, since no switches (with the exception below) are allowed in 
the protocol. 
Section 9.3.4 Interim Analysis:
Previous text: 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 will be made as the Week 24 analyses will be secondary.
Current text:
Week 96, Week 144 and Week 196 data cuts and analyses will be conducted.  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 
will be made as the Week 24 analyses will be secondary, and other analyses are 


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secondary/exploratory and will occur after the primary endpoint analysis at Week 
48.
Section 9.4.1 Efficacy Analyses
Removed text:  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.
Previous text:
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 subjects who discontinue from the study with viral load <50 c/mL or for 
non-efficacy-treatment related reasons. In these analyses, subjects will be considered to 
have had an event if they have a confirmed viral load ≥50 c/mL or discontinue for 
efficacy related reasons.
Changes from baseline in CD4+ lymphocyte count and in CD4+/CD8+ lymphocyte 
counts ratio and resistance data will be summarized overall and by baseline third agent 
class.  Details for secondary efficacy endpoints will be discussed in the RAP.
The incidence of HIV-1 disease progression (AIDS and death) will be presented. The 
proportion of subjects with Snapshot virologic failure and changes from baseline in 
CD4+ lymphocyte count will be summarized by subgroups (e.g., age, gender, race).
Data gathered after subjects 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 (CSR).
Current text:
Further efficacy analyses to assess the sensitivity of the primary endpoint will be 
performed and included in the RAP.


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Changes from baseline in CD4+ lymphocyte count and in CD4+/CD8+ lymphocyte 
counts ratio and resistance data will be summarized.  The incidence of HIV-1 disease 
progression (AIDS and death) will be presented.
The proportion of subjects with plasma HIV-1 RNA <50 c/mL using the Snapshot 
algorithm and changes from baseline in CD4+ lymphocyte count will be summarized by 
subgroups (e.g., age, gender, race).
Data gathered after subjects 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, unless otherwise stated. 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 (CSR).
Section 9.4.2 Safety Analyses:
Previous text:
Exposure to study medication, measured by the number of weeks on study drug, will be
summarized by treatment group.  The proportion of subjects 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

Cumulative incidence of AEs by time to first occurrence

Cumulative incidence of treatment related AEs by time to first occurrence
The incidence and severity of treatment related AEs, SAEs and AEs leading to 
withdrawal will also be assessed by baseline third agent class.
Current text:
Exposure to study medication, measured by the number of weeks on study drug, will be 
summarized by treatment group.  The proportion of subjects 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 and AEs leading to withdrawal will 
also be assessed by baseline third agent class.


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Section 12 References:
Added text: Cahn P, Madero JS, Arribas J, et al. Non-inferior efficacy of 
dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine 
(TDF/FTC) fixed-dose combination in antiretroviral treatment-naive adults with 
HIV-1 infection: 48-week results from the GEMINI studies. AIDS 2018: 22nd 
International AIDS Conference, Amsterdam, Netherlands, July 23-27, 2018. 
Abstract TUAB0106LB. http://programme.aids2018.org/Abstract/Abstract/13210.
Section 13.3.2 Collection of Pregnancy Information:
Previous text:

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.
Current text:

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.
Section 13.10.1 United Kingdom:
Previous text:
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 Treatment for similar Phase III trials being conducted with 
dolutegravir.
The date of last study treatment administration in the UK will be determined by the 
completion of the Week 100 randomised phase of the study for the last UK subject 
enrolled (it will not be determined by the completion of the Continuation Phase).  The 
last subject will be enrolled by Q2/Q3 2018, and hence the last study treatment
administration will occur by Q2/Q3 2020. (Note: The Continuation Phase is intended to 
provide subjects randomised to DTG plus 3TC with post-study access to DTG plus 3TC 
until the DTG plus 3TC is approved as a dual regimen in their local countries.  For 
subjects in the UK, the Continuation Phase is anticipated to conclude by Q3/Q4 2020, 
when the dual regimen of DTG plus 3TC is anticipated to be approved).
Current text:
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 Treatment for similar Phase III trials being conducted with 
dolutegravir.


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The date of last study treatment administration in the UK will be determined by the 
completion of the Week 200 visit for the last UK subject enrolled.  The last subject was 
enrolled by June 2018, and hence the last study treatment administration will occur by 
Q3 2022. (Note: For subjects in the UK, the study and provision of IP is anticipated to 
conclude by Q3 2022, at which time the dual regimen of DTG plus 3TC would be 
available as it is anticipated to be approved in Q3/Q4 2020).
13.12.7.
Protocol changes for Amendment 07 (27-APR-2020) from 
Amendment 06 (29-AUG-2018)
Summary of Key Changes in Protocol Amendment 07 and Rationale
Changes were made to the protocol to introduce metabolic health exploratory objectives 
including metabolic syndrome, cardiovascular risk and other anthropomorphic measures 
to assess type and implication of weight change overtime.  Additional on-treatment 
assessments from Week 144 through Week 196, include resting blood pressure, waist 
circumference and hip circumference.  Changes were also made to include an additional 
appendix to provide standardized procedural guidance on obtaining the above mentioned 
measurements.  A missing assessment of concomitant medication at Week 148 was also 
corrected.  Results from the Botswana outcome surveillance study were updated for DTG 
and neural tube defects.
List of Specific Changes. Unless stated otherwise, new text is represented in bold 
font, and deleted text in strikethrough font.
Section Sponsor Signatory
Revised text:
Sherene Shakib Min, MD, MPH
Vice President, Head of Clinical Development
ViiV Healthcare
Kimberly Y. Smith, MD, MPH
Vice President and Head, 
Global Research and Medical Strategy,
ViiV Healthcare


2 0 1 5 N 2 4 2 9 9 2 _ 0 7
C O N FI D E N TI A L
2 0 4 8 6 2
2 5 6
Secti o n Me dic al M o nit or/ S A E C o nt act I nf or m ati o n
Re vise d te xt:
S e c o n d ar y 
M e di c al 
M o nit or
 M D
M: +
Vii V H e alt hc ar e
5 M o or e Driv e
R es e arc h Tri a n gl e P ark, 
N C 2 7 7 0 9
T erti ar y 
M e di c al 
M o nit or
M D
M: +
Vii V H e alt hc ar e
M ailst o p U P 4 4 1 0
C oll e g evill e, P A ( U S A)
Secti o n 2. 1: St u d y R ati o n ale
Re vise d te xt:
Para gra p h 6 of t he secti o n was u p date d wit h t he f oll o wi n g te xt.
Rece nt d at a h a ve i m plic ate d t he i nte gr ase i n hi bit or cl ass a n d T A F -b ase d re gi me n 
wit h wei g ht g ai n [ Ve nter, 2 0 1 9; S a x, 2 0 1 9] a n d f urt her rese arc h is re q uire d t o 
u n derst a n d t he mec h a nis ms, t y pe of wei g ht g ai n a n d met a b olic he a lt h i m plic ati o ns 
of t hese o bser v ati o ns. I n t he c urre nt st u d y Wee k 4 8 pri m ar y a n al ysis, we o bser ve d 
si mil ar a dj uste d me a n wei g ht i ncre ase fr o m b aseli ne t o Wee k 4 8 of 0. 8 k g i n b ot h 
gr o u ps a n d t he a dj uste d me a n i ncre ase i n B MI w as 0. 2 5 k g/ m 2 i n t he D T G/ 3 T C 
g r o u p a n d 0. 2 6 k g/ m 2 i n t he T A F-b ase d re gi me n gr o u p [ v a n W y k, 2 0 2 0].  I n t his 
pr ot oc ol a me n d me nt t o be i m ple me nte d pri o r t o t he first st u d y p artici p a nt 
perf or mi n g t heir Wee k 1 4 4 visit, we are a d di n g met a b olic he alt h a n d c ar di o v asc ul ar 
dise ase ris k e x pl or at o r y o bjecti ves. T hese i ncl u de met a b olic s y n dr o me, 
c ar di o v asc ul ar ris k a n d ot her a nt hr o p o m or p hic me as ures t o e x pl ore p ote nti al 
i m plic ati o n of wei g ht c h a n ge o verti me o n met a b olic he alt h. 
Secti o n 3: O bjecti ve(s) a n d E n d p oi nt(s)
Re vise d te xt:
Si x ne w e x pl orat o r y o bjecti ves a n d its relate d e n d p oi nts were a d de d.
O bj e cti v e
E n d p oi nt
E x pl or at or y
T o d e s cri b e b o d y m or p h ol o g y at W e e k 1 4 4 
i n s u bj e ct s tr e at e d wit h D T G + 3 T C a n d T B R

W ai st t o h ei g ht r ati o at W e e k 1 4 4 i n e a c h 
ar m

W ai st t o hi p r ati o at W e e k 1 4 4 i n e a c h 
ar m
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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To assess metabolic health and 
Cardiovascular disease risk at Week 144 in 
subjects treated with DTG + 3TC and TBR

Proportions of subjects with Metabolic 
Syndrome at Week 144 in each arm

Change from Baseline in Framingham 
risk Score through Week 144 in each 
arm

Change from Baseline in resting Blood 
Pressure at Week 144 in each arm
To describe body morphology at Week 196 
in subjects treated with DTG + 3TC since 
the Early Switch Phase

Waist to height ratio at Week 196

Waist to hip ratio at Week 196 
To assess metabolic health and 
Cardiovascular disease risk at Week 196 in 
subjects treated with DTG + 3TC since the 
Early Switch Phase

Proportions of subjects with Metabolic 
Syndrome at Week 196 

Change from Baseline in Framingham 
risk Score through Week 196

Change from Baseline in resting Blood 
Pressure at Week 196 
To assess body morphology at Week 196 in 
subjects switching to DTG + 3TC in the Late 
Switch Phase

Change in waist to height ratio from 
Switch to Week 196

Change in waist to hip ratio from Switch 
to Week 196 
To assess metabolic health and 
Cardiovascular disease risk at Week 196 in 
subjects treated with DTG + 3TC since the 
Late Switch Phase

Proportions of subjects with Metabolic 
Syndrome at Week 196 

Change from Baseline in Framingham 
risk Score through Week 196

Change from Baseline in resting Blood 
Pressure at Week 196 
Section 4.6.1.:Risk Assessment
Revised text:
Summary of Data/Rationale for Risk for DTG: Neural tube defects was modified as 
follows:
In one ongoing birth outcome surveillance study in Botswana, early updated results from 
an unplanned interim analysis show that 45/4261683 (0.93%) of women who were taking 
DTG when they became pregnant had babies with neural tube defects compared to a 
background rate of 0.1%.
Section 6.11.2.1: Prohibited Medications for Subjects Receiving DTG + 3TC
Revised text:
First paragraph, last bullet point
Fampridine/Dalfampridine


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Section 7.1.1: Early Switch Phase Time and Events Table (Screening to Week 148)
Revised text:
The following assessments and time points were added.

Vital Signs: Resting Blood pressure (See Section 7.4.4 and Appendix 10) at 
Week 144, Week 148 and Withdrawal. 

Vital Signs: Hip and waist circumference (See Section 7.4.4 and Appendix 10) at 
Week 144.

A missed time point for concomitant medication was added at Week 148.
Section 7.1.2 Late Switch Phase Time and Events Table: TBR subjects who 
switched to DTG + 3TC at Week 148
Revised text:
The following assessments and time points were added.

Vital Signs: Resting Blood pressure (See Section 7.4.4 and Appendix 10) at 
Week 172, Week 196, Week 200 and Withdrawal.

Vital Signs: Hip and waist circumference (See Section 7.4.4 and Appendix 10) at 
Week 172, Week 196 and Withdrawal. 
Section 7.1.3 Late Switch Phase Time and Events Table: DTG + 3TC arm
The following assessments and time points were added.

Vital Signs: Resting Blood pressure (See Section 7.4.4 and Appendix 10) at 
Week 172, Week 196, Week 200 and Withdrawal.

Vital Signs: Hip and waist circumference (See Section 7.4.4 and Appendix 10) at 
Week 172, Week 196 and Withdrawal.
Section 7.4.4: Vital Signs
Revised Text:
At the Screening visit, vital signs will be measured in semi-supine position after 5 
minutes rest and will include height, weight, systolic and diastolic blood pressure and 
Body Mass Index (BMI).  Systolic and diastolic resting blood pressure, bBody weight 
and BMI will also be assessed at each visit according to the Time and Events Table 
(Section 7.1). Procedures to be followed for resting blood pressure and body weight 
assessments are provided in Appendix 10.  Waist and hip circumference will be 
assessed from Week 144 onwards according to the Time and Events Table (Section 
7.1).  Procedures to be followed for waist and hip circumference assessments are 
provided in Appendix 10.
Section 9.3.4.:Interim Analysis


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Added following text in Paragraph 3:
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].
Section 9.4.2: Safety Analyses
Text added at the end of the section:
Waist to height ratio and waist to hip ratio will be summarized by visit.  Further 
details will be included in the RAP.
Metabolic syndrome will be calculated at Baseline, Week 144 and Week 196.  
Further details will be included in RAP.
Section 12.
REFERENCES
Following references were added:
European Medicines Agency (EMA). Guidance on the Management of Clinical Trials 
during the COVID-19 (Coronavirus) pandemic. Version 1 March 2020(a). 
European Medicines Agency (EMA). Points to consider on implications of 
Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials. 
25 March 2020(b).
Sax PE, Erlandson KM, Mccomsey GA, et al. Weight gain following initiation of 
antiretroviral therapy: risk factors in randomized comparative clinical trials. Clin 
Infect Dis. 2019. pii: ciz999. doi: 10.1093/cid/ciz999.
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, 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. pii: ciz1243. doi: 10.1093/cid/ciz1243.


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Venter WDF, Moorhouse M, Hillexpand A, et al. Dolutegravir plus two different 
prodrugs of tenofovir to treat HIV. N Engl J Med. 2019;381(9):803-815.
New Section added:
13.10 Appendix 10: Protocol Recommendation for Assessment of Waist 
Circumference, Hip Circumference and Weight (Adapted from WHO STEPS 
Surveillance Manual, 2017) and for Resting Blood Pressure
[WHO, 2017]
13.10.1
Waist Circumference
Equipment 
To take waist circumference measurements you will need a:

Constant tension tape (for example, Figure Finder or Myo Tape Body Tape 
Measure);
o
Tape measures will be provided for the study

Chair or coat stand for participants to place their clothes.
Privacy
A private area is necessary for this measurement. This could be a separate room, or 
an area that has been screened off from other people.
Preparing the participant
This measurement should be taken without clothing, meaning, directly over the 
skin.
If this is not possible, the measurement may be taken over light clothing (for 
example, a hospital gown, an undergarment or thin t-shirt). Thick or bulky clothing 
must be removed.  Body shaping garments are not allowed to be worn during this 
measurement.
How to take the measurement
We recommend having the same study staff performing the measurement across 
visits for individual study participants.
This measurement should be taken:

at the end of a normal expiration;

with the arms relaxed at the sides;

at the midpoint between the lower margin of the last palpable rib and the top of 
the iliac crest (hip bone).


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Figure 5
Location of Midpoint for Waist Circumference Measurement 
Procedure
Follow the steps below to measure the waist circumference of a participant:
1.
Standing to the side of the participant, locate the last palpable rib and the top of 
the hip bone. You may ask the participant to assist you in locating these points 
on their body.
2.
Wrap the tension tape around the participant and position the tape at the 
midpoint of the last palpable rib and the top of the hip bone, making sure to 
wrap the tape over the same spot on the opposite side.
Note: Check that the tape is horizontal across the back and front of the participant 
and as parallel with the floor as possible.
3.
Ask the participant to:

stand with their feet together with weight evenly distributed across both feet;

hold the arms in a relaxed position at the sides;

breathe normally for a few breaths, then make a normal expiration.


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4.
Measure waist circumference and read the measurement at the level of the tape 
to the nearest 0.1 cm, making sure to keep the measuring tape snug but not 
tight enough to cause compression of the skin.
5.
Record the measurement, in centimetres to one decimal place, within the eCRF.
Note: Measure once and record.
13.10.2
Hip Circumference
Equipment
To take hip circumference measurements you will need a:

Constant tension tape (for example, Figure Finder or Myo Tape Body Tape 
Measure);
o
Tape measures will be provided for the study

Chair or coat stand for participants to place their clothes.
Privacy
A private area is necessary for this measurement. This could be a separate room, or 
an area that has been screened off from other people. Hip measurements are taken 
immediately after waist circumferences.
Preparing the participant
This measurement should be taken without clothing, that is, directly over the skin.
If this is not possible, the measurement may be taken over light clothing (for 
example, a hospital gown, an undergarment). Thick or bulky clothing must be 
removed.  Body shaping garments are not allowed to be worn during this 
measurement.
How to take the measurement
We recommend having the same study staff performing the measurement across 
visits for individual study participants.
This measurement should be taken:

with the arms relaxed at the sides

at the maximum circumference over the buttocks.
Procedure
Follow the steps below to take hip circumference measurements.


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1.
Stand to the side of the participant and wrap the tension tape around them.
2.
Position the measuring tape around the maximum circumference of the 
buttocks.
3.
Ask the participant to:

Stand with their feet together with weight evenly distributed over both feet;

Hold their arms relaxed at the sides.
4.
Check that the tape position is horizontal all around the body and snug without 
constricting.
5.
Measure hip circumference and read the measurement at the level of the tape to 
the nearest 0.1 cm.
6.
Record the measurement, in centimetres to one decimal place, within the eCRF. 
Note: Measure once and record.
13.10.3
Weight
Equipment
To measure weight, you will need a weighing scale, (such as a SECA scale or the 
Tanita HS301 Solar Scale). Alternatively, a BMI scale measuring both height and 
weight (e. g. Growth Management Scale) can be used.
Ensure the scale has been regularly calibrated according to the manufacturer 
instructions and that calibration documentations are filed and available to the study 
CRA as required.
We recommend using the same scale across visits for individual study participants.
We recommend having the same study staff performing the measurement across 
visits for individual study participants.
We recommend that the time of day a participant’s weight is measured is consistent 
for every participant at the site within the study. (ex. If measured at 10 a.m. at 
initial measurement, attempt to have the participant measured at 10 a.m. at 
subsequent visits).
Set up requirements
Make sure the scales are placed on a firm, flat surface. Do not place the scales on:

carpet

a sloping surface

a rough, uneven surface.
Set up scales 


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Follow the steps below before measuring the weight of a participant:
1.
Make sure the scale is on a firm, flat surface.
2.
Turn on the scale and wait until the display shows 0.0.
Procedures
Follow the steps below to measure the weight of a participant:
1.
Ask the participant to remove their footwear (shoes, slippers, sandals, etc). They 
should also take off any heavy belts and remove all objects out of their pockets 
(example:  mobile phones, wallets, coins).
2.
Ask the participant to step onto scale with one foot on each side of the scale.
3.
Ask the participant to:

stand still

face forward

place arms on the side and

wait until asked to step off.
4.
Record the weight in kilograms to one decimal place in the eCRF.
References
World Health Organization (WHO). STEPS Surveillance Manual. The WHO 
STEPwise approach to noncommunicable disease risk factor surveillance, 2017; 3-5-9 
to 3-5-13.
13.10.4
Resting Blood Pressure
General instructions

Ensure that healthcare professionals taking blood pressure measurements have 
adequate initial training and periodic review of their performance.

Healthcare providers must ensure that devices for measuring blood pressure 
are properly validated, maintained and regularly recalibrated according to 
manufacturers' instructions.

When measuring blood pressure in the clinic or in the study site, standardise 
the environment and provide a relaxed, temperate setting, with the person quiet 
and seated, and their arm outstretched and supported. Use an appropriate cuff 
size for the person's arm.

Measure the blood pressure in one arm (after 5 minutes rest in semi-supine* 
position or seated).  
*Semi-supine position: Laying /sitting back (at 45angle or variations) in a relaxed 
position with feet touching a flat surface.

SAP_003.pdf: 
 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
2 0 4 8 6 2  
 
1 
 
Di visi o n  
: W orld wide  D e velo p me nt  
I nfo r m ati o n T y pe  
: Re p ortin g  a n d A nalysis  Pla n  ( R A P) 
 
Title  
: Re p ortin g  a n d A nalysis  Pla n f or A P has e III, 
ra n d o mise d, m ultic e nter, parallel-gr o u p,  n o n - infe riorit y 
st u d y e valuatin g  t he effic a c y, s afet y, a n d t olera bilit y  of 
s witc hin g  t o d olute gra vir  plus la miv u dine  in HI V 1 
infe cte d  a d ults  w h o are vir olo gic all y  s u p press e d 
C o m p o u n d N u m be r  
: 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)  
Effe cti v e D ate  
: 2 5  Ma y 2 0 2 2  
 
D e s c ri pti o n:  
•  
T he p ur p os e of t his R A P is t o des cribe t he pla n ne d a nalys es a n d o ut p ut t o be 
inclu de d in t he  Clinic al  St u d y Re p orts f or Pr ot oc ol 2 0 4 8 6 2 . 
•  
T his R A P will  be pr o vide d  t o t he st u d y te a m me m bers t o c o n ve y t he c o nte nt of t he 
2 0 4 8 6 2 Statistic al A nalysis C o m plete  ( S A C) delivera ble s f or t he re p ortin g  eff ort 
u p t o We e k 2 0 0 , inclu din g  a n y p ost-We e k  2 0 0 f ollo w -u p  visits  f or participa nts 
wit h o n -g oin g  A E or clinic ally  sig nific a nt  la b ora t or y  a b n or malit y  at We e k 2 0 0 
( Final  E n d of St u d y ( E O S) A nalysis). 
•  
T his versio n  of t he R A P is a me n d me nt  t o pre vio us  a me n d me nt 3 R A P ( We e k 1 4 4 ) 
date d  0 4 -Ma y -2 0 2 1 . 
 
R A P A ut h o r(s):  
 
D ate  
Le a d  
 
Le a d Statisticia n,  Biostatistics  
1 7- Ma y -2 0 2 2  
 
 
 
 
C o p yrig ht  2 0 2 2 t he Gla x o S mit h K li ne  gr o u p  of c o m pa nies.  All  rig hts res er ve d.  
U na ut h oris e d  c o p yin g  or us e of t his inf or matio n  is pr o hibite d.  
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 4 8 6 2  
 
2 
 
R A P Te a m A p pr o v al s  
( M et h o d: E-m ail) : 
A p pr o v e r  
D ate  
 
, Vii V H e alt hc are 
1 8 -Ma y -2 0 2 2  
  
Me dicines D e velo p me nt Le a d, Res e arc h a n d D e velo p me nt/ Gl o ba l 
Me dic al Strate g y Te a m  
1 9 -Ma y -2 0 2 2  
 
Pr incipal  Clinic al  D ata Ma na ger, I nfe ctio us  Dis e as e, Clinic al  D ata 
Ma na ge me nt  
1 9 -Ma y -2 0 2 2  
  
St u d y D eliver y Le a d , R & D G C S D 
1 9 -Ma y -2 0 2 2  
, Safet y a n d Me dic al Go ver na nc e 
1 8 -Ma y -2 0 2 2  
 
Clin ic a l D e velo p me nt Le a d , Vii V H e alt hc are  
1 8 -Ma y -2 0 2 2  
  
Cl inic al D e velo p me nt Ma na ger, Vii V H e alt hc are  
1 9 -Ma y -2 0 2 2  
Cli nic al St atistics a n d Cli nic al Pr o g r a m mi n g Li ne  A p pr o v als  
( M e t h o d: P h ar m a  T M F e Si g n at ure ): 
A p pr o v e r  
A p pr o v al M e t h o d  
 
  
 P rinc ipa l  Sta tistic ia n,  Biosta tistic s  
e-Sig nat ure  
 
, Clinic a l  P r o gra m min g  
e-Sig nat ure  
 
 
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
P P D
P P D
P P D


 
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The main changes included in RAP Amendment are as follows (and pertain to analyses 
relevant to Week 196/200): 
The following displays have been added:  
Study Population 
1. Summary of Subject Disposition for the Subject Conclusion Record - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 1.101) 
2. Summary of Reasons for Withdrawal by Visit - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) (Table 1.601) 
3. Summary of Important Protocol Deviations - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) (Table 1.701) 
4. Summary of Demographic Characteristics - TBR arm – Late Switch Phase 
(Table 1.1102) 
5. Summary of Race and Racial Combinations Details - TBR arm – Late Switch 
Phase (Table 1.1402) 
6. Summary of Hepatitis Status at Entry - TBR arm – Late Switch Phase 
(Table 1.1502) 
7. Summary of CDC Classification of HIV Infection at Baseline - TBR arm - Late 
Switch Phase (Table 1.1602) 
8. Summary of HIV Risk Factors - TBR arm – Late Switch Phase (Table 1.1702) 
9. Summary of Screening  Cardiovascular Risk Assessments - TBR arm – Late 
Switch Phase (Table 1.1802) 
10. Summary of Distribution of CD4+ Cell Count (cells/mm^3) Results at LS 
Baseline - TBR arm – Late Switch Phase (Table 1.1902) 
11. Summary of Current Medical Conditions - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) (Table 1.2001) 
12. Summary of Past Medical Conditions - TBR arm – Late Switch Phase 
(Table 1.2101) 
13. Summary of Concomitant Medications by Ingredient ATC Level 1 - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 1.2201) 
14. Summary of Concomitant Medication Ingredient Combinations - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 1.2301) 
15. Summary of Concomitant Medications by Combination Term ATC Level 1 - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 1.2401) 
16. Summary of Antiretroviral Therapy Received at Screening - TBR arm – Late 
Switch Phase (Table 1.2602) 
17. Summary of Current Cardiac, Gastrointestinal, Metabolism and Nutrition, 
Psychiatric, Renal and Urinary, and Nervous System Conditions - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 1.2701) 
18. Summary of Past Cardiac, Gastrointestinal, Metabolism and Nutrition, 
Psychiatric, Renal and Urinary, and Nervous System Conditions - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 1.2801) 


 
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19. Summary of Lipid Modifying Agent Use at LS Baseline - TBR arm – Late Switch 
Phase (Table 1.2902) 
20. Summary of Lipid Modifying Agent Use Starting Post-Baseline - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 1.3001) 
21. Summary of History of Depression and Anxiety at LS Baseline - TBR arm – Late 
Switch Phase (Table 1.3102) 
22. Summary of Baseline Third Agent Class - TBR arm - Late Switch Phase 
(Table 1.3202) 
23. Summary of Number of Subjects Enrolled by Country and Site ID – TBR arm - 
Late Switch Phase (Table 1.3302) 
24. Summary of Antiretroviral Therapy at Screening by Regimen - TBR arm - Late 
Switch Phase (Table 1.3602) 
25. Summary of Distribution of Quantitative Plasma HIV-1 RNA Results at LS 
Baseline - TBR arm - Late Switch Phase (Table 1.3702) 
26. Summary of Time since First Antiretroviral Therapy until Day 1 - TBR arm - Late 
Switch Phase (Table 1.3802) 
27. Summary of On-Treatment Antiretroviral Therapy Starting after Day 1 for DTG + 
3TC arm (Early and Late Switch Phase) and Starting after switch for TBR arm 
(Late Switch Phase) (Table 1.4001) 
28. Summary of Antiretroviral Therapy Starting after Treatment Discontinuation - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 1.4101) 
29. Summary of On-Treatment Antiretroviral after Day 1 for DTG + 3TC arm (Early 
and Late Switch Phase) and after switch for TBR arm (Late Switch Phase) by 
Regimen (Table 1.4201) 
30. Summary of Antiretroviral Therapy Starting after Treatment Discontinuation by 
Regimen - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 1.4301) 
31. Summary of Important COVID-19 Protocol Deviations - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 1.4401) 
32. Summary of COVID-19 Pandemic Visit Impacts - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) (Table 1.4601) 
Efficacy 
33. Summary of Study Outcomes (Plasma HIV-1 RNA ³ / < 50 c/mL) at Week X – 
Snapshot Analysis - DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) (Table 2.401) 
34. Summary of Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL by Visit – 
Snapshot Analysis - DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) (Table 2.1201) 
35. Summary of Change from Baseline in CD4+ count (cells/mm3) by Visit - DTG + 
3TC arm - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 2.1701) 
36. Summary of Change from Baseline in in CD4+/CD8+ count ratio (cells/mm3) by 
Visit - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 2.1801) 


 
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37. Summary of Post-Baseline HIV-1 Associated Conditions Including and Excluding 
Recurrences - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 2.1901) 
38. Summary of Post-Baseline HIV-1 Disease Progressions - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 2.2101) 
39. Cumulative Proportion of Subjects Meeting Confirmed Virologic Withdrawal 
Criteria by Visit - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) (Table 2.2201) 
40. Summary of Study Outcomes (<40 c/mL and Target Not Detected Status) at 
Week X – Snapshot - DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) (Table 2.3101) 
41. Summary of Study Outcomes (<40 c/mL) at Week X - Snapshot Analysis - DTG 
+ 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 2.3501) 
42. Individual Plasma HIV-1 RNA and CD4+ Profiles by Visit for subjects with at 
least one viral load ≥50 c/Ml - DTG + 3TC arm - Early and Late Switch Phase 
(Figure 2.401) 
43. Individual Plasma HIV-1 RNA and CD4+ Profiles by Visit for subjects with at 
least one viral load ≥50 c/Ml - TBR arm - Late Switch Phase (Figure 2.402) 
Safety 
44. Summary of All Adverse Events by System Organ Class and Preferred Term and 
by Maximum Grade - DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) (Table 3.601) 
45. Summary of Common (>=2%) Adverse Events by Overall Frequency - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase)  
(Table 3.701) 
46. Summary of Common (>=2%) Grade 2-5 Adverse Events by Overall Frequency - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.801) 
47. Summary of All Drug-Related Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.1001) 
48. Summary of All Drug-Related Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade – TBR -  Late Switch Phase (Table 3.1002) 
49. Summary of Common (>=2%) Non-serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subject and Occurrences) - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.1101) 
50. Summary of Common (>=0.5%) Drug-Related Grade 2-5 Adverse Events by 
Overall Frequency - DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) (Table 3.1201) 
51. Summary of Serious Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.1401) 


 
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52. Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment or Withdrawal from Study by Maximum Grade - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.1601) 
53. Summary of Serious Adverse Events by System Organ Class - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.1801) 
54. Summary of Drug-Related Serious Adverse Events by System Organ Class - DTG 
+ 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.2001) 
55. Summary of Chemistry Changes from Baseline by Visit - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.2201) 
56. Summary of Maximum Post-Baseline Emergent Chemistry Toxicities - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.2301) 
57. Summary of Fasting Lipids Percentage Changes from Baseline by Visit - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.2601) 
58. Summary of Changes in NCEP Lipid Baseline Category to Week X Category - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.3001) 
59. Summary of Changes in Total Cholesterol /HDL Ratio Baseline Category to 
Week 196 - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 3.3201) 
60. Summary of Hematology Changes from Baseline - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.3401) 
61. Summary of Maximum Post-Baseline Emergent Hematology Toxicities - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.3501) 
62. Summary of Change from Baseline in Bone Biomarkers by Visit - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.3701) 
63. Summary of Change from Baseline in Renal Biomarkers by Visit - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.3801) 
64. Summary of Change from Baseline in Renal Biomarkers by Visit - Loge 
Transformed Data - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) (Table 3.3901) 
65. Summary of Liver Monitoring/Stopping Event Reporting - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.4501) 
66. Summary of Subjects Meeting Hepatobiliary Abnormality Criteria – All Post-
Baseline Abnormalities - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) (Table 3.4601) 
67. Summary of True Positive Suicidal Indication Alerts Based on eCSSRS by Visit - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.4701) 
68. Summary of Subjects with Post Baseline C-SSRS Suicidal Ideation or Behaviour 
- DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.4901) 


 
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69. Summary of Characteristics of Post Baseline Anxiety Adverse Events of Special 
Interest - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 3.5001) 
70. Summary of Characteristics of Post Baseline Depression Adverse Events of 
Special Interest - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) (Table 3.5101) 
71. Summary of Characteristics of Post Baseline Suicidality and Self Injury Adverse 
Events of Special Interest - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) (Table 3.5201) 
72. Summary of Characteristics of Post Baseline Insomnia  Adverse Events of Special 
Interest - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 3.5301) 
73. Summary of Characteristics of Post Baseline Rash  Adverse Events of Special 
Interest - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 3.5401) 
74. Summary of Characteristics of Post Baseline Nightmare/Abnormal Dreams  
Adverse Events of Special Interest - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.5501) 
75. Summary of Characteristics of Post Baseline Drug Hypersensitivity  Adverse 
Events of Special Interest - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) (Table 3.5601) 
76. Summary of Onset and Duration of the First Occurrence of Post Baseline Anxiety 
Adverse Events of Special Interest - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.5701) 
77. Summary of Onset and Duration of the First Occurrence of Post Baseline 
Depression Adverse Events of Special Interest - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) (Table 3.5801) 
78. Summary of Onset and Duration of the First Occurrence of Post Baseline 
Suicidality and Self Injury Adverse Events of Special Interest - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.5901) 
79. Summary of Onset and Duration of the First Occurrence of Post Baseline 
Insomnia Adverse Events of Special Interest - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) (Table 3.6001) 
80. Summary of Onset and Duration of the First Occurrence of Post Baseline Rash 
Adverse Events of Special Interest - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.6101) 
81. Summary of Onset and Duration of the First Occurrence of Post Baseline 
Nightmare/Abnormal Dreams Adverse Events of Special Interest - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.6201) 
82. Summary of Onset and Duration of the First Occurrence of Post Baseline Drug 
Hypersensitivity Adverse Events of Special Interest - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.6301) 
83. Summary of Post Baseline Depression and Suicidal and Self-Injury Adverse 
Events by AE of Special Interest, Maximum DAIDS Toxicity Grade, and Prior 
History of Depression and Anxiety - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.7101) 


 
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84. Summary of Change from Baseline in Weight (kg) by Visit - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.7501) 
85. Summary of Change from Baseline in BMI (kg/m2) by Visit - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.7601) 
86. Summary of HOMA-IR Shifts from Baseline to Week X - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.8101) 
87. Summary of Change from Baseline in Inflammatory Biomarkers - Loge 
Transformed Data - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) (Table 3.9601) 
88. Summary of Proportion of Subjects with Change from Baseline in Weight (>=3%, 
>=5% and >=10%) at Week X - DTG + 3TC arm (Early and Late Switch Phase) 
and TBR arm (Late Switch Phase) (Table 3.9801) 
89. Summary of All Drug-Related Adverse Events by System Organ Class and 
Preferred Term up to the End of the Week 196 Reporting Window (USPI)  - DTG 
+ 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 3.9901) 
90. Summary of Common (>=0.5%) Drug-Related Grade 2-5 Adverse Events by 
Overall Frequency up to the End of the Week X Reporting Window (USPI)  - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.10001) 
91. 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 up to the End of the Week X Reporting Window (USPI)  - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.10101) 
92. Summary of Characteristics of Post Baseline Increase in Weight Adverse Events 
of Special Interest - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) (Table 3.10401) 
93. Summary of Characteristics of Post Baseline Decrease in Weight Adverse Events 
of Special Interest - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) (Table 3.10501) 
94. Summary of Maximum Post-Baseline Emergent Clinical Chemistry Toxicities to 
the End of the Week X Reporting Window (USPI) – LOCF - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.10801) 
95. Summary of Maximum Post-Baseline Emergent Hematology Toxicities to the 
End of the Week X Reporting Window (USPI) - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) (Table 3.11001) 
96. Summary of COVID-19 Assessments - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.11101) 
97. Summary of Waist to Height Ratio and Waist to Hip Ratio by Visit - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.11801) 
98. Summary of Change from LS Baseline in Waist to Height Ratio and Waist to Hip 
Ratio at Week 196 - TBR arm – Late Switch Phase (Table 3.11803) 
99. Proportion of Subjects with Metabolic Syndrome at Week 196 - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch Phase) (Table 3.11901) 


 
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100. 
Summary of Change from Baseline in Framingham Risk Score at Week 
196 - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) (Table 3.12001) 
101. 
Summary of Change from Baseline in Systolic Blood Pressure  and 
Diastolic Blood Pressure at week 196 - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) (Table 3.12101) 
102. 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin - DTG + 
3TC arm - Early and Late Switch Phase (Figure 3.301) 
103. 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin - TBR arm - 
Late Switch Phase (Figure 3.302) 
104. 
Heatmap plot of Triglycerides, LDL Cholesterol, Total Cholesterol 
(mmol/L) NCEP Categories and Total Cholesterol/HDL Ratio at Week X vs. 
Baseline – DTG + 3TC arm - Early and Late Switch Phase (Figure 3.401) 
105. 
Heatmap plot of Triglycerides, LDL Cholesterol, Total Cholesterol 
(mmol/L) NCEP Categories and Total Cholesterol/HDL Ratio at Week X vs. LS 
Baseline - TBR arm - Late Switch Phase (Figure 3.402) 
106. 
Heatmap plot of BMI at Week X vs. Baseline - DTG + 3TC arm - Early 
and Late Switch Phase (Figure 3.2501) 
107. 
Heatmap plot of BMI at Week X vs. LS Baseline - TBR arm - Late Switch 
Phase (Figure 3.2502) 
Virology 
108. 
 
Summary of INSTI Mutations and Major Mutations of NRTI, 
NNRTI and PI Classes by region at Baseline and Time of CVW at or prior to 
Week X - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 4.101) 
109. 
Summary of Phenotype at Baseline and Time of CVW by Phenotypic Cut-
off at or prior to Week X - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) (Table 4.401) 
110. 
Summary of Phenotype at time of CVW by Number of Drugs to Which 
Subject are Resistant at or prior to Week X - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) (Table 4.501) 
111. 
Summary of Fold Change to DTG, 3TC, TDF and FTC at - Time of CVW 
at or prior to Week X - DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) (Table 4.601) 
112. 
Summary of Subject Accountability: Genotypes Available at or prior to 
Week X - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 4.701) 
113. 
Summary of Subject Accountability: Phenotypes Available at or prior to 
Week X - DTG + 3TC arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) (Table 4.801) 
Health Outcomes 
114. 
Summary of EQ-5D Utility and Thermometer Scores by visit – DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm (Late Switch Phase) 
(Table 6.201) 
There are numerous displays that have been removed but these are not listed for reasons 
of brevity. 


 
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TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS .............................................................................................. 10 
1. 
INTRODUCTION ................................................................................................. 13 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION ............................................... 13 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ......................... 13 
2.2. 
Study Objective(s) and Endpoint(s) ........................................................... 13 
2.3. 
Study Design ............................................................................................ 17 
2.4. 
Statistical Hypotheses / Statistical Analyses .............................................. 18 
3. 
PLANNED ANALYSES ........................................................................................ 19 
3.1. 
Interim Analyses ....................................................................................... 19 
3.2. 
Final Analyses .......................................................................................... 19 
4. 
ANALYSIS POPULATIONS ................................................................................. 20 
4.1. 
Protocol Deviations ................................................................................... 23 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS .................................................................................................. 25 
5.1. 
Study Treatment & Subgroup Display Descriptors ..................................... 25 
5.2. 
Baseline Definitions .................................................................................. 25 
5.2.1. 
Baseline for Late Switch Phase .................................................. 25 
5.3. 
Multicentre Studies ................................................................................... 26 
5.4. 
Examination of Covariates, Other Strata and Subgroups ........................... 26 
5.4.1. 
Covariates and Other Strata ....................................................... 26 
5.4.2. 
Examination of Subgroups.......................................................... 27 
5.5. 
Multiple Comparisons and Multiplicity ........................................................ 28 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ............................................................................................. 29 
6. 
STUDY POPULATION ANALYSES ...................................................................... 29 
6.1. 
Overview of Planned Study Population Analyses ....................................... 29 
7. 
EFFICACY ANALYSES........................................................................................ 32 
7.1. 
Primary Efficacy Analysis .......................................................................... 32 
7.1.1. 
Summary Measure ..................................................................... 32 
7.1.2. 
Population of Interest ................................................................. 32 
7.1.3. 
Strategy for Intercurrent (Post-Randomisation) Events ................ 32 
7.1.4. 
Statistical Analyses / Methods .................................................... 32 
7.2. 
Secondary Efficacy Analyses .................................................................... 36 
7.2.1. 
Endpoint / Variables ................................................................... 36 
7.2.2. 
Summary Measures ................................................................... 36 
7.2.3. 
Populations of Interest................................................................ 36 
7.2.4. 
Strategy for Intercurrent (Post-Randomisation) Events ................ 36 
7.2.5. 
Statistical Analyses / Methods .................................................... 36 
7.3. 
Exploratory Efficacy Analyses ................................................................... 41 
7.3.1. 
Endpoint / Variables ................................................................... 41 
8. 
SAFETY ANALYSES ........................................................................................... 41 


 
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8.1. 
Adverse Events Analyses ......................................................................... 42 
8.2. 
Adverse Events of Special Interest Analyses ............................................. 44 
8.3. 
Clinical Laboratory Analyses ..................................................................... 44 
8.4. 
Other Safety Analyses .............................................................................. 52 
9. 
OTHER STATISTICAL ANALYSES ...................................................................... 55 
9.1. 
Health Outcomes ...................................................................................... 55 
9.1.1. 
Overview of Planned Analyses ................................................... 55 
9.1.2. 
Planned Health Outcomes Statistical Analysis ............................ 55 
9.2. 
Virology .................................................................................................... 56 
9.2.1. 
Overview of Planned Analyses ................................................... 56 
9.2.2. 
Planned Virology Statistical Analysis .......................................... 56 
10. PHARMACOKINETIC ANALYSES ....................................................................... 58 
10.1. Pharmacokinetic Analyses ........................................................................ 58 
10.1.1. Endpoint / Variables ................................................................... 58 
10.1.2. Summary Measure ..................................................................... 59 
10.1.3. Population of Interest ................................................................. 59 
10.1.4. Strategy for Intercurrent (Post-Randomisation) Events ................ 59 
10.1.5. Statistical Analyses / Methods .................................................... 59 
11. POPULATION PHARMACOKINETIC (POPPK) ANALYSES ................................. 60 
12. REFERENCES .................................................................................................... 61 
13. APPENDICES ..................................................................................................... 62 
13.1. Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population................................................................................... 63 
13.1.1. Exclusions from Per Protocol Population..................................... 63 
13.2. Appendix 2: Protocol Defined Schedule of Activities .................................. 65 
13.2.1. Early Switch Phase Time and Events Table (Screening to 
Week 148) ................................................................................. 65 
13.2.2. Late Switch Phase Time and Events Table: TBR subjects 
who switched to DTG + 3TC at Week 148................................... 69 
13.2.3. Late Switch Phase Time and Events Table: DTG + 3TC 
arm ............................................................................................ 71 
13.3. Appendix 3: Assessment Windows............................................................ 74 
13.3.1. Definitions of Assessment Windows for Analyses........................ 74 
13.3.2. Definitions of Assessment Windows for Inclusion in the PK 
Analysis ..................................................................................... 77 
13.4. Appendix 4: Study Phases and Emergent Adverse Events ........................ 78 
13.4.1. Study Phases............................................................................. 78 
13.4.2. Combining Treatment Phases and States ................................... 83 
13.4.3. Emergent Flag for Adverse Events ............................................. 83 
13.5. Appendix 5: Data Display Standards & Handling Conventions ................... 84 
13.5.1. Reporting Process...................................................................... 84 
13.5.2. Reporting Standards .................................................................. 84 
13.5.3. Reporting Standards for Pharmacokinetic ................................... 86 
13.6. Appendix 6: Derived and Transformed Data .............................................. 87 
13.6.1. General...................................................................................... 87 
13.6.2. Study Population ........................................................................ 88 
13.6.3. Efficacy ...................................................................................... 90 


 
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13.6.4. Safety ........................................................................................ 92 
13.6.5. Pharmacokinetic ........................................................................ 99 
13.6.6. Population Pharmacokinetic (PopPK) ....................................... 100 
13.6.7. Not applicable to analyses post Week 48.Viral Genotyping 
and Phenotyping ...................................................................... 100 
13.6.8. Health Outcomes ..................................................................... 105 
13.6.9. Cut-off date for protocol deviations ........................................... 106 
13.6.10. PK Data ................................................................................... 107 
13.6.11. eCRF Baseline Third Agent Class Determination ...................... 107 
13.7. 
Appendix 7: Reporting Standards for Missing Data .................................. 108 
13.7.1. Premature Withdrawals ............................................................ 108 
13.7.2. Handling of Missing Data.......................................................... 108 
13.8. Appendix 8: Values of Potential Clinical Importance ................................ 111 
13.9. Appendix 9: Population Pharmacokinetic (PopPK) Analyses .................... 112 
13.10. Appendix 10: Time to Event Details......................................................... 113 
13.10.1. TRDF Detailed Steps ............................................................... 113 
13.10.2. TRDF Detailed Steps for the Kaplan-Meier plot ......................... 117 
13.10.3. ERDF Detailed Steps ............................................................... 118 
13.11. Appendix 11: Snapshot ........................................................................... 119 
13.12. Appendix 12: Abbreviations & Trade Marks ............................................. 123 
13.12.1. Abbreviations ........................................................................... 123 
13.12.2. Trademarks.............................................................................. 124 
13.13. Appendix 13: Model Checking and Diagnostics for Statistical 
Analyses ................................................................................................ 125 
13.13.1. Statistical Analysis Assumptions ............................................... 125 
13.14. Appendix 14: COVID-19 Modified Analyses and Supportive 
Sensitivity Analyses ................................................................................ 126 
13.14.1. Efficacy Analyses (Snapshot) ................................................... 126 
13.15. Appendix 15: List of Data Displays .......................................................... 130 
13.15.1. Data Display Numbering........................................................... 130 
13.15.2. Mock Example Shell Referencing ............................................. 130 
13.15.3. Deliverables ............................................................................. 130 
13.15.4. Study Population Tables........................................................... 131 
13.15.5. Efficacy Tables......................................................................... 141 
13.15.6. Efficacy Figures ....................................................................... 148 
13.15.7. Safety Tables ........................................................................... 149 
13.15.8. Safety Figures.......................................................................... 172 
13.15.9. Virology tables ......................................................................... 176 
13.15.10.Pharmacokinetic Tables ........................................................... 179 
13.15.11.Pharmacokinetic Figures .......................................................... 180 
13.15.12.Health Outcomes Tables .......................................................... 181 
13.15.13.Health Outcomes Figures ......................................................... 182 
13.15.14.ICH Listings ............................................................................. 183 
13.15.15.Non-ICH Listings ...................................................................... 188 
13.16. Appendix 16: Example Mock Shells for Data Displays ............................. 195 
 


 
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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: 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There are no changes or deviations to the originally planned statistical analysis specified 
in the protocol amendment 7 (Dated: 27-APR-2020). 
2.2. 
Study Objective(s) and Endpoint(s) 
Objective 
Endpoint 
Primary 
To demonstrate the non-inferior antiviral 
activity of switching to DTG +3TC once daily 
compared to continuation of Tenofovir 
alafenamide (TAF) based regimen (TBR) over 
48 weeks in HIV-1 infected, ART therapy 
(ART)-experienced, virologically suppressed 
subjects 
Virologic failure (subjects with plasma HIV-1 
RNA ≥50 copies c/mL) endpoint as per FDA 
snapshot category at Week 48 
 
Secondary 
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 48 weeks  
Proportion of subjects with plasma HIV-1 RNA 
<50 copies c/mL at Week 48 using the 
Snapshot algorithm for the ITT-E population 
To demonstrate the antiviral activity of 
switching to DTG + 3TC once daily compared 
to continuation of TBR over 24, 96 and 144 
weeks  
• Subjects with plasma HIV 1 RNA ≥50 copies 
c/mL endpoint as per FDA snapshot 
category at Weeks 24, 96 and 144 
• Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Weeks 24, 96 and 144 
using the Snapshot algorithm for the ITT-E 
population 
To evaluate the immune effects of DTG + 3TC 
once daily compared to continuation of TBR 
over 24, 48, 96 and 144 weeks 
• Change from Baseline in CD4+ cell count 
and in CD4+/CD8+ cell count ratio at Weeks 
24, 48, 96 and 144 
• Incidence of disease progression (HIV-
associated conditions, AIDS, and death) 
through Weeks 24, 48, 96 and 144 


 
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Objective 
Endpoint 
To evaluate the safety and tolerability of DTG 
+ 3TC once daily compared to TBR over time  
• Incidence and severity of AEs and laboratory 
abnormalities through 144 weeks 
• Proportion of subjects who discontinue 
treatment due to AEs through 144 weeks 
To evaluate the effects of DTG + 3TC once 
daily on fasting lipids over time compared to 
TBR 
Change from Baseline in fasting lipids at 
Weeks 24,48, 96 and 144 
To assess viral resistance in subjects meeting 
Virologic Withdrawal Criteria 
Incidence of observed genotypic and 
phenotypic resistance to ARVs for subjects 
meeting Virologic Withdrawal Criteria  
To evaluate renal (in urine and blood) and 
bone (in blood) biomarkers in subjects treated 
with DTG + 3TC compared to TBR 
Change from Baseline in renal and bone 
biomarkers at Weeks 24,48, 96 and 144 
To assess health related quality of life for 
subjects treated with DTG + 3TC compared to 
TBR 
Change from Baseline in health status using 
EQ-5D-5L at Weeks 24, 48, 96 and 144 (or 
Withdrawal from the study) 
Exploratory 
To evaluate the effect of patient 
characteristics (e.g., demographic factors, 
Baseline CD4) on antiviral and immunological 
responses to DTG + 3TC compared to TBR  
• Proportion of subjects by subgroup(s) (e.g., 
by age, gender, Baseline CD4) with plasma 
HIV-1 RNA <50c/mL using the Snapshot 
algorithm at Weeks 24, 48, 96 and 144 
• Change from Baseline in CD4+ cell counts 
at Weeks 24, 48, 96 and 144 by patient 
subgroups 
To assess willingness to switch for subjects 
treated with DTG + 3TC compared to TBR 
Reasons for Willingness to Switch at Day 1 
To evaluate biomarkers of telomerase 
function in a subset of subjects treated with 
DTG + 3TC compared to TBR. 
Change from baseline in biomarkers of 
telomerase function at Weeks 48, 96 and 144 
To evaluate inflammation biomarkers and 
insulin resistance in a subset of subjects 
treated with DTG+ 3TC compared to TBR 
Change from Baseline in inflammation 
biomarkers and homeostasis model of 
assessment-insulin resistance (HOMA-IR) at 
Weeks 48, 96 and 144 
To describe body morphology at Week 144 in 
subjects treated with DTG + 3TC and TBR 
• Waist to height ratio at Week 144 in each 
arm 
• Waist to hip ratio at Week 144 in each arm 
To assess metabolic health and 
Cardiovascular disease risk at Week 144 in 
subjects treated with DTG + 3TC and TBR 
• Proportions of subjects with Metabolic 
Syndrome at Week 144 in each arm 
• Change from Baseline in Framingham risk 
Score through Week 144 in each arm 


 
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Objective 
Endpoint 
• Change from Baseline in resting Blood 
Pressure at Week 144 in each arm 
To evaluate the longer term antiviral and 
immunological effects, safety and tolerability 
of DTG + 3TC once daily in subjects treated 
with DTG + 3TC since the Early Switch Phase 
For subjects in the DTG + 3TC arm since Early 
Switch Phase: 
• Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E 
population  
• Change from Baseline in CD4+ 
lymphocyte count and in CD4+/CD8+ cell 
count ratio at Week 196 
• Incidence and severity of AEs and 
laboratory abnormalities over 196 weeks 
• Proportion of subjects who discontinue 
treatment due to AEs over 196 weeks 
• Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
through Week 196 
• Change from Baseline in renal and bone 
biomarkers at Week 196 
• Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at Week 196 
To describe body morphology at Week 196 in 
subjects treated with DTG + 3TC since the 
Early Switch Phase 
• Waist to height ratio at Week 196 
• Waist to hip ratio at Week 196 
To assess metabolic health and 
Cardiovascular disease risk at Week 196 in 
subjects treated with DTG + 3TC since the 
Early Switch Phase 
• Proportions of subjects with Metabolic 
Syndrome at Week 196 
• Change from Baseline in Framingham risk 
Score through Week 196 
• Change from Baseline in resting Blood 
Pressure at Week 196 
To evaluate the antiviral and immunological 
effects, safety and tolerability of DTG + 3TC 
for subjects switching in the Late Switch 
Phase 
For subjects switching to DTG + 3TC in the 
Late Switch Phase: 
• Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E 
population  
• Change from Baseline in CD4+ 
lymphocyte count and in CD4+/CD8+ cell 
count ratio at Week 196 


 
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Objective 
Endpoint 
• Incidence and severity of AEs and 
laboratory abnormalities during the Late 
Switch Phase 
• Proportion of subjects who discontinue 
treatment due to AEs during the Late 
Switch Phase 
• Incidence of disease progression (HIV 
associated conditions, AIDS and death) 
during the Late Switch Phase 
• Change from Baseline in renal and bone 
biomarkers at Week 196 
• Change from baseline in biomarkers of 
inflammation, HOMA-IR and telomerase 
function at Week 196 
To assess body morphology at Week 196 in 
subjects switching to DTG + 3TC in the Late 
Switch Phase 
• 
Change in waist to height ratio from Switch 
to Week 196 
• 
Change in waist to hip ratio from Switch to 
Week 196 
To assess metabolic health and 
Cardiovascular disease risk at Week 196 in 
subjects treated with DTG + 3TC since the 
Late Switch Phase 
• 
Proportions of subjects with and incidence 
of Metabolic Syndrome at Week 196 
• 
Change from Baseline in Framingham risk 
Score through Week 196 
• 
Change from Baseline in resting Blood 
Pressure at Week 196 
To assess the steady-state DTG and 3TC 
exposure in HIV-1 infected patients 
Steady state plasma PK parameters of DTG 
and 3TC will be assessed using intensive PK 
collected at week 4 (not applicable to analyses 
post Week 48). 
To characterize the DTG and 3TC steady-
state PK of the DTG/3TC FDC in HIV-1 
infected patients 
Population estimates of DTG and 3TC PK 
parameters (e.g. apparent clearance [CL/F], 
apparent volume of distribution [V/F]) using 
DTG and 3TC intensive and sparse plasma 
concentrations at Weeks, 4, 8, 12, 24, 36 and 
48 (not applicable to analyses post Week 48). 
 
 
 
 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• This is a 200-week, Phase III, randomised, open-label, active-controlled, 
multicenter, parallel-group non-inferiority study.  The study will include a Screening 
Phase (up to 28 days), a Randomised Early Switch Phase (Day 1 up to Week 148), 
a Randomised Late Switch Phase (Week 148 up to Week 200), and a Continuation 
Phase (post Week 200).   
Dosing 
• Patients receiving DTG + 3TC will receive DTG (50mg) + 3TC (300mg) once daily.  
Patients receiving TBR will receive the dose as determined by their prescribing 
physician.    
Time & 
Events 
• [Refer to Appendix 2: Schedule of Activities] 
Treatment 
Assignment 
• Approximately 550 subjects will be randomised 1:1 to switch to DTG + 3TC once 
daily (DTG + 3TC arm) for up to 196 weeks, or to continue their TBR for 148 weeks, 
and then switch to DTG + 3TC up to Week 196 (if HIV1 RNA <50 c/mL at Week 144 
(or at Week 148 if re-tested))  
Interim 
Analysis 
• One 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 Weeks 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. Interim analyses will also be 
performed at Week 96 and Week 144. 
See study protocol for further details 
 
 


 
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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 once-daily is not inferior to continuation of their TBR at 
week 48 in HIV-1 infected ART-experienced subjects.  Assuming a true 2% virologic 
failure rate in each arm, a non-inferiority margin of 4%, and a 2.5% one-sided 
significance level, this study requires 275 subjects per treatment arm. This would provide 
92% power to show non-inferiority for the proportion of subjects with virologic failure 
according to the FDA snapshot algorithm at 48 weeks post-switch. 
 
While the targeted study size was 550 randomised subjects (from a target of 800 screened 
subjects), the study was over-enrolled based on an unexpected surge in recruitment in the 
last week of screening ending with a final number of 743 subjects randomised. This will 
provide 97.3% power to show non-inferiority with the current assumptions, and non-
inferiority can be declared if the actual observed treatment difference in the trial is less 
than or equal to 1.6%.  
Non-inferiority can 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 4%. If rd is the virologic failure rate on DTG + 3TC and rf is the virologic 
failure rate on the current ART regimen, then the hypotheses can be written as follows: 
H0:  rd – rf  ≥ 4%                   H1: rd – rf < 4% 
 


 
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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 if required.  
• All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
• All criteria for unblinding1 the randomisation 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 virologic failure rates between the two 
treatment arms is less than 4% 2. 
An IDMC was instituted to ensure external objective medical and/or statistical review of 
efficacy and safety in order to protect the ethical interests and well-being of subjects and 
to protect the scientific validity of 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.  
3.2. 
Final Analyses 
The primary analysis is at Week 48.  Additional analyses will be performed at Weeks 96, 
144 and 196 and at the end of the continuation phase, if applicable. Analyses performed 
after Week 48 are considered interim analyses beyond the primary analysis.      
                                              
1 Although this is considered an open-label study, any data transfers/dry-runs prior to formal analyses will 
be based on blinded or dummy treatment allocation. Any references to unblinding the study in this 
analysis plan pertains to the process of unmasking the actual randomisation codes at formal data base 
locks. 
2 Please refer to Section 7.1.4 for details and conditions for presentation of test for superiority. 


 
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The planned analyses at Weeks 48, 96, 144 and 196 and end of continuation phase (if 
applicable)3 will be performed after the completion of the following sequential steps: 
• Last subject has completed their relevant visit at week 48 (96, 144, 196 or end of 
continuation) as defined in the protocol (or surpassed the time point at which their 
visit was scheduled but not completed due to COVID-19 at time of Week 196 
analysis), including any re-test if required 
• All required database cleaning activities have been completed as specified in the 
monitoring plan and Data Validation Manual and final database release and 
database freeze has been declared by Data Management. Any impact of COVID-
19 on data management activities will be documented in the DBF Memo. 
• All criteria for unblinding the randomisation codes at Week 48 (96, 144, 196 or 
end of continuation) have been met.  
Further data cuts and analyses may be conducted as necessary in order to support 
regulatory submissions and publications.  
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All subjects 
screened 
• Comprises all subjects screened for inclusion 
in the study, including screen-failures. 
• This population will be based on the treatment 
to which the subject was randomised. Screen-
failures will be categorised as “Non-
randomised”. 
• Study Population 
Randomised 
• The Randomised population will consist of all 
subjects who are randomised in the study 
• Study Population 
 
Intent-to-Treat 
(ITT) 
• Comprises all randomised subjects 
• Subjects will be assessed according to the 
treatment to which the subject was randomised 
regardless of treatment actually received. 
• Any subject receiving a treatment 
randomisation number will be considered to be 
randomised. 
• Efficacy (sensitivity 
analyses) 
 
Intent-To-Treat 
Exposed (ITT-E) 
• Comprises all randomised subjects who 
receive at least one dose of study treatment 
either DTG + 3TC or TBR. 
• This population will be based on the treatment 
to which the subject was randomised. 
• Study Population, 
Efficacy and Health 
Outcomes 
 
                                              
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, Week 96, Week 144, Week 196 and end of continuation 
phase.  


 
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Population 
Definition / Criteria 
Analyses Evaluated 
• Any subject who receives a treatment 
randomisation number will be considered to 
have been randomised. 
Late-Switch 
Intent-to-Treat 
(Exposed) (LS-
ITT-E)  
• Comprised of all subjects randomised to TBR 
who receive at least one dose of study 
treatment at or after the Week 148 Switch visit. 
• Subjects will be assessed according to the 
treatment intended regardless of treatment 
actually received (i.e., subjects not receiving 
TBR in the Early Switch Phase or failing to 
switch to DTG + 3TC at Week 148 will be 
included provided they progress to the Late 
Switch Phase). 
• Any subject who receives a treatment 
randomisation number will be considered to 
have been randomised. 
• Any subject receiving a treatment at or after 
Week 148 will be considered treated within the 
Late Switch Phase.  
 
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 Section 
13.1 (Protocol Deviation Management and 
Definition for Per-Protocol Population). 
• Efficacy (Sensitivity 
Analysis) (not 
applicable to post 
Week 144) 
CVW 
• Comprises all subjects in the ITT-E population 
who have met the derived CVW criteria 
Note: For TBR arm, this only includes subjects 
who have met CVW criteria before the switch (both 
assessments in early switch phase). For DTG/3TC 
subjects, this includes subjects who have met 
CVW criteria in either early or late switch phases 
• Genotypic 
• Phenotypic 
• Efficacy  
 
Late-Switch  
CVW (LS-CVW) 
• Comprises all subjects in the LS-ITT-E 
population who have met the derived CVW 
criteria in the late switch phase 
• Genotypic 
• Phenotypic 
• Efficacy  
potential 
Precautionary 
Virologic 
Withdrawal 
(pPVW) 
• Comprises subjects in the ITT-E population 
having 2 consecutive measurements between 
50 and 200 c/mL 
Note: For TBR arm, this only includes subjects 
who have met pPVW criteria before the switch 
(both assessments in early switch phase). For 
DTG/3TC subjects, this includes subjects who 
have met pPVW criteria in either early or late 
switch phases 
• Genotypic 
• Phenotypic 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
Late-Switch 
potential 
Precautionary 
Virologic 
Withdrawal (LS-
pPVW) 
• Comprises subjects in the LS-ITT-E population 
having 2 consecutive measurements between 
50 and 200 c/Ml in late switch phase 
• Genotypic 
• Phenotypic 
Viral Genotypic 
• Comprises all subjects in the ITT-E population 
who have available on-treatment genotypic 
resistance data. Assessed according to the 
treatment they actually received 
Note: For TBR arm, this only includes subjects with 
available on-treatment genotypic resistance data 
based n a viral load assessed before the switch 
(early switch phase). For DTG/3TC subjects, this 
includes subjects with available on-treatment 
genotypic resistance data in either early or late 
switch phases 
• Genotypic 
Late-Switch Viral 
Genotypic 
• Comprises all subjects in the LS-ITT-E 
population who have available on-treatment 
genotypic resistance data based on a viral 
load assessed in the late switch phase. 
Assessed according to the treatment they 
actually received 
• Genotypic 
Viral Phenotypic 
• Comprises all subjects in the ITT-E population 
who have available on-treatment phenotypic 
resistance data. Assessed according the 
treatment they actually received 
 
Note: For TBR arm, this only includes subjects 
with available on-treatment phenotypic 
resistance data based on a viral load assessed 
before the switch (early switch phase). For 
DTG/3TC subjects, this includes subjects with 
available on-treatment phenotypic resistance 
data in either early or late switch phases 
• Phenotypic 
Late-Switch Viral 
Phenotypic 
• Comprises all subjects in the LS-ITT-E 
population who have available on-treatment 
phenotypic resistance data based on a viral 
load assessed in the late switch phase . 
Assessed according the treatment they 
actually received 
 
• Phenotypic 
Efficacy 
Evaluable 
• Comprises all subjects who did not have 
missing Week 96 (and repeated at Week 144) 
HIV-1 RNA visit data as a result of the COVID-
19 pandemic i.e. discontinuation due to 
COVID-19 or on-study but missed visit due to 
• Efficacy 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
COVID-19 (see Section 13.14.1 for further 
details) 
Safety 
• Comprises all subjects who receive at least 
one dose of study treatment either DTG + 3TC 
or TBR. 
• This population will be based on the treatment 
the subject actually received4. 
• Safety 
 
Late-Switch 
Safety (LS-
Safety) 
• Comprised of all subjects randomised to TBR 
who received at least one dose of DTG+3TC 
at or after the Week 148 Switch visit. 
• Safety Late-Switch 
Phase 
Sparse 
Pharmacokinetic 
Population  
• All subjects who received at least 1 dose of 
DTG/3TC FDC and have evaluable sparse 
samples with drug concentrations reported, 
where samples are collected according to the 
sparse sampling schedule (through Week 48). 
• PK (not applicable to 
analyses post Week 
48) 
Intensive 
Pharmacokinetic 
Concentration 
Population  
• The subset of subjects enrolled into intensive 
PK sampling, who received at least 1 dose of 
DTG/3TC FDC and have evaluable drug 
concentrations reported, where samples are 
collected according to the intensive sampling 
schedule (Week 4 only). 
• PK (not applicable to 
analyses post Week 
48) 
Intensive 
Pharmacokinetic 
Parameter 
Population 
• All subjects in the Intensive Pharmacokinetic 
Concentration Population who provide at least 
one evaluable PK parameter. 
• PK (not applicable to 
analyses post Week 
48) 
NOTES :  
1. Please refer to Appendix 15: List of Data Displays which details the population to be used for each display being 
generated. 
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. 
                                              
4 As recorded on IVRS. If the randomised treatment is incorrect, the actual treatment will only be recorded 
in IVRS through sponsor intervention. 


 
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Term 
Definition 
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. 
COVID-19 
Protocol 
Deviations 
Important protocol deviations relating to the COVID-19 
pandemic will be documented in CTMS with their respective 
rule number followed by ‘COVID-19’ before text description. 
All other COVID-19 related protocol deviations not associated 
with a rule number will be documented with ‘COVID-19’ before 
the text description. 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Important deviations which result in exclusion from the analysis population (Significant 
deviations) will also be summarised and listed (see Section 13.1).  
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.  
o Data will be reviewed prior to unblinding and freezing of the database with the 
aim of capturing and categorising all important deviations and deviations which 
may lead to exclusion from the analysis in the protocol deviations SDTM dataset.  
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 & Subgroup Display Descriptors 
Treatment Group Description 
Order [1] 
DTG + 3TC 
1 
TBR 
2 
Late Switch Phase 
 
ES DTG+3TC 
1 
LS DTG+3TC 
2 
NOTES: 
1. Order represents treatments being presented in TFL, as appropriate. 
ES DTG+3TC – Early Switch DTG+3TC 
LS DTG+3TC – Late Switch DTG+3TC 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. DTG + 3TC vs TBR 
5.2. 
Baseline Definitions 
For all endpoints/parameters (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] 
 
5.2.1. 
Baseline for Late Switch Phase 
For the Late Switch Phase for TBR subjects, the last pre-switch data will be used to 
represent ‘baseline’ for DTG+3TC assessment.  In most cases, this will be Week 144 data 
and summaries will be labelled accordingly (e.g., ‘LS Baseline’).  In particular, for 
disease progressions, this will involve assessing the disease progression observed during 
the Early Switch Phase (up to Week 144) and using any known progressed status as 
‘baseline’ for assessing disease progression in the Late Switch Phase of the study.   
 


 
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5.3. 
Multicentre Studies 
Data will be summarised for all centres combined. Country will be treated as an 
exploratory subgroup for analyses of the primary efficacy endpoint.   
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
• 
The following is a list of 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.  
Category 
Details 
Randomisation Strata  
Randomisation is stratified by baseline third agent class: 
 
• Baseline third agent class (PI, NNRTI, INI). 
 
For analysis purposes, randomisation 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 
13.6.11) 
 
All statistical analyses will adjust for the above randomisation 
strata, unless stated otherwise.  Treatment-by-Strata 
interactions will be assessed as specified in the analysis 
sections. 
Covariates 
• Age (years):  <35, 35 to <50, ≥50 (or continuous) 
• Gender: Male & Female 
• Baseline CD4+ cell count: 
o <200, 200 to <350, ≥350 cells/mm3 (or continuous) 
• Race (White, Black or African American, Asian, Other), or 
(White, Non-White) 
• BMI (<vs. ≥ 25 kg/m2) (or continuous) 
• Smoking status (Never vs. Former vs. Current Smoker),  
• Vitamin D use (Yes vs. No) 
• Diabetes mellitus (Yes vs. No) 
• Hypertension (Yes vs. No) 
• HCV-coinfection (Yes vs. No) 
• Prior TAF duration:  (continuous) 
• Region 
o North America (USA, Canada) 
o Europe (Belgium, France, Germany, Netherlands, 
Spain, UK) 
o Asia/Australia (Japan, Australia) 


 
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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. No subgroup analysis 
planned for W196/W200. 
• 
If the percentage of subjects is small within a particular 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 
Randomisation Strata  
Randomisation is stratified by baseline third agent class: 
 
• Baseline third agent class (PI, NNRTI, INI). 
 
For analysis purposes, randomisation 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 randomisation 
strata, unless stated otherwise.  Treatment-by-Strata 
interactions will be assessed as specified in the analysis 
sections. 
Demographic and Baseline 
Characteristics 
• Age (years):  <35, 35 to <50, ≥50, and <50 vs. >=50 
• An additional split of Age <50 and ≥60, or <60 and ≥60 may 
also be performed if specifically required for regulatory 
purposes) 
• Gender: Male & Female 
• Baseline CD4+ cell count: 
o <200, 200 to <350, ≥350 cells/mm3 
o <500, ≥500 cells/mm3 
o <350, ≥350 cells/mm3 
• CDC HIV-1 classification 
• Country 
• Race: White, Black or African American, Asian, Other; and: 
White vs non-White 
• The prior TAF duration (duration of TAF prior to study 
entry): <1 year, >=1 year 
 
 
 


 
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Subgroup analyses for endpoints will be presented as shown in the table below. 
 
Endpoint 
Subgroup 
Proportion of 
patients with 
plasma HIV-1 
RNA <505 copies 
c/mL6 
Summary of 
Study 
Snapshot 
outcomes 
(Plasma HIV-
1 RNA >=/< 
50 c/mL) 
CD4+ Cell 
Count and 
CD4+/CD8+ 
Ratio Change 
from Baseline 
AEs7 
Baseline third agent class (PI, 
NNRTI, INI) 
Y 
Y 
Y 
Y 
Age (years): <35, 35 to <50, ≥50  
Y 
Y 
Y 
Y 
Age (years): <50, ≥50 
Y 
Y 
 
 
Gender: Male & Female 
Y 
Y 
Y 
Y 
Baseline CD4+ cell count:  <200, 2
00 to <350, ≥350 cells/mm3 and 
<500, ≥500 cells/mm3 and <350, 
≥350 cells/mm3 
Y 
Y 
Y 
Y 
CDC HIV-1 classification: Stage 0-
3 
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 
 
 
5.5. 
Multiple Comparisons and Multiplicity 
The primary comparison of interest is the comparison between DTG + 3TC and TBR 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 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. This subgroup analysis is not applicable 
post Week 48. 
6 Includes forest plot for unadjusted difference of patients with plasma HIV 1 RNA <50 copies c/mL 
between treatment arms. 
7 Subgroup analyses will be presented for the following analyses: Adverse Events by System Organ Class, 
Maximum Toxicity; and Adverse Events Leading to Permanent Discontinuation of Study Treatment or 
Withdrawal from Study (see Section 13.15 Full Data Displays for more information). Not applicable to 
analyses post Week 48.  


 
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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 13.1 
Appendix 1: Protocol Deviation Management 
Section 13.2 
Appendix 2: Schedule of Activities 
Section 13.3 
Appendix 3: Assessment Windows 
Section 13.4 
Appendix 4: Study Phases and Emergent Adverse Events 
Section 13.5 
Appendix 5: Data Display Standards & Handling Conventions 
Section 13.6 
Appendix 6: Derived and Transformed Data 
Section 13.7 
Appendix 7: Reporting Standards for Missing Data 
Section 13.8 
Appendix 8: Values of Potential Clinical Importance 
Section 13.9 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Section 13.10 
Appendix 10: Time to Event Details 
Section 13.11 
Appendix 11: Snapshot 
Section 13.12 
Appendix 12: Abbreviations & Trade Marks 
Section 13.13 
Appendix 13: Model Checking and Diagnostics for Statistical Analyses 
Section 13.14 
Appendix 14: COVID-19 Modified Analysis and Supportive Sensitivity Analyses 
Section 13.15 
Appendix 15: List of Data Displays 
Section 13.16 
Appendix 16: Example Mock Shells for Data Displays 
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 1 provides an overview of the planned study population analyses, with full details of 
data displays being presented in Section 13.15: List of Data Displays. 


 
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Table 1 
Overview of Planned Study Population Analyses 
Display Type 
Data Displays Generated 
Table 
Listing 
Randomisation 
Randomisation 
 
Y [1] 
Subject Disposition 
Subjects Enrolled by Country and Site ID [2] 
Y 
Y 
History of Rescreened Subjects[2] 
 
Y 
Reasons for Screen Failure [2]  
Y 
Y 
Subject Disposition 
Y [3,4, 11,12] 
 
Reasons for Withdrawal by Visit 
Y [11,12] 
Y 
Study Visit Dates   
 
Y 
Populations Analysed 
Study Populations [2] 
Y 
Y 
Protocol deviations 
Important Protocol Deviations 
Y [11,12,13] 
Y 
Deviations leading to exclusion from PP 
Y 
Y 
Inclusion and Exclusion Criteria Deviations 
 
Y 
Demography and baseline characteristics 
Demographic Characteristics[5] 
Y [12] 
Y 
Summary of Age Ranges 
Y 
 
Race & Racial Combinations[6] 
Y [12]  
Y 
Hepatitis C Status 
Y [12] 
Y 
CDC Classification of HIV infection at Baseline 
Y [12] 
Y 
HIV Risk Factor 
Y [12] 
Y 
Cardiovascular Risk Assessments at Baseline 
Y [12] 
Y 
Distribution of Quantitative Plasma HIV-1 RNA 
Y [12] 
Y 
Distribution of CD4+ Cell Counts 
Y [12] 
Y 
History of Cardiac Therapeutic Procedures 
 
Y 
Medical Conditions, Concomitant  Medications & Antiretroviral Therapy 
Medical Conditions (Current and Past)  
Y [11,12] 
Y 
Medical Conditions: Sub-conditions (Current/Past)  
Y [11,12]  
 
Concomitant Medications (non-ART) 
Y[7,11,12] 
Y[8] 
Prior,Concomitant ART and post ART Medications 
Y [11,12] 
Y[9]  
Baseline third agent class (Strata) [10] 
Y [12] 
Y 
Lipid Modifying agents (Baseline and Post-Baseline) 
Y [11,12] 
 


 
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Display Type 
Data Displays Generated 
Table 
Listing 
Other  
History of Depression and Anxiety at Baseline 
Y [12] 
 
Summary of Past and Current Cardiac, 
Gastrointestinal, Metabolism and Nutrition, 
Psychiatric, Renal and Urinary, and Nervous 
System Conditions 
Y [11,12,13] 
 
History of Cardiac Therapeutic Procedures 
 
Y 
Investigational Product Accountability 
 
Y 
Important COVID-19 Protocol Deviations 
Y [11,12,13] 
 
Important non-COVID-19 Protocol Deviations 
Y [11,12,13] 
 
Non-important COVID-19 Protocol Deviations 
 
Y 
Summary of COVID-19 Pandemic Assessments and 
Visit Impacts 
Y [11,12,13] 
Y 
NOTES: 
• 
Y = Display Generated, T = Tables, L = Listings, IP = Investigational Product 
1. ITT-E. One listing of subjects randomised but not treated, and one listing of planned and actual treatment strata. 
2. ITT-E and All Subjects screened population. 
3. Subject Accountability by Phase (Overall, Early Switch Phase, Late Switch 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. Three separate tables, summarised by: 1) Ingredient ATC Level 1, 2) Ingredient combinations and 3) Combination 
term ATC Level 1 (EG Includes single-ingredient medications with multi-ingredient medications labelled according 
to the sum of their ingredients, e.g., “TYLENOL Cold and Flu” would appear as “CHLORPHENAMINE MALEATE 
+ DEXTROMETHORPHAN HYDROBROMIDE + PARACETAMOL +  PSEUDOEPHEDRINE HYDROCHLORIDE” 
under the ATC headings for “Nervous System” and “Respiratory System” (the combination’s ATC classifications).) 
8. One listing for concomitant non-ART medications,one listing showing the relationship between verbatim text, 
ingredient and ATC Level 1 and and one listing showing the relationship between verbatim text, ingredient, 
combination and ATC Level 4. 
9. One listing for Prior ART, one listing for ART received at screening, one listing for concomitant ART starting after 
screening while still on-treatment and one listing for post ART. 
10. Based on the actual third agent class that subjects were classified into according to data captured on the eCRF. 
11. Repeat for the Early + Late Switch Phase for the DTG+3TC arm  
12. Repeat for the Late Phase for the TBR arm 
13. Include Week 200 data 
 
 
 


 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analysis 
7.1.1. 
Summary Measure 
Proportion of subjects with plasma HIV-1 RNA ≥50 copies c/mL at Week 48 using the 
snapshot algorithm. 
7.1.2. 
Population of Interest  
The primary efficacy analyses will be based on the Intent-To-Treat Exposed (ITT-E) 
population unless otherwise specified. 
7.1.3. 
Strategy for Intercurrent (Post-Randomisation) Events 
Intercurrent events will be accounted for as per the FDA snapshot algorithm.  
7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Section 13.15: List of Data Displays and 
will be based on GSK data standards and statistical principles commonly applied in GSK 
HIV-1 trials. 
Table 2 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Section 13.15: List of Data Displays. 
Table 2 
Overview of Planned Primary Efficacy Analyses 
Endpoint 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Proportion of Subjects with plasma HIV 1 RNA ≥50 copies c/mL at week 48 – Snapshot  
Primary Analysis 
Y[1] 
 
Y[4] 
 
 
 
 
Study Outcome [2] 
based on the 
Snapshot  
 
 
 
Y 
 
 
Y 
Sparse Data 
Analysis 
Y[5] 
 
 
 
 
 
 
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. 
[1] Generated using the ‘Intent-to-Treat Exposed’ (primary), ‘Per-Protocol’ and ‘Intent-to-Treat’ (sensitivity) 
populations. 
[2] Study outcomes (i.e., virologic failure, virologic success (response below 50 c/mL) or no virologic data at Week 
X window) based on the snapshot algorithm. 
[3] Line plots, with 95% confidence intervals, for the proportion of subjects with virologic failure by treatment group 
at each visit. 
[4] Listing of Quantitative and Qualitative Plasma HIV-1 RNA Data based on the snapshot algorithm. 
[5] See methodology section below for more information. 


 
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7.1.4.1. 
Statistical Methodology Specification 
Endpoint  
• Proportion of subjects with plasma HIV 1 RNA ≥50 copies c/mL at Week 48 using the 
Snapshot algorithm for the ITT-E population 
• The Snapshot algorithm treats all subjects without HIV-1 RNA data at the visit of interest 
(due to missing data or discontinuation of IP prior to the visit window) as non-responders.  
The nature of this missing data will be further classified in Snapshot summaries as either 
‘Virologic Failure’ or ‘No Virologic Data at Week 48’.  Subjects who change their ART 
regimen prior to the visit of interest will be considered virologic failures since changes in 
ART are not permitted in this protocol (with the exception of a change in the booster ART as 
detailed below). 
• ‘Virologic failure’ includes subjects who changed any ART; subjects who discontinued study 
drug or study before Week 48 for lack or loss of efficacy, discontinued for other reason while 
not < 50 c/mL, and subjects who have HIV-1 RNA ≥ 50 c/mL at the visit of interest. 
• Virologic success includes subjects who have HIV-1 RNA <50 c/mL at the visit of interest. 
• The only protocol-permitted substitutions are as follows: 
o A switch from a PI boosted with RTV to the same PI boosted with cobicistat is 
allowed. 
o A switch from a PI boosted with cobicistat to the same PI boosted with RTV is 
allowed. 
Virologic success or failure will be determined by the last available HIV-1 RNA assessment while 
the subject is On-treatment within the visit of interest analysis window see Section 13.3. Full 
details of the Snapshot algorithm are in Section 13.11.  Note: for Week 96 reporting onwards, 
refer to Section 13.14.1 instead for Modified Snapshot algorithm in presence of COVID-19 
missing data. 
Model Specification 
• The primary endpoint will be analysed using a stratified analysis with Cochran-Mantel-
Haenszel (CMH) weights, adjusting for baseline third agent class (PI, NNRTI, INI).  
• 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: NNRTI 
o Baseline third agent: INI 
• If nk is the number of DTG + 3TC treated subjects, mk is the number of PI-, NNRTI- or INI-
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: 


 
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       where, 
  
are CMH weights and dk are estimates of the differences in virologic failure proportions 
between the two treatment arms, rd-ra, for the kth strata. 
• The corresponding two-sided 95% CI will be calculated as 
 
using the variance estimator, var(dcmh), given by [Sato ,1989], which is consistent in both 
sparse data and large strata.   
(
)
(
)
(
)
(
)
(
)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
−
+
−
=
. 
Model Checking & Diagnostics 
• Not applicable 
Model Results Presentation 
• Adjusted CMH estimate of the difference in the proportion of virologic failure between each 
treatment group (DTG + 3TC – TBR) and corresponding 95% confidence interval. 
• 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 virologic failure in the 
DTG +3TC group minus the proportion of patients with virologic failure in the TBR group is 
less than 4%.   
• If ITT-E and Per Protocol analyses show non-inferiority (see Sensitivity and Supportive 
Analyses section below), then a superiority hypothesis will be tested at the two-sided 5% 
level of significance. Superiority favouring 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.' Figures: Line plots, with 95% confidence intervals, for the 
proportion of subjects >= 50 c/mL as per the FDA snapshot by treatment group at each visit 
(not applicable to analyses post Week 48). 
 
∑
∑
=
k
k
k
cmh
W
d
W
d
ˆ
ˆ
)
ˆ
r(
aˆ
v
96
.1
ˆ
cmh
cmh
d
d
×
±


 
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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 TBR will be tested at the two-sided 5% level of significance (as described 
above).   
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 randomised but not exposed to study treatment will be 
classified as non-responders. 
 
3. A sensitivity analysis will be conducted to assess the impact of sparse data (Miettinen, 
1985).  
• The estimate is computed from Miettinen-Nurminen (score) confidence limits for the 
stratum risk differences. The score confidence interval for the risk difference in stratum h 
can be expressed as 
, where is the midpoint of the score confidence 
interval and is the width of the confidence interval divided by 
. The summary 
score estimate of the common risk difference is computed as:  
 
where  
 
The variance of is computed as  
 
The 
% summary score confidence limits for the common risk difference are:  
. 


 
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7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
• Patients with plasma HIV 1 RNA ≥50 copies c/mL at week 24, 96 and 144.  
• Patients with plasma HIV 1 RNA <50 copies c/mL at weeks 24, 48, 96 and 144.  
• CD4+ cell count at Weeks 24, 48, 96 and 144. 
• CD4+/CD8+ cell count ratio at Weeks 24, 48, 96 and 144. 
• Incidence of disease progression (HIV-associated conditions, AIDS, and death) 
through Weeks 24, 48, 96 and 144. 
7.2.2. 
Summary Measures 
• Proportion of subjects with plasma HIV 1 RNA ≥50 copies c/mL at weeks 24, 96 
and 144 using the snapshot algorithm. 
• Proportion of subjects with plasma HIV 1 RNA <50 copies c/mL at weeks 24, 48, 
96 and 144 using the snapshot algorithm. 
• Change from baseline in CD4+ cell count at Weeks 24, 48, 96 and 144. 
• Change from baseline in CD4+/CD8+ cell count ratio at Weeks 24, 48, 96 and 
144. 
• Incidence of disease progression (HIV-associated conditions, AIDS, and death) 
through Weeks 24, 48, 96 and 144. 
7.2.3. 
Populations of Interest  
The secondary efficacy analyses will be based on the ITT-E population. 
7.2.4. 
Strategy for Intercurrent (Post-Randomisation) Events 
Intercurrent events will be accounted for as per the FDA snapshot algorithm for the 
analyses of secondary endpoints of plasma HIV 1 RNA <50 copies c/mL and plasma HIV 
1 RNA ≥50 copies c/mL. Intercurrent events will not be controlled for in disease 
progression and CD4+ cell count analyses. Intercurrent events as a result of COVID-19 
will be accounted for as per the Modified Snapshot algorithm (see Section 13.14.1) for 
analyses post-Week 48. 
7.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 15: List of Data Displays.  
Table 3 provides an overview of the planned secondary efficacy analyses, with full 
details of data displays being presented in Appendix 15: List of Data Displays. 


 
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Table 3 
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 
Proportion of Subjects with Plasma HIV-1 RNA ≥50 copies/mL–  Snapshot 
Secondary 
analysis at Weeks  
24, 96 and 144 
Y[15] 
 
Y 
 
 
 
 
 
 
 
 
 
 
 
Study Outcome 
based on the 
Snapshot at 
Weeks 24, 96 and 
144 
 
 
 
Y[14] 
 
 
Y 
 
 
 
 
 
 
 
By Visit 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Proportion of 
subjects without 
virologic 
or 
virologic/tolerability 
failure at Week 
X[10]   
Y 
Y[11] 
 
 
 
 
Y 
 
 
 
 
 
 
 
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL –  Snapshot 
Secondary 
analysis at Week 
X[6]  
Y[12,1
3, 15]   
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary 
analysis by Visit 
through Week X[6]   
 
 
 
Y 
Y 
 
 
 
 
 
 
 
 
 
Secondary 
analysis by 
subgroup at Week 
X[6]   
 
 
 
Y 
Y[1] 
 
 
 
 
 
 
 
 
 
Study Outcomes 
at Week X[6]   
 
 
 
Y[12, 
16]  
 
 
 
 
 
 
 
 
 
 
Study Outcomes 
by subgroup at 
Week X[6] 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 


 
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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 
Confirmed Virologic Withdrawal (CVW) 
CVW by Visit   
Y 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
HIV-1 RNA 
distribution at time 
of suspected and 
confirmed 
Virologic 
withdrawal 
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] Y[2,9] 
 
 
 
Y[5,16] 
 
 
 
CD4+ Cell Counts[3]   
By Visit through 
Week X[6] 
 
 
 
 
 
Y[2] 
Y 
 
 
 
Y[16] 
 
 
Y 
By Subgroup at 
Week X[6] 
 
 
 
 
 
 
 
 
 
 
Y 
 
 
 
CD4+/CD8+ Cell Count Ratio[3]     
By Visit through 
Week X[6] 
 
 
 
 
 
Y[2] 
Y 
 
 
 
Y[16] 
 
 
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[16,
17] 
 
 
Y 
 
 
 
 
 
 
 
HIV Conditions 
excluding 
Recurrences at 
Week X[6,7]  
 
 
 
Y[16,
17] 
 
 
 
 
 
 
 
 
 
 
HIV Disease 
Progressions at 
Week X[6,8] 
 
 
 
Y[16,
17] 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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. 
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 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 96 and week 144. 
7. Stage 3 only. 
8. Progression to Stage 3 or death. 
9. Includes target detected/not detected flag see Section 13.6.3 for more information.  
10. Outputs will be produced for Efficacy related discontinuation = Failure (ERDF) and Treatment related 
discontinuation = Failure (TRDF). 
11. Kaplan-Meier Plot of Time to Failure – ERDF/TRDF. 
12. Repeated on the following endpoints: <40 c/mL and <40 c/mL and Target Not Detected Status. For Week 96 
reporting onwards, analyses will be based on Modified Snapshot algorithm relevant to 40 c/mL and <40 c/mL 
and Target Not Detected Status endpoints (see Section 13.14.1 for more details) 
13. Repeated for the withdrawal bias sensitivity analysis 
14. To be based on Modified Snapshot algorithm (see Section 13.14.1 for more details). Note this is only relevant 
to analyses performed at Week 96 onwards.  
15. Repeated as a sensitivity analysis based on Evaluable Efficacy Population (see Section 13.14.1 for more 
details), for endpoints HIV-1 RNA >=50 c/mL, <50 c/mL and <40 c/mL and TND. Note this is only relevant to 
analyses performed at Week 96 onwards. 
16. Repeat for the Early + Late Switch Phase for the DTG+3TC arm and for the Late Phase for the TBR arm 
17. Week 200 data to be included 
 
7.2.5.1. 
Statistical Methodology Specification 
Endpoint  
• Proportion of subjects with plasma HIV 1 RNA ≥50 copies c/mL at Weeks 24, 96 and 144, 
and plasma HIV 1 RNA <50 copies c/mL at Week 24, Week 48, Week 96 and Week 144 
using the Snapshot algorithm for the ITT-E population.   
• 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.  


 
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• Proportion subjects with plasma HIV 1 RNA ≥50 copies c/mL will be analysed at Weeks 24, 
96 and 144. Proportion subjects with plasma HIV 1 RNA <50 copies c/mL will be analysed at 
Week 24, Week 48, Week 96 and Week 144  
• For virologic success (plasma HIV-1 RNA <50 c/mL) endpoint, non-inferiority of switching to 
DTG + 3TC compared to continuation of TBR (as per FDA snapshot algorithm) will be 
assessed using a -8% 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 -8%. Figures: Line plots, with 95% confidence intervals 
(figures not applicable for analyses post Week 48). 
Subgroup Analyses 
• Subgroup analyses will be performed for the proportion of patients with plasma HIV 1 RNA 
<50 copies c/mL, study outcomes and unadjusted difference in proportion of patients with 
plasma HIV 1 RNA <50 copies c/mL between treatment arms forest plot at Week 24,Week 
48, Week 96 and Week 144 endpoints only. 
Sensitivity and Supportive Analyses 
1. A sensitivity analysis will be performed on the proportion of patients with plasma HIV-1 RNA 
<50 c/mL endpoint at Week 48, Week 96 and Week 144. For this analysis, patients who 
withdrew from the study due to the prolongation of the study as defined in the protocol 
amendment 6 (as captured on the study discontinuation CRF) before providing virologic data 
within the analysis window of interest will be removed from the denominator in both arms. 
The purpose of this analysis is to investigate the impact of snapshot categorisation bias that 
may be introduced in the event of a higher withdrawal rate in the TBR arm. The Cochran-
Mantel-Haenzel approach will then be followed as described in the primary analysis section. 
2. A sensitivity analysis based on the <50 HIV-1 RNA endpoint will be performed based on the 
same analysis for the following endpoints: 
• Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL at Week X 
• Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL and Target Not Detected Status at 
Week X 
• Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL and Target Not Detected Status at 
Week X by Baseline Third Agent Class (not applicable for analyses post Week 48) 
3. 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-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 Section 13.10. 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 X will be presented 
by treatment group, along with estimated difference in proportions between treatment 
groups and its associated two-sided 95% CI.  
 
 


 
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7.3. 
Exploratory Efficacy Analyses 
7.3.1. 
Endpoint / Variables 
Randomised Early Switch Phase analyses:  
• Subjects with plasma HIV-1 RNA <50 c/mL using the Snapshot algorithm at 
Week 24, 48, 96 and 144 by subgroup, based on the ITT-E population. 
• Change from baseline CD4+ and CD4+/CD8+ ratio cell counts at Week 24, 48, 
96 and 144 by subgroup 
For subjects in the DTG + 3TC arm since Early Switch Phase and for subjects (TBR arm) 
switching to DTG + 3TC in the Late Switch Phase:   
• Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 196 using the 
Snapshot algorithm for the ITT-E population for DTG+3TC arm and LS-ITT-E 
population for subjects in TBR arm switched to DTG+3TC in the Late Switch 
Phase  
•  Change from Baseline in CD4+ lymphocyte count and in CD4+/CD8+ cell count 
ratio at Week 196 
• Incidence of disease progression (HIV associated conditions, AIDS and death) 
through Week 196 
These analyses have been specified in previous sections.  
8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population (and Late-Switch Safety 
Population, where applicable), unless otherwise specified.   
For Week 24, 48 96 and 144 analyses, outputs will be presented for the Early Switch 
Phase unless otherwise specified.  
For W196 analysis,\ 
• For subjects in the DTG + 3TC arm since Early Switch Phase, outputs will be 
presented for Early and Late Switch Phase [DTG + 3TC arm only]  
• For subjects switching to DTG + 3TC in the Late Switch Phase, outputs will be 
presented for Late Switch Phase [TBR arm switching to DTG + 3TC]).  
Safety data presented through weeks 24,48, 96, 144 and 196 will comprise all available 
safety data collected at that time point within the phase reported.The safety endpoints 
collected at Week 200 will be included in Week 196 outputs. 


 
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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 15: 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.  
In the event withdrawal rate due to PAM6 study design change is higher in the TBR arm, 
similar sensitivity analyses to that stated for the HIV-1 RNA <50 c/mL endpoint as 
detailed in Section 7.2.5.1  considered for some AE analyses at Weeks 96 and 144.  
Table 4 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays. 
Table 4 
Overview of Planned Safety Analyses 
Endpoint 
 
Absolute 
 
Summary 
Individual 
T 
F 
F 
L 
Exposure 
Extent of Exposure 
Y[1] [9] 
 
 
Y[2] 
Adverse Events[3] 
All AEs by SOC and PT 
Y[1] [9] 
 
 
Y 
All AEs by Maximum Grade[3] 
Y[9] 
 
 
Y[4] 
Common AEs by freq [5] 
Y[9] 
Y[6] 
 
 
Common Grade 2-5 AEs [5] 
by freq 
Y[9] 
 
 
 
Drug-Related AEs by SOC 
and PT 
Y[9] 
 
 
Y 
All Drug-Related AEs by 
SOC and Maximum Grade[3] 
Y[1] [9] 
 
 
 
Common non-Serious AEs 
by SOC and PT (subjects 
and number of occurrences) 
Y 
 
 
 
Common Drug-related Grade 
2-5 AEs [5] 
Y[9] 
 
 
 
Common Non-Serious AEs 
(FDAAA) 
Y[9] 
 
 
 
Cumulative AEs by visit 
Y 
 
 
 


 
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Endpoint 
 
Absolute 
 
Summary 
Individual 
T 
F 
F 
L 
Drug-Related AE leading to 
withdrawal from study 
Y[9] 
 
 
 
AEs Leading to Withdrawal 
from Study / Permanent 
Discontinuation of Study 
Treatment[8] 
Y[1] [9] 
 
 
Y 
Serious and Other Significant AEs 
All SAEs by SOC 
Y[1] [9] 
 
 
 
Fatal SAEs  
 
 
 
Y 
Non-Fatal SAEs 
 
 
 
Y 
All Drug-Related SAEs by 
SOC 
Y[9] 
 
 
 
Drug-Related Non Fatal 
Serious AEs 
 
 
 
Y 
Drug-Related Fatal Serious 
AEs 
Y[9] 
 
 
Y 
Serious AEs by SOC and PT 
Y[9] 
 
 
 
Reason for Considering as a 
Serious Adverse Event  
 
 
 
Y  
Possible Suicidality-Related 
Adverse Event (PSRAE) 
 
 
 
Y[7] 
Cardiovascular events 
 
 
 
Y 
NOTES : 
• 
T = Table, F = Figures, L = Listings, 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.  
1. Repeat for the Early + Late Switch Phase for the DTG + 3TC arm and for the Late Phase for the TBR arm (Late 
Phase outputs to be included in an amendment of the RAP). 
2. Includes reason for any dose change/interruption in both arms. 
3. For AEs reported more than once by a subject, the most severe intensity will be included. 
4. 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. 
5. Common AEs are those with >=2% (or 0.5% for drug-related grade 2-5 AEs) incidence in either treatment group 
summarised by frequency. 
6. Plots of incidence rates and relative risk with 95% CI for DTG+3TG vs. TBR. 
7. Four PSRAE listings: Event and Description (Section 1 to Section 2), Possible Cause (Section 3), Section 4 and 
Section 5 to Section 8 (see ICH Listings Section 13.15.14). 
8. Repeated by maximum grade as well. 
9. Repeat for the Early + Late Switch Phase for the DTG+3TC arm and for the Late Phase for the TBR arm at Week 
196 and including Week 200 datag 
 


 
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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. 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 5 and full 
details of the planned displays are provided in Appendix 15: List of Data Displays. 
Table 5 
Overview of Planned Adverse Events of Special Interest Analyses 
Endpoint 
 
Absolute 
 
Summary 
Individual 
T 
F 
F 
L 
Adverse Events of Special Interest 
Characteristics of Post 
Baseline AESI 
Y[1] 
 
 
 
Onset and Duration of the 
First Occurrence of Post 
Baseline AESI 
Y[1] 
 
 
 
Post Baseline 
Depression, Suicidal and 
Self-Injury Adverse 
Events by AE of Special 
Interest, Maximum DAIDS 
Toxicity Grade, and Prior 
History of Depression and 
Anxiety 
Y[1] 
 
 
 
NOTES : 
• 
T = Table, F = Figures, L = Listings, 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.  
1. Repeat for the Early + Late Switch Phase for the DTG+3TC arm and for the Late Phase for the TBR arm at Week 
196 and including Week 200 data 
 
8.3. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and Liver Function tests will be based on GSK Core Data 
Standards. Table 6 provides an overview of the planned laboratory analyses, with full 
details of data displays being presented in Appendix 15: List of Data Displays. 
 


 
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Table 6 
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  
Y 
 
 
Y[1] Y[9,10] 
 
 
 
 
 
 
 
 
 
Lipids (%) 
 
 
 
 
Y[4,9] 
 
 
 
 
 
 
 
 
 
Fasted Lipid 
(Triglycerides, 
LDL, HDL and TC 
and TC/HDL)  
Y[4]   
 
 
 
Y[4]  
 
 
 
Y 
Y 
 
 
 
 
Hematology  
Y 
 
 
Y[1] Y[9,10] 
 
 
 
 
 
 
 
 
 
Urine Dipstick 
 
 
 
Y[1] 
 
 
 
 
 
 
 
 
 
 
Urine 
Concentration 
 
 
 
Y[1] 
 
 
 
 
 
 
 
 
 
 
Liver Chemistries 
 
 
 
 
 
 
 
 
 
 
 
Y[2] 
 
  
NCEP shifts in 
lipids 
 
 
 
 
Y[4] [9] Y[3,4] 
 
 
 
 
Y[4] Y[3,4] 
 
 
Total 
Cholesterol/HDL 
ratio  
 
 
 
 
Y[4] [9] Y[3,4] 
 
 
 
 
Y[4] Y[3,4] 
 
 
Biomarkers 
Bone biomarkers 
 
 
 
Y 
Y[9] 
 
 
Y 
Y 
Y 
 
 
 
 
Bone biomarkers 
(%) 
 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
Renal biomarkers 
 
 
 
Y 
Y[9] 
 
 
Y 
Y 
Y 
 
 
 
 
Renal biomarkers 
(%) 
 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
Inflammation 
Biomarkers 
 
 
 
Y 
Y[9]  
 
 
Y 
Y 
 Y 
 
 
 
 
Telomere length[8] 
 
 
 
Y 
Y[9] 
 
 
Y 
 
 
 
 
 
 
Change from 
baseline in HOMA-
IR at Week 24, 48, 
96 and 144 
 
 
 
Y 
Y[9] 
 
 
Y 
Y[5] 
 Y 
 
 
 
 
HOMA-IR vs 
weight scatter plot 
 
 
 
 
 
 
Y[6] 
 
 
 
 
 
 
 
HOMA-IR shift 
table[7] 
 
 
 
 
Y[9] 
 
 
 
 
 
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 
Emergent Laboratory Toxicities 
Clinical Chemistry 
 
 
 
 
 
 
 
 
 
 
Y[9, 
10] 
 
 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
Y[9, 
10] 
 
 
 
Fasting LDL 
Cholesterol 
Abnormalities of 
Grade 2 or 
Greater 
  
 
 
 
 
 
 
 
 
 
Y[4] 
[9] 
 
 
 
AST, ALT and 
Total Bilirubin 
Maximum Post-
Baseline 
Emergent Toxicity 
By Baseline 
Hepatitis C Status 
 
 
 
 
 
 
 
 
 
 
Y[9, 
10] 
 
 
 
NOTES : 
• 
T = Table, F = Figures, L = Listings, 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.  
1. Listings for subjects with abnormalities for potential clinical concern/importance, defined as any Grade1-5 toxicity.  
2. Scatter plot of baseline vs. maximum post-baseline for ALT. Scatter plot of maximum ALT vs. maximum Bilirubin.  
3. Bar chart for LDL, HDL, TC, Trig and TC/HDL ratio. 
4. Subjects on lipid-lowering agents at baseline are not included in summaries, see Lipids. Section 13.7.2 for more 
details. 
5. Not performed at Week 24. Also repeated on HOMA-IR >=2 endpoint (logistic regression) at Week 96 and Week 
144 (dependent on degree of missing data resulting from COVID-19 – see below for further details). 
6. A scatter plot of change in HOMA-IR (y-axis) vs change in weight (x-axis) at Weeks 24, 48. 
7. See Section 13.6.4 for more details. 
8. Presented at Week 196 only. 
9. Repeat for the Early + Late Switch Phase for the DTG + 3TC arm and for the Late Phase for the TBR arm at 
Week 196 
10. Week 200 data to be included 
 
 
 
 


 
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Statistical Analyses 
Endpoints 
• Change from baseline in bone biomarkers marker (bone specific alkaline phosphatase, 
procollagen type I N-terminal propeptide, type I collagen cross-linked C-telopeptide, 
osteocalcin, 25-hydroxyvitamin D) at Weeks 24, 48, 96 and 144 
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) 
• Vitamin D use (Yes vs. No) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• 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 TBR. 
• 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 (ie. 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). 
• Interactions between treatment and each of the covariates will not be assessed. 
Model Checking & Diagnostics 
• Refer to Section 13.13: 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 – TBR) 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. 


 
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Statistical Analyses 
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 
 
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, 48, 96 and 144 
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) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• 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 TBR. 
• 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 (ie. 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 (ie. baseline value*visit 
interaction will be included in the model). 
• Interactions between treatment and each of the covariates will not be assessed.  
 
 


 
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Statistical Analyses 
Model Checking & Diagnostics 
• Refer to Section 13.13: 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 – TBR) 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 
 
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 48, 96 and 144 
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) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• 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 TBR. 
• 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. 


 
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Statistical Analyses 
• 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 (ie. 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 Section 13.13: 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 – TBR) 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 
• Not applicable 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 
 
Statistical Analyses 
Endpoints 
• Change from baseline in HOMA-IR at Weeks 48, 96 and 144 (refer to Section 13.6.4 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) 
• Hypertension (Yes vs no) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• If change in HOMA-IR 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 HOMA-IR for the comparison between DTG + 3TC 
and TBR. 


 
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Statistical Analyses 
• Using OC dataset, the Mixed Model Repeated Measures (MMRM), using the observed 
margins (OM) option, will adjust for treatment, covariates (listed above) and baseline HOMA-
IR 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 (ie. 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 Section 13.13: 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 – TBR) and corresponding 95% confidence interval and p-value. 
• Note: If change from baseline in HOMA-IR 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 and Supportive 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 
>=2  at Week 96 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. Odds ratios for CD4+, age 
and BMI will be presented on the 100 cells,10-years and unit incremental scale respectively. 
This analysis will be repeated on the proportion of subjects with HOMA-IR>=2 at Week 144. 
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 96 as a result of 
COVID-19 is substantial, the logistic regression analysis may not be performed.  
Subgroup Analyses 
• Not applicable 
 
Statistical Analyses 
Endpoints 
• Change from baseline in fasting lipids (Total Cholesterol, HDL, LDL, Triglycerides and Total 
Cholesterol/HDL ratio) at Week 96 and 144 
Covariates & Factors 
• Baseline 3rd Line Agent  
• CD4+ cell count (continuous) 
• Age (continuous) 
• Race (White, Black or African American, Asian, Other) 


 
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Statistical Analyses 
• BMI (continuous) 
Data Handling 
• No multiple imputation techniques will be used to deal with the missing data. 
Model Specification 
• Provided assumptions are satisfied, lipid data willl be log transformed and geometric mean 
ratios with 95% CIs will be presented. Mean changes from baseline will be presented as 
geometric mean ratios. 
• Change from baseline will be analysed for each lipid for the comparison between DTG + 3TC 
and TBR. 
• Using OC dataset, the Mixed Model Repeated Measures (MMRM), using the observed 
margins (OM) option, will adjust for treatment, covariates (listed above) and baseline fasted 
lipid 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 (ie. 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.   
• Lipid parameters only summarised on fasting data. Lipid parameter data collected after the 
introduction of a lipid-modifying agent are censored and an LOCF method applied such that 
the last available fasted, on-treatment lipid value prior to the initiation of a lipid-lowering 
agent is used in place of future, observed values. Subjects on lipid-lowering agents at 
baseline are excluded. 
Model Checking & Diagnostics 
• Refer to Section 13.13: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• 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 geometric means with 95% confidence intervals for geometric mean ratio 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 7 and full details of the planned displays are presented in Appendix 12 Section 
13.15: List of Data Displays.  Note that ECGs and vital signs are only collected at 
screening, so will only be listed. 
 


 
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Table 7 
Overview of Other Safety Analyses 
Endpoint 
 
Absolute 
 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
Stats 
Analysis 
T 
F 
F 
L 
T 
F 
F 
L 
T 
F 
Other 
ECG at screening 
 
 
 
Y 
 
 
 
 
 
 
Vital Signs 
 
 
 
Y 
 
 
 
 
 
 
Liver Assessment 
Y[7] 
 
 
Y  
 
 
 
 
 
 
Hepatobiliary 
Abnormality criteria 
Y[3, 4] 
[7] 
 
 
Y[3, 4] 
 
 
 
 
 
 
eC-SSRS 
Y[7] 
 
 
Y[1] 
 
 
 
 
 
 
Subjects who became 
Pregnant 
 
 
 
Y 
 
 
 
 
 
 
Patient Profiles 
 
 
 
Y[2] 
 
 
 
 
 
 
Weight, by visit 
Y 
 
 
 
Y[7,8] 
 
 
 
Y 
Y 
BMI, by visit 
Y 
 
 
 
Y[7,8] 
 
 
 
Y 
Y 
BMI category shifts from 
baseline 
 
 
 
 
Y 
 
 
 
 
 
Waist to height ratio at 
Week 144 
Y[7] 
 
 
 
Y[9]  
 
 
 
 
 
Waist to hip ratio at 
Week 144 
Y[7] 
 
 
 
 Y[9] 
 
 
 
 
 
Proportion of subjects 
with Metabolic syndrome 
at Week 144[5] 
Y[7] 
 
 
 
 
 
 
 
 
 
Framingham Risk Score 
at Week 144[6] 
 
 
 
 
Y[7] 
 
 
 
 
 
SBP and DBP at week 
144 
 
 
 
 
Y[7,8] 
 
 
 
 
 
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 virologic failure. 
Patient profiles can also be provided for any other subjects. 
3. All post-baseline abnormalities meeting Hepatobiliary Abnormality Criteria. 
4. Repeat for the Early + Late Switch Phase for the DTG + 3TC arm and for the Late Phase for the TBR arm (Late 
Phase outputs to be included in an amendment of the RAP). 
5. See Section 13.6.4 for more details on Metabolic syndrome derivation. 
6. See Section 13.6.2 for more details on Framingham Risk Score 
7. Repeat for the Early + Late Switch Phase for the DTG + 3TC arm and for the Late Phase for the TBR arm at 
Week 196 
8. Week 200 data to be included 
9. For Late Switch Phase only 
 


 
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Statistical Analyses 
Endpoints 
• Change from baseline in weight (kg) and BMI (kg/m2) at Weeks 24, 48, 96 and 144  
Covariates & Factors 
• Baseline 3rd Line Agent  
• CD4+ cell count (continuous) 
• Age (continuous) 
• Sex (Female vs. Male) 
• Race (White, Black or African American, Asian, Other) 
• Prior TAF duration (Continuous) 
• Region (North America, Europe, Asia/Australia) 
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 TBR. 
• 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 Section 13.13: 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 – TBR) 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. 


 
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Statistical Analyses 
Subgroup Analyses 
• Subgroup analysis (including summary table and figure) will be performed for change 
from baseline in weight by BMI category(underweight/normal, overweight, obese). 
Analysis will be performed as described above and will adjust for the covariates listed 
above, treatment, visit, BMI subgroup category, treatment*visit interaction, 
treatment*subgroup, subgroup*visit, treatment*subgroup*visit interaction terms with visit 
as the repeated factor regardless of their significance. Exclude Baseline Weight 
(continuous) from the model to avoid collinearity with Baseline BMI Category. 
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. 
Full details of data displays being presented in Section 13.15: List of Data Displays. 
9.1.2. 
Planned Health Outcomes Statistical Analysis 
Statistical Analyses 
Endpoint(s) 
• Change from baseline in EQ-5D-5L Utility Score at Weeks 24, 48, 96 and 144 
• Change from baseline in EQ Visual Analogue Scale (VAS) at Weeks 24, 48, 96 and 144 
Covariates & Factors 
• Baseline 3rd Line Agent 
Data Handling 
• LOCF dataset will be used.  
Model Specification 
• If HO endpoints will 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. 
• Any missing values should be imputed using LOCF. In the last observation carried forward 
(LOCF) dataset missing values will be carried forward from the previous, non-missing 
available On-treatment assessment from the same dimension. This technique will be applied 
for all missing values, regardless if the subject discontinued the treatment. Missing total 
values can then be calculated using a combination of present and carried forward individual 
items. 
• With LOCF dataset, Mixed Model Repeated Measures (MMRM), using the observed 
margins (OM) option, will adjust for treatment, covariates (listed above) and baseline EQ-
5D-5L value as a covariate, with visit as the repeated factor. 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (ie. 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 (ie. baseline score*visit 
interaction will be included in the model). 


 
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Statistical Analyses 
• 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). 
Model Results Presentation 
• Adjusted means and corresponding standard errors (SEs) of adjusted means will be 
presented for each treatment by visit, together with estimated treatment difference (DTG + 
3TC – TBR) and corresponding 95% confidence interval and p-value.  
• Figures showing the adjusted mean change from baseline with 95% CIs for each treatment 
group across visits in EQ-5D-5L Utility Score and EQ Visual Analogue scale.   
• Figures to show the differences for subjects treated with DTG + 3TC compared to TBR in 
adjusted mean change from baseline with 95% CIs in Utility Score and Visual Analog Scale 
at each visit. 
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 (and LS-CVW, LS-pPVW, LS-populations, LS-Virologic 
Genotypic and LS-Virologic Phenotypic populations where applicable). Please see 
Section 13.6.3 for details of the derivation of CVW. Please see Section 4 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 at the time point of the SVW (or first elevation 
if this was >=50 c/mL and <200 c/mL). Listings will present CVWs occurring at any 
point, and within the analysis visit in which the CVW date occurred. CVWs must be 
confirmed within the phase in which they are reported. Full details of data displays being 
presented in Appendix 15: List of Data Displays. 
Table 8 provides an overview of the planned virology analyses, with full details of data 
displays being presented in Section 13.15: List of Data Displays. 
Reisistance testing will also be performed on any participant with a last on-treatment 
plasma HIV-1 RNA >=400 c/mL. 


 
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Table 8 
Overview of Planned Virology Analyses 
Endpoint  
Absolute 
Summary 
Individual 
T 
F 
F 
L 
Genotypic resistance 
Incidence of genotype at time of CVW[1] 
Y[2,6] 
 
 
Y[4] 
Phenotypic resistance[5] 
Incidence of phenotype at time of CVW[1] 
Y[3,6] 
 
 
Y[4] 
INI replication capacity at time of CVW[1] 
 
 
 
Y[4] 
Fold Change at CVW 
Y[6] 
 
 
 
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 a subject confirms virologic failure at a subsequent visit. Occasionally, if the viral load sample of 
SVW timepoint is below the assay cut-off (<400 c/mL), resistance testing using CVW timepoint sample may be 
atttemped.  
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 population (athough not for pPVW populations for Week 96 or Week 
144). 
5. Phenotypic data are not generated for Baseline using proviral -DNA GenoSure Archive assay  
6. Repeat for the Early + Late Switch Phase for the DTG+3TC arm and for the Late Phase for the TBR arm at 
Week 196 


 
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10. 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic analyses are not applicable to analyses post Week 48.  
Steady state plasma PK parameters of DTG and 3TC will be assessed using intensive PK 
collected at week 4 in a sub-set of subjects. PK concentrations summaries for intense and 
Sparse PK will be performed. 
10.1. 
Pharmacokinetic Analyses 
10.1.1. Endpoint / Variables 
10.1.1.1. Drug Concentration Measures 
All PK concentration listing displays will be based on the Intensive and Sparse 
Pharmacokinetic populations. Concentrations of DTG and 3TC in plasma will be listed and 
summarized according to GSK standards, where applicable (Refer to Appendix 5: Data 
Display Standards & Handling Conventions (Section 13.5.3 Reporting Standards for 
Pharmacokinetic)).  
DTG and 3TC concentration listings for the intensive PK population will be sorted by 
subject and time relative to dose, noting the study visit; summaries will be presented by 
study visit and time relative to dose. 
DTG and 3TC concentration listings for the sparse PK population will be sorted by subject, 
study visit and time (or sampling window) relative to dose; summaries will be presented 
by study visit and time (or sampling window) for weeks 4, 24, 36, and 48 and by sampling 
window for weeks 8 and 12.  Patient profiles refer to a collection samples collected 
sequentially with regard to the dosing schedule for the intensive PK population. Please 
refer to Section 13.3.2 for definitions of assessment windows for inclusion of PK 
concentrations in summary statistics. Please refer to Section 13.6.10 for rules around data 
derivation and imputation. Please refer to Section 13.6.5 for rules regarding exclusions for 
the intensive and sparse PK populations. Please refer to the protocol for more information 
regarding the sparse and intensive populations and dosing schedules. 
10.1.1.2. Derived Pharmacokinetic Parameters for subjects participating in the 
intense PK sub-study 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin 5.3 or higher. All calculations of non-compartmental parameters will be 
based on actual sampling times. Pharmacokinetic parameters listed will be determined 
from the plasma concentration-time data, as data permits.  
Parameter 
Parameter Description 
Cmax 
3TC and DTG maximum observed plasma concentration, determined directly from 
the concentration-time data 
tmax 
3TC and DTG time to reach Cmax, determined directly from the concentration-time 
data 
Cτ 
3TC and DTG observed plasma concentration at the end of the dosing interval, 
determined directly from the concentration-time data 


 
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Parameter 
Parameter Description 
C0 
3TC and DTG observed pre-dose plasma concentration, determined directly from 
the concentration-time data 
AUC(0-τ) 
3TC and DTG area under the concentration-time curve in one dosing interval 
10.1.2. Summary Measure 
Not applicable. 
10.1.3. Population of Interest  
The primary pharmacokinetic analyses will be based on the Sparse and Intensive 
Pharmacokinetic Populations population, unless otherwise specified. 
10.1.4. Strategy for Intercurrent (Post-Randomisation) Events 
Not applicable. 
10.1.5. Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 15: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
Table 9 provides an overview of the planned analyses, with full details being presented in 
Appendix 15: List of Data Displays. 
Table 9 
Overview of Planned Pharmacokinetic Analyses 
End Point 
Untransformed 
Log-Transformed 
Stats Analysis 
Summary 
Individual 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
F 
L 
Intensive PK Concentrations 
Plasma 3TC 
Concentrations 
 
 
 
Y 
Y 
Y 
Y 
Y 
Y 
 
 
Plasma DTG 
Concentrations 
 
 
 
Y 
Y 
Y 
Y 
Y 
Y 
 
 
Sparse PK Concentrations 
Plasma 3TC 
Concentrations 
by Visit and 
sampling 
window  
 
 
 
Y 
Y 
 
Y 
 
 
 
 
Plasma DTG 
Concentrations 
by Visit and 
 
 
 
Y 
Y 
 
Y 
 
 
 
 


 
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End Point 
Untransformed 
Log-Transformed 
Stats Analysis 
Summary 
Individual 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
F 
L 
sampling 
window 
Intensive PK Parameters 
Plasma 3TC 
Parameters 
 
 
 
Y 
 
 
Y 
Y 
 
 
 
Plasma DTG 
Parameters 
 
 
 
Y 
 
 
Y 
Y 
 
 
 
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. 
1. Individual = Represents FL related to any displays of individual subject observed raw data. 
 
11. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
Population PK analyses are not applicable to analyses post Week 48. 
If data permits, the sparse concentrations of 3TC and DTG collected at weeks 4, 8, 12, 
24, 36 and 48 will be pooled with the intensive PK concentrations and potentially data 
from other studies to perform integrated PK analyses for DTG and 3TC. The primary 
goal of this analysis is to characterize the population pharmacokinetics of 3TC and DTG 
administered as a dual regimen maintenance treatment for HIV in participants who are 
virologically suppressed.  The influence of subject demographics, baseline 
characteristics, including disease activity, and co-medication on the pharmacokinetics of 
3TC and DTG in this population will be investigated. The individual subject PK 
parameters will be estimated and documented for the purposes of any subsequent 
exposure response (PK/PD) analyses. The PopPK analyses for DTG and 3TC will be 
performed under a separate RAP and will be reported separately. 
Further details to be included in a separate RAP. 
 


 
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12. 
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. 
Devlin N., Shah K., Feng Y., Mulhern B, Hout VB. Valuing Health-Related Quality of 
Life: An EQ-5D-5L Value Set for England. Office of Health Economics, 2016 
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  
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.   
Kalbfleisch J.D., Prentice R.L. The Statistical Analysis of Failure Time Data. 1st ed. New 
York: John Wiley & Sons; 1980.  
Klingenberg. A new and improved confidence interval for the Mantel-Haenszel risk 
difference. Statistics in Medicine. 2014; 2968-2983. 
Levey A.S., Stevens L.A., Schmid C.H., Zhang Y.L., Castro A.F. 3rd, Feldman H.I., 
Kusek J.W., Eggers P., Van Lente F., Greene T., Coresh J. CKD-EPI (Chronic Kidney 
Disease Epidemiology Collaboration). A New Equation to Estimate Glomerular Filtration 
Rate. Ann Intern Med 2009;150(9):604-612. 
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. 
Ralph B. D’Agostino, Ramachandran S. Vasan, Michael J. Pencina, Philip A. Wolf, Mark 
Cobain, Joseph M. Massaro, William B. Kannel. 2008. General Cardiovascular Risk 
Profile for Use in Primary Care (The Framingham Heart Study). Circulation 2008; 117: 
743-753. 
Sato T. On the variance estimator for the Mantel-Haenszel risk difference. Biometrics. 
1989;42:311-323.  
 


 
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13. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 13.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 13.2 
Appendix 2: Schedule of Activities 
Section 13.3 
Appendix 3: Assessment Windows 
Section 13.4 
Appendix 4: Study Phases and Emergent Adverse Events 
Section 13.5 
Appendix 5: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 13.6 
Appendix 6: Derived and Transformed Data 
Section 13.7 
Appendix 7: Reporting Standards for Missing Data 
• Premature Withdrawals 
• Handling of Missing Data 
• Handling of Missing and Partial Dates 
Section 13.8 
Appendix 8: Values of Potential Clinical Importance 
Section 13.9 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses  
Section 13.10 
Appendix 10: Time to Event Details 
Section 13.11 
Appendix 11: Snapshot 
Other RAP Appendices 
Section 13.12 
Appendix 12: Abbreviations & Trade Marks 
Section 13.13 
Appendix 13: Model Checking and Diagnostics for Statistical Analyses 
Section 13.14 
Appendix 14: COVID-19 Modified Analyses and Supportive Sensitivity 
Analyses 
Section 13.15 
Appendix 15: List of Data Displays 
Section 13.16 
Appendix 16: Example Mock Shells for Data Displays 
 


 
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13.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
13.1.1. 
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 Description 
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 
randomised 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 
CONART 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, Oxcarbazepine, 
Phenobarbital, Phenytoin, St. John's wort 
(Hypericum perforatum), rifampin 
06 
Concomitant use of rifapentine 
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 144 
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 


 
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Number 
Exclusion Description 
11 
Dofetilide or pilsicainide used concurrently 
with DTG 
12 
Subject's change (i.e., substitution or dose 
modification) of DTG, 3TC or component of 
TBR (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, which are defined in a separate protocol 
deviations specification document. 
Please refer to Section 13.6.9 regarding cut-off dates regarding protocol deviations 
leading to exclusion from the per protocol set. 


 
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13.2. 
Appendix 2: Protocol Defined Schedule of Activities 
13.2.1. Early Switch Phase Time and Events Table (Screening to Week 148)  
Procedures 
Screening Visita 
Open-label Randomised Early Switch Phase 
Switch 
Visit 
Withdrawal 
Follow-upd 
Baseline / 
Day 1 
Week 
4 
8 
12 
24 
36 
48 
60 
72 
84 
96 
108 
(optional)b 
120 
132 
(optional)b 
144 
148c 
Clinical and Other Assessments 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteriae 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior ART history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular risk 
assessment, including 
vital signsg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs: Resting 
Blood pressure (see 
Section 7.4.4 and 
Appendix 10 of 
Protocol)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Body Weight (BMI will 
be calculated within the 
eCRF) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
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Procedures 
Screening Visita 
Open-label Randomised Early Switch Phase 
Switch 
Visit 
Withdrawal 
Follow-upd 
Baseline / 
Day 1 
Week 
4 
8 
12 
24 
36 
48 
60 
72 
84 
96 
108 
(optional)b 
120 
132 
(optional)b 
144 
148c 
Vital Signs: Hip and 
waist circumference 
(see Section 7.4.4 and 
Appendix 10 of 
Protocol) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
HIV risk factors and 
mode of transmission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CDC HIV-1 
classification 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV associated 
conditions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Columbia Suicidality 
Severity Rating Scale 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Directed 
Physical Exami 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECGj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Willingness to Switchl 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5m 
 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Laboratory Assessments 
Quantitative plasma 
HIV-1 RNAn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 


 
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Procedures 
Screening Visita 
Open-label Randomised Early Switch Phase 
Switch 
Visit 
Withdrawal 
Follow-upd 
Baseline / 
Day 1 
Week 
4 
8 
12 
24 
36 
48 
60 
72 
84 
96 
108 
(optional)b 
120 
132 
(optional)b 
144 
148c 
Lymphocyte subset 
(CD4+ at all visits and 
CD8+ at Baseline, and 
Weeks 24, 48, 96, 144 
and 196 only)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Plasma for storageo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipids and 
glucosep 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Xq 
 
Urinalysis and spot 
urine for protein 
analysisr 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Pregnancy tests,t,u 
S 
U/Sv 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
U 
S 
 
HbsAg, anti-HBc, anti-
HBs, and HBV DNAw 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Insulin, HbA1c and 
renal, and bone marker 
analytes (blood/urine)x 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Xq 
 
Whole Blood (Virology)y 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Whole Blood (Telomere 
length)z 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Xaa 
 
Cryopreserved 
PBMCsbb 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Xaa 
 


 
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Procedures 
Screening Visita 
Open-label Randomised Early Switch Phase 
Switch 
Visit 
Withdrawal 
Follow-upd 
Baseline / 
Day 1 
Week 
4 
8 
12 
24 
36 
48 
60 
72 
84 
96 
108 
(optional)b 
120 
132 
(optional)b 
144 
148c 
Inflammation 
biomarkers (Blood)cc 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Xaa 
 
Study Treatment 
IVRS/IWRSdd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study 
treatment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
Study treatment 
accountability (pill 
counts) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Pharmacokineticee 
 
Intensive PK sample 
collection at selected 
sites for subset of ~30 
subjects (Fasting)ee 
 
 
Xff 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense PK Diary 
Card to intensive PK 
sub-set 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sparse PK sample 
collectionee 
 
 
Xgg 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense PK Diary 
Card to Sparse PK 
subjects 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
anti-HBc = antibody to hepatitis B core antigen, anti-HBs = hepatitis B surface antibody, ART = antiretroviral therapy, CDC = Centers for Disease Control and Prevention, DNA = 
deoxyribonucleic acid, HbA1c = Glycated hemoglobin, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus type 1, IVRS = interactive 
voice recognition system, IWRS = interactive web recognition system, PBMC = peripheral blood mononuclear cell, RNA = ribonucleic acid, RPR = rapid plasma reagin 
 


 
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13.2.2. Late Switch Phase Time and Events Table: TBR subjects who switched to DTG + 3TC at Week 148 
TBR subjects switching at Week 148 are followed up at 4, 12 and 24 weeks post-switch after which 24 weekly visits are resumed. 
Procedures 
Late Switch Phase through End of Study 
Continuation Phase 
Withdrawal 
Follow-up 
Week 
Every 24 weeks after Week 200b,ii 
152 
160 
172 
184 
(optional)b 
196 
200hh 
Clinical and Other Assessments 
Vital Signs: Resting Blood 
pressure (see  Section 7.4.4 and 
Appendix 10 of Protocol) 
 
 
X 
 
X 
X 
 
X 
 
Body Weight (BMI will be 
calculated within the eCRF) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs: Hip and waist 
circumference (see  Section 
7.4.4 and Appendix 10 of 
Protocol) 
 
 
X 
 
X 
 
 
X 
 
HIV associated conditions 
X 
X 
X 
X 
X 
X 
X 
X 
 
Columbia Suicidality Severity 
Rating Scale 
X 
X 
X 
X 
X 
 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Directed Physical 
Exami 
X 
X 
X 
X 
X 
X 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5Lm 
 
 
 
 
X 
 
 
X 
 
Laboratory Assessments 
Quantitative plasma HIV-1 RNAn 
X 
X 
X 
X 
X 
 
X 
X 
 
Lymphocyte subset (CD4+ at all 
visits and CD8+ at Baseline, and 
Weeks 24, 48, 96, 144 and 196 
only)  
X 
X 
X 
X 
X 
 
 
X 
 
Plasma for storageo 
X 
X 
X 
X 
X 
 
X 
X 
 


 
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Procedures 
Late Switch Phase through End of Study 
Continuation Phase 
Withdrawal 
Follow-up 
Week 
Every 24 weeks after Week 200b,ii 
152 
160 
172 
184 
(optional)b 
196 
200hh 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
 
X 
X 
Fasting lipids and glucosep 
 
 
 
 
X 
 
 
Xq 
 
Urinalysis and spot urine for 
protein analysisr 
 
 
 
 
X 
 
 
X 
X 
Pregnancy tests,t,u 
S 
S 
S 
S 
S 
S 
S 
S 
 
Insulin, HbA1c and renal, and 
bone marker analytes 
(blood/urine)x 
 
 
 
 
X 
 
 
Xq 
 
Whole Blood (Virology)y 
 
 
 
 
X 
 
 
X 
 
Whole Blood (Telomere length)z 
 
 
 
 
X 
 
 
Xaa 
 
Cryopreserved PBMCsbb 
 
 
 
 
X 
 
 
Xaa 
 
Inflammation biomarkers 
(Blood)cc 
 
 
 
 
X 
 
 
Xaa 
 
Study Treatment 
IVRS/IWRSdd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study treatment 
X 
X 
X 
 
X 
 
X 
 
 
Study treatment accountability 
(pill counts) 
X 
X 
X 
 
X 
X 
X 
X 
 
 


 
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13.2.3. Late Switch Phase Time and Events Table: DTG + 3TC arm 
Procedures 
Late Switch Phase through End of Study 
Continuation Phase 
Withdrawal 
Follow-up 
Week 
Every 24 weeks after Week 200b,ii 
160 
(optional)b 
172 
184 
(optional)b 
196 
200hh 
Clinical and Other Assessments 
Vital Signs: Resting Blood pressure (see  
Section 7.4.4 and Appendix 10 of Protocol) 
 
X 
 
X 
X 
 
X 
 
Body Weight (BMI will be calculated within the 
eCRF) 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs: Hip and waist circumference (see  
Section 7.4.4 and Appendix 10 of Protocol) 
 
X 
 
X 
 
 
X 
 
HIV associated conditions 
X 
X 
X 
X 
X 
X 
X 
 
Columbia Suicidality Severity Rating Scale 
X 
X 
X 
X 
 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Directed Physical Exami 
X 
X 
X 
X 
X 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5Lm 
 
 
 
X 
 
 
X 
 
Laboratory Assessments 
Quantitative plasma HIV-1 RNAn 
X 
X 
X 
X 
 
X 
X 
 
Lymphocyte subset (CD4+ at all visits and 
CD8+ at Baseline, and Weeks 24, 48, 96, 144 
and 196 only)  
X 
X 
X 
X 
 
 
X 
 
Plasma for storageo 
X 
X 
X 
X 
 
X 
X 
 
Clinical chemistry 
X 
X 
X 
X 
X 
 
X 
X 
Hematology 
X 
X 
X 
X 
X 
 
X 
X 
Fasting lipids and glucosep 
 
 
 
X 
 
 
Xq 
 
Urinalysis and spot urine for protein analysisr 
 
 
 
X 
 
 
X 
X 
Pregnancy tests,t,u 
S 
S 
S 
S 
S 
S 
S 
 
Insulin, HbA1c and renal, and bone marker 
analytes (blood/urine)x 
 
 
 
X 
 
 
Xq 
 
Whole Blood (Virology)y 
 
 
 
X 
 
 
X 
 


 
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Procedures 
Late Switch Phase through End of Study 
Continuation Phase 
Withdrawal 
Follow-up 
Week 
Every 24 weeks after Week 200b,ii 
160 
(optional)b 
172 
184 
(optional)b 
196 
200hh 
Whole Blood (Telomere length)z 
 
 
 
X 
 
 
Xaa 
 
Cryopreserved PBMCsbb 
 
 
 
X 
 
 
Xaa 
 
Inflammation biomarkers (Blood)cc 
 
 
 
X 
 
 
Xaa 
 
Study Treatment 
IVRS/IWRSdd 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study treatment 
 
X 
 
X 
 
X 
 
 
Study treatment accountability (pill counts) 
 
X 
 
X 
X 
X 
X 
 
a. As soon as all Screening results are available, randomization may occur. 
b. This optional study visit is ONLY to be conducted in countries that require visits every 3 months per standard of care. 
c. Subjects with plasma HIV-1 RNA ≥50 c/mL at Week 144 must have HIV-1 RNA level re-assessed by a second measurement performed 2-4 weeks later. Subjects should have 
received full doses of study treatment for at least 2 weeks at the time of HIV-1 RNA re-assessment. Subjects randomized to DTG + 3TC do not attend a Week 148 switch visit.   
d. An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study medication for subjects with the following conditions at the last on-study visit:  ongoing AEs, 
serious adverse events (SAEs) regardless of attributability, any laboratory abnormalities considered to be AEs or potentially harmful to the subject. Only the laboratory tests 
necessary to evaluate the AE/SAE/laboratory abnormality should be collected. 
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 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. 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. 
h. On Day 1, the electronic Columbia Suicidality Severity Rating Scale eC-SSRS, patient completed questionnaire) is to be administered prior to randomization.  
i. 
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.  
j. 
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes. 
k. Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and administration of study 
drug at Day 1.  
l. 
Willingness to Switch Survey must be done prior to randomization. 


 
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m. 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 196. 
n. See Virologic Withdrawal and Stopping Criteria Section of protocol (Section 5.4 of Protocol). 
o. Plasma samples for storage will be collected at each visit starting at Screening, 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 subjects meet 
Suspected and Confirmed Virologic Withdrawal criteria.  
p. An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable. 
q. Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 24, 48, 96, 144 or 196. 
r. 
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate. 
s. 
Women of childbearing potential only. S=serum, U=urine. Pregnancy events will be captured starting at Day 1 following exposure to study drug. 
t. 
Remind females of reproductive potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements.   
u. Beginning after Week 96, if study visits are every 24 weeks, participants who are women of child bearing potential must also do a home-based urine pregnancy test approximately 
every 12 weeks between study visits at approximately Weeks 108, 132, 160 and 184 and during the Continuation Phase.  Site staff must contact the participants who are women 
of child bearing potential to remind them to complete the test and to verify and record pregnancy test results in the source documents.  The site must also complete the pregnancy 
status eCRF if a pregnancy occurs and report the pregnancy to ViiV/GSK per Section 13.3.2 of Protocol. 
v. 
Local serum pregnancy test on Day 1 is allowed if it can be done, and results obtained, within 24 hours prior to randomization 
w. HBV DNA testing will be performed for subjects with positive anti-HBc and negative HBsAg and negative anti-HBs (past and/or current evidence).  Subjects will have to return to 
the clinic to provide a sample for HBV DNA testing prior to randomisation. 
x. 
Blood sample for insulin, HbA1c, and renal and bone biomarker assessments: Renal: Cystatin C; Beta-2-Microglobulin; Retinol Binding Protein (RBP); Bone: bone specific 
alkaline phosphatase, procollagen type 1-N-propeptide, type 1 collagen cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin D.  
y. Whole blood (Virology) may be used for virologic analyses as described in the protocol.   
z. Whole blood will be used for telomere length evaluation at Day 1, Week 48, Week 96, Week 144, Week 196 and at the Withdrawal visit. 
aa. Collect sample for these assessments ONLY if the Withdrawal visit occurs at Week 48, 96, 144 or 196 
bb. PBMCs will be collected, cryopreserved and stored in a subset of sites. These samples will be used for the measurement of telomerase activity. 
cc. Blood sample for inflammation biomarker assessments: IL-6, hs-CRP, d dimer, sCD14, sCD163. 
dd. At Screening, a subject number will be generated. 
ee. PK sampling in subjects from the DTG/3TC FDC arm only, as detailed in Section11 of Protocol. 
ff. Intensive PK sampling in a subset of subjects from the DTG/3TC FDC arm at select sites at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours post-dose. On the intensive PK day, 
patients are required to fast from 8 hours prior to dosing and then through 4 hours post-dose. Detailed in Section 11 of Protocol. 
gg. At Week 4, subjects who performed intensive PK do not perform Sparse PK sampling. 
hh. Subjects must return to the clinic for a Week 200 End of Study visit when transitioning to commercial supplies or to an alternate ART regimen, if appropriate. Do not dispense 
study treatment at this study completion visit unless the participant is entering the Continuation Phase. 
ii. 
Only in case of non-availability of DTG + 3TC FDC.  Subjects 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 with the exception of 
dispensing study treatment. 
 
 


 
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13.3. 
Appendix 3: Assessment Windows 
Laboratory data, health outcomes, vital signs 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. 
13.3.1. Definitions of Assessment Windows for Analyses 
Early Switch Phase 
Analysis Set / Domain 
Parameter      
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
All  
All 
-35 
≤-4 
≤-4 
Screening 
 
 
1 
-3 
1 
Day 1 
 
 
29 
2 
42 
Week 4 
 
 
57 
43 
70 
Week 8 
 
 
85 
71 
126 
Week 12 
 
 
169 
127 
210 
Week 24 
 
 
253 
211 
294 
Week 36 
 
 
337 
295 
378 
Week 48 
 
 
421 
379 
462 
Week 60 
 
 
7*w+1 
7*w-41 
7*w+42 
Week w, w=72, 
84, 96, 120 
 
 
757 
715 
798 
Week 108 
(Optional 
Visits) * 
 
 
925 
883 
966 
Week 132 
(Optional 
Visits) * 
 
 
1009 
967 
1036, but can be 
extended up to latest 
day of scheduled 
Week 144 visit or 
unscheduled visit that 
occurs between Day 
1037 and Day 1050 
(inclusive).  
Week 144 
 
NOTES : 
1. For parameters which are not scheduled to be assessed at particular visits, the all-inclusive windows defined will still be 
used.  
2. 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.  
* Optional study visit is conducted as per a site and/or participant decision. Data from these visits will be listed but not 
summarized 
 


 
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Late Switch Phase 
Analysis Set / 
Domain 
Parameter      
(if applicable) 
Arm 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy/HO/Safety 
 Snapshot 
endpoints, 
CD8+,lipids, 
glucose,Insulin, 
HbA1c 
biomarkers 
telomere, 
urinalysis, 
EQ5D & 
CSSRS 
DTG+3TC 
(Visit Not 
Applicable) 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
Week 148 
TBR 
1037 
 1037 
  1037 
 
 
DTG+3TC 
(Visit Not 
Applicable) 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
Week 152 
 
 
TBR 
1065 
1038 
1092 
 
 
DTG+3TC 
(Optional 
visit)* 
1121 
1093 
1162 
Week 160 
TBR 
1121 
1093 
1162 
 
 
 
DTG+3TC 
1205 
1163 
1246 
Week 172 
TBR 
1205 
1163 
1246 
 
 
DTG+3TC 
(Optional 
visit)* 
1289 
1247 
1330 
Week 184 
 
 
TBR 
(Optional 
visit)* 
1289 
1247 
1330 
 
 
DTG+3TC 
1373 
1331 
1414 
Week 196 
(7*w-41d, 
7*w+42d) 
 
 
TBR 
1373 
1331 
1414 
 
 
Forcing snapshot window to be -/+6 weeks, Week 200 nominal visit will be 
counted under Week 196 analysis window for HIV-1 RNA 
 
 
 
Study Day 
of last 
dose + 28 
>Study Day 
of last dose 
+1 
>Study Day 
of last dose 
+1 
Follow-up 
NOTES : 
1. For parameters which are not scheduled to be assessed at particular visits, the all-inclusive windows defined 
will still be used.  
2. 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). 
3. 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.  
4. This assessment windows applies to the endpoints collected at Week 196, but not at Week 200 visit. 
* Optional study visit is conducted as per a site and/or participant decision. Data from these visits will be listed but 
not summarized 
 


 
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Late Switch Phase 
Analysis Set / 
Domain 
Parameter     
(if 
applicable) 
Arm 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy/Safety Vital Signs, 
BMI, clinical 
chemistry, 
Haematology, 
HIV 
associated 
conditions, 
AEs, 
concomitant 
medications 
DTG+3TC 
(Visit Not 
Applicable) 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
Week 148 
TBR 
1037 
 1037 
  1037 
 
 
DTG+3TC 
(Visit Not 
Applicable) 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
Week 152 
 
 
TBR 
1065 
1038 
1092 
 
 
DTG+3TC 
(Optional 
visit)* 
1121 
1093 
1162 
Week 160 
TBR 
1121 
1093 
1162 
 
 
 
DTG+3TC 
1205 
1163 
1246 
Week 172 
TBR 
1205 
1163 
1246 
 
 
DTG+3TC 
(Optional 
visit)* 
1289 
1247 
1330 
Week 184 
 
 
TBR 
(Optional 
visit)* 
1289 
1247 
1330 
 
 
DTG+3TC 
1373 
1331 
1386 
Week 196  
 (7*w-41d, 
7*w+14d) 
 
 
TBR 
1373 
1331 
1386 
 
 
DTG+3TC 
1401 
1387 
1414 
Week 200 (7*w-
13d, 7*w+14d) 
 
 
TBR 
1401 
1387 
1414 
 
 
 
Study Day 
of last 
dose + 28 
>Study Day 
of last dose 
+1 
>Study Day 
of last dose 
+1 
Follow-up 
NOTES : 
1. For parameters which are not scheduled to be assessed at particular visits, the all-inclusive 
windows defined will still be used.  
2. 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). 
3. 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.  
4. This assessment windows applies to the endpoints collected at both W196 and W200 visit. 
* Optional study visit is conducted as per a site and/or participant decision. Data from these visits will 
be listed but not summarized 
 


 
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13.3.2. Definitions of Assessment Windows for Inclusion in the PK 
Analysis 
Not applicable to analyses post Week 48. 
The windows for inclusion of PK samples in summary statistics will be as follows: 
• For intensive PK population (Week 4 only):  
o Samples collected 1 hour prior to dose for pre-dose sample  
o Samples collected within ±15 min of the 0.5, 1, 1.5, 2 H time points 
o Samples collected within ± 30 min of the 3h, 4h, 6h time points 
o Samples collected within ± 1h for the 10h time point 
o Samples collected within ± 2h for the 24 h time point 
• For sparse PK population (Weeks, 4, 8, 12, 24, 36 and 48):  
o Samples collected within 1 hour prior to dose for pre-dose sample, within ±15 min 
of the 1H time point, within ±30 min window for 1-4hr post dose sample (i.e. 
between 0.5-4.5hr) and within ±60 min window for 4-12hr post dose sample (i.e. 
between 3-13hr).  
Outside these allowed windows, concentration results will be flagged and NOT included in the 
calculations for the summaries, but will be used in listings. 
Given steady state will be reached by Day 5, sparse PK analyses will use nominal visit windows for 
all sparse PK analyses. 
 


 
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13.4. 
Appendix 4: Study Phases and Emergent Adverse Events 
13.4.1. Study Phases 
Data collected from both arms up to and including the date of the Week 148 visit will be 
considered to be during the Early Switch Phase of the study. For subjects randomised to 
TBR, this will be the date of their Week 148 switch visit.  For subjects randomised to DTG 
+ 3TC, this will be calculated as 1035 (=[148x7] - 1) ) days after exposure start date or if 
the latest of scheduled or unscheduled W144 visit  takes place between Day 1037 and Day 
1050 (inclusive) then the day of W144 visit. 
 
For subjects randomised to DTG + 3TC, data collected from 1036 days after IP start day 
to Week 200 will be considered to be during the Late Switch Phase. Data collected after 
Week 200 will be considered to be during the Continuation Phase of the study (if 
applicable). 
 
For subjects randomised to the TBR arm, data collected from the date of the Week 148 
switch visit to Week 200 will be considered to be during the Late Switch Phase of the 
study. Data collected after Week 200 will be considered to be during the Continuation 
Phase of the study (if applicable). 
 
Phase 
Randomised 
Arm 
Start 
End  
Early Switch Phase DTG + 3TC 
IP start date 
IP start date + 1035 (=[148x7 – 1). If 
the latest of scheduled or 
unscheduled W144 visit  takes place
between Day 1037 and Day 1050 
(inclusive) then the day of W144 
visit 
or  
Withdrawal date on or before study 
day 1036 
TBR 
Day 1 DOV 
IP start date for switch to DTG + 
3TC -1  
or 
Withdrawal date before Week 148 
Late Switch Phase DTG + 3TC * 
 IP start date +1036 
Or the day after the 
latest of scheduled 
or unscheduled 
W144 visit if this 
visit takes place 
between Day 1037 
and Day 1050 
(inclusive) 
Week 200 DOV -1  
or 
Withdrawal date before Week 200 
TBR ** 
IP start date for 
DTG + 3TC 
Week 200 DOV -1 
or 
Withdrawal date before week 200 


 
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Phase 
Randomised 
Arm 
Start 
End  
Continuation 
Phase(if applicable) 
DTG + 3TC 
Week 200 DOV 
IP end date or Withdrawal date 
TBR 
Week 200 DOV 
IP end date or Withdrawal date 
* For subjects randomised to DTG + 3TC, data collected from day1037(or the day after  
scheduled W144 visit if scheduled W144 visit takes place between Day 1037 and Day 1050 
(inclusive)) to Week 200 will be considered to be during the Late Switch Phase. There will 
not be a visit at week 148 in DTG + 3TC arm, so this needs to be derived programmatically. 
** For subjects randomised to the TBR arm, IP start date as collected on the late switch 
eCRF at the Week 148 switch visit will be used to define the beginning of the Late Switch 
Phase of the study. 
13.4.1.1. Study Phases 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 
NOTES:  
1. If the study treatment stop date is missing then the assessment will be considered to be On-Treatment 
13.4.1.2. Study Phases for Adverse Events 
For adverse events, partial AE start date will use imputation as described in Section 
13.7.2.1. 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. 
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 CRF.  


 
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NOTES:  
• 
Partial AE start date will use imputation as described in Section 13.7.2.1 
• 
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. 
13.4.1.3. 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: 
• ART starting on or after 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 Day 1 while still on study treatment includes 
all ART that started after Day 1 and before study treatment discontinuation. Note 
this will be recorded as ConART  
• 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 
Conco-
mitant 
Post 
(a) 
x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x 
 
N 
Y 
N 
(e) 
 
x 
x 
N 
Y 
Y 
(f) 
 
 
x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 
 
 


 
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13.4.2. 
Combining Treatment Phases and States 
On-treatment and Post-treatment assessments and events will be classified as occurring 
during the Early Switch, Late Switch or Continuation Phase of the study (if applicable) as 
follow: 
• 
If a subject did not enter the Late Switch Phase, then any Post-treatment data will be 
assigned to the Early Switch Phase.  
• 
For subjects who did enter the Late Switch Phase, If a subject did not enter the 
Continuation Phase, then any Post-treatment data will be assigned to the Late Switch 
Phase (provided this was after the Early Switch 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 early switch phase only then phase is set to “Early 
Switch Phase” 
• Is taken at any point during the late switch phase only then phase is set to “Late 
Switch 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 early and late switch phases only then phase is set 
to “Early and Late Switch Phase” 
• Is taken at any point across the late and continuation phases only then phase is set 
to “Late Switch and Continuation Phase” 
• Is taken at any point across all three phases then phase is set to “Early Switch and 
Late Switch and Continuation Phase”. 
13.4.3. 
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 
13.7.2. 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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13.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
13.5.1. 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\mid204862\reporting_effort_number 
Analysis Datasets  
• Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & 
ADaM IG Version 1.0).  
• 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. 
13.5.2. Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, 
unless otherwise stated (IDSL Standards 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 IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
• For [Insert Endpoint / Parameter] the following DP’s places will be applied: 
• Summary Statistics: 
• Listings:  


 
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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 
IDSL Statistical 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 13.3. 
• 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). 
Optional Visits 
• For optional visits (DTG+3TC - Week 108, 132, 160 & 184, TBR- Week 108, 132 &184), 
data will be listed but will not be summarized 
Listings 
• Listings will include all data, regardless of treatment phase or state. 
Treatment Phases and States 
• Study population, efficacy, virology and health outcome tables will not include post-treatment 
data according to the phase, unless otherwise stated. The data will be presented up to the 
visit window of interest.  
• Safety tables will present on-treatment and post-treatment data according to the phase, 
unless otherwise stated. 
 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 


 
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13.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-Linear 
(WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by 
Clinical Pharmacology Modelling and Simulation function will be 
created according to PK One document (Standards for the Transfer 
and Reporting of PK Data using HARP).   
Note: Concentration values will be imputed as per GUI_51487 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for 
descriptive summary statistics/analysis and summarized graphical 
displays only.  
NONMEM/Pop PK File 
Pop-PK file (CSV format) for the POP-PK analysis by Clinical 
Pharmacology Modelling and Simulation function will be created 
according to the data specification detailed in a separate RAP 
NONMEM/PK/PD File 
Pop-PKPD file (CSV format) for the POP-PK analysis by Clinical 
Pharmacology Modelling and Simulation function will be created 
according to the data specification detailed in a separate RAP. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by Programmer 
The PK parameters will be calculated by standard non-
compartmental analysis according to current working practices and 
using WinNonLin v 5.2 or above. All calculations of non-
compartmental parameters will be based on actual sampling times.  
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule Being 
Followed 
If any PK parameter is not calculable because of NQs, it will be 
noted as NC (non-calculable) for the PKPar file and excluded (set to 
missing) from the PK parameter summary statistics. Refer to PK 
One document (Standards for the Transfer and Reporting of PK 
Data using HARP) for handling of non-numeric values in the 
parameter data. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
 
 
Not applicable to analyses post Week 48. 
 


 
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13.6. 
Appendix 6: Derived and Transformed Data 
13.6.1. 
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 13.3), 
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 
the mean of these values will be used. 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 or LOCF). 
• 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: Randomised Early 
Switch, Late Switch and Continuation Phase. 
Study Drug 
• Study Drug refers to either Investigational Product DTG + 3TC or TBR. 


 
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13.6.2. 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 standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
o Any subject with a 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 standard IDSL 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, , of having a cardiovascular disease (CVD) within the next 10-years 
according to the Framingham formula [D’Agostino, 2008] is 
 
for females: 
F = 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: 
M = 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) =  
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
 
• Smoking status is collected in the eCRF on Day 1. A current smoker is defined as 
currently smoking/using tobacco or has smoked/used tobacco within the previous 6 
months; a former smoker is defined as previously smoked/used tobacco products and 
has not smoked/used tobacco products within the previous 6 months. 


 
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Demographics 
 
• Risk score needs to be calculated at baseline  week 144 and Week 196. For deriving 
week 144 and Week 196 risk score, use the  lab and vital signs values of the respective 
visits and target age at that visit needs to be derived 
 
• This calculation will not be performed for subjects who have indicated current or past 
myocardial infarction conditions on the eCRF. These subjects will not be included in 
summary statistics of risk and change from baseline in risk, but will be counted in the 
highest category of risk in the summary by category 
Extent of Exposure 
• Exposure to DTG + 3TC will be calculated from the IP eCRF pages.  Exposure to TBR will be 
calculated from the CONART eCRF pages.  
• Subjects who were randomised to DTG + 3TC but did not report a IP start date will be 
categorised as having zero days of exposure.  
• Subjects who were randomised to TBR 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%). 
• Further clarifications on extent of exposure during the early and late switch phases is provided 
inthe Section 13.6.4. 
 
Strata 
• For analysis purposes, randomisation strata will be used from that derived using eCRF data, 
even if this differs from the strata captured in IVRS. 
• For patients randomised to DTG + 3TC, baseline third agent class is collected on the prior ART 
history form. For patients randomised to current TBR, 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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13.6.3. 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. 
• Virologic Success (e.g., <50 c/mL) or Virologic Failure within an analysis window (see Section 
13.3) is typically determined by the last available 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 a Virologic 
Success.  Depending on the reason for lack of data, the subject will be classified as a Virologic 
Failure 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 Virologic Failure. 
• For each scheduled assessment time, the snapshot response rate for a given threshold (e.g., 
<50 c/mL) is defined as: 
population
 
analysis
 
in the
 
subjects
 
of
Number 
 window
analysis
in that 
 
responders
 
of
Number 
Rate
Snapshot 
=
 
• Full details of the algorithm, including the handling of special cases, are included in Section 
13.11 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 5.4.1 for more details of the derivation of CVW, 
PVW, pPVW and SVWs.  


 
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HIV-1 RNA 
PVW (leading to discontinuation – this  definition will not be used in statistical analysis or 
reporting) 
• 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, ORWill be met with three consecutive 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 
(instances where a first elevation of HIV-1 RNA >=200 c/mL followed by HIV-1 RNA >=50 
and <200 c/mL will also be considered pPVW 
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 5.4) 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. 
• Please refer to Section 5.4.1 of the protocol for details of the derivation. 


 
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HIV-1 RNA 
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 13.7).  
• Any 'other’ conditions reported in the CRFs 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. 
13.6.4. Safety 
Extent of Exposure 
 
• Exposure to DTG + 3TC will be calculated from the IP eCRF pages.  Exposure to TBR 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 randomised to DTG + 3TC at Day 1: 
• For Early Switch Phase: 
o For subjects completing the early switch phase Exposure = IP Start Date + 1035 
(=[7*148] -1) or if the latest of scheduled or unscheduled W144 visit takes place 
between Day 1037 and Day 1050 (inclusive) then the day of W144 visit 
o If a subject discontinues prior to Week 144 (Day 1036), the IP Stop Date recorded 
in the eCRF will be used. A partial or missing IP stop date is handled as described 
in Section 13.7.2.1.  
• A Day 1 Date of Visit will be used for partial or missing IP start date.For Late switch phase: 
o Start date of late switch phase is IP start date +1036 or the day after the latest of 
scheduled or unscheduled W144 visit if this visit takes place between Day 1037 
and Day 1050 (inclusive) 
 
• The overall exposure is calculated as 
o Exposure = IP Stop Date – IP Start Date + 1 
For subjects randomised to TBR at Day 1: 
• For Early Switch Phase: 
o Exposure = (IP Start Date – 1) – Day 1 DOV + 1 
o If a subject discontinues prior to Week 148, the Withdrawal Date (earliest of date 
recorded in disposition, study visit page and TBR stop date) recorded in the eCRF 
will be used in the following way: 
Exposure = (earliest of date recorded in disposition, study visit page and TBR stop 
date) – Day 1 DOV + 1  
• After the Week 148 switch visit, the exposure to DTG + 3TC is calculated as 
o Exposure = IP Stop Date – IP Start Date + 1. 
 


 
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Extent of Exposure 
• 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 randomised to DTG + 3TC but did not report a IP start date will be 
categorised as having zero days of exposure.  
• Subjects who were randomised to TBR 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. 
• See protocol for DAIDS grading criteria. 
Adverse Events of Special Interest (AESI) 
The preferred terms for each AESI will be updated on an ongoing effort before each formal analysis 
in a separate document. The following table below shows the AESI categories. 
AESI  
Anxiety 
  
Depression 
  
Drug Hypersensitivity 
 
Insomnia 
 
Nightmare/Abnormal Dreams 
  
Rash 
  
Suicidality and self-injury 
Weight increased 
Weight decreased 
 
 


 
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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 
National Cholesterol Education Program (NCEP) Lipid 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 


 
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Laboratory Parameters 
Glomerular Filtration Rate (GFR) 
• Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [Levey, 2009] 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: 
 
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 µmol/L as CRTmg/dL =0.0113x CRTµmol/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 
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 
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. 
 


 
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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 
Note: Any shift to a higher BMI category counts as a shift to a ‘worse category’. 
 
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 CRF 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 CRF 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. 


 
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Homeostatic model assessment-Insulin Resistance (HOMA-IR) 
 
• HOMA-IR = (fasting plasma insulin (mU/L) * fasting plasma glucose (mmol/L)) / 22.5. 
• HOMA-IR categories will be categorised as follows for the HOMA-IR shift table analysis: 
o <2 
o 2 to <3 
o 3 to <4 
o >=4 
HOMA-IR shift tables will be presented for baseline vs maximum value post-baseline and Week 
X, for Weeks 24, 48 and only for baseline vs Week X for Weeks 96 and 144. HOMA-IR 
categories will be broken down into: <2, 2 to <3, 3 to <4 and >=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, patients with anti-
diabetic medication starting at or prior to screening are excluded. 
Metabolic Syndrome per IDF definition 
Metabolic syndrome (required at Baseline, Week 144 and Week 196) is defined as a 
subject having: 
Central obesity (defined as the last value within the visit window of interest as 
BMI>=30kg/m2)  
plus any two of the following four factors: 
Raised 
triglycerides 
The last fasted value within visit window of interest >=150 
mg/dL (1.7 mmol/L)  
or specific treatment for this lipid* abnormality at any time 
prior the end of the visit window of interest  
Reduced HDL 
cholesterol 
The last fasted value within visit window of interest: 
< 40 mg/dL (1.03 mmol/L) in males 
< 50 mg/dL (1.29 mmol/L) in females 
or specific treatment for this lipid* abnormality at any time 
prior the end of the visit window of interest 
Raised blood 
pressure 
Systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg  
or treatment* of previously diagnosed hypertension at any time 
prior the end of the visit window of interest 


 
CONFIDENTIAL 
 
 
 
204862 
 
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or any AE with preferred term “Hypertension”, “Essential 
hypertension”, “Blood pressure increased” or “Blood pressure 
diastolic increased” experienced at any time prior to the end of 
the visit window of interest 
Raised fasting 
plasma glucose 
The last value within visit window of interest (FPG) >= 100 
mg/dL (5.6 mmol/L), 
or previously diagnosed type 2 diabetes at any time prior the 
end of the visit window of interest 
* List of the unique medications identified by the clinical review of the Week  196 data 
for determination of Metabolic Syndrome (for lipid abnormalities i.e. triglyceride 
elevations and HDL reductions, and hypertension-related medications) will be provided. 
 


 
CONFIDENTIAL 
 
 
 
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13.6.5. Pharmacokinetic 
General 
• Data at specific timepoints of subjects who had major PK protocol deviations that could 
impact DTG or 3TC exposure will be removed, as detailed below:   
PK Protocol Deviation 
Populations Affected 
Analysis Consideration 
Non-fasting 8 hours pre-dose - Intensive Concentration and 
Parameter Populations  
Pre-dose and subsequent 
samples that day (not 
including 24 hours) will be 
excluded from summaries 
and figures but will be 
included in listings and 
flagged  
Use of prohibited 
medications* at time of 
sample  
- Intensive Concentration and 
Parameter Populations 
- Sparse Population 
Samples will be excluded 
from summaries and figures 
but will be included in listings 
and flagged 
• The Intensive pharmacokinetic population will be used for listing PK concentrations, 
calculating PK parameters, summaries of concentration-time data and plotting of 
individual concentration-time files for the intensive PK population. 
• The Intensive Pharmacokinetic Parameter Population will be used for intensive PK 
parameter analyses  
• If during clinical phase, 3 consecutive samples in any phase i.e.(Absorption, Distribution 
and Metabolism / Excretion) are found to be missing then data for that subject will not be 
included in PK and only the concentration data of that subject(s) will be presented 
• The sparse pharmacokinetic population will be used for summarising PK concentrations. 
• Listings will be based on the safety population, and only patients with a sample from the 
relevant dosing schedule will be presented in these listings. 
• * Prohibited medications that could decrease DTG or 3TC exposure will be identified as 
leading to exclusion from PK summaries and figures if they are ongoing at the visit at 
which the analysis is taking place. If a prohibited medication has a non-missing start and 
stop date before, say Week 24, then there will be no exclusion from PK analyses at the 
Week 24 analysis. Prohibited medications are defined as follows:  
o Carbamazepine 
o Oxcarbazepine 
o Phenobarbital  
o Phenytoin 
o Rifampin 
o Rifapentine  
o St. John’s wort 
Not applicable to analyses post Week 48. 


 
CONFIDENTIAL 
 
 
 
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13.6.6. Population Pharmacokinetic (PopPK) 
13.6.7. Not applicable to analyses post Week 48.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, G140A/C/S, Y143C/H/R/K/S/G/A, P145S, Q146P, S147G, 
Q148N/H/K/R, V151I/L/A, S153F/Y, N155H/S/T, E157Q, G163R/K, 
S230R, R263K, L68V/I*, L74I*, E138T*, G193E* 
NOTES: 
1. 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.    
2. INSTI mutations underlined and in bold have a maximum score of 60 for any INSTI drug in the Stanford 
database v8.9 (http://hivdb.stanford.edu/DR/cgi-bin/rules_scores_hivdb.cgi?class=INI last 
updated on 25 OCT 2019 and accessed on 17 FEB 2020); the rest have a maximum score <60. 
3. This table is updated only by Virologists. 
• 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. 


 
C O N FI D E N TI A L  
 
 
 
2 0 4 8 6 2  
1 0 1  
 
G e n oty p e  
A mi n o A ci d C h a n g e s  
Cl a s s  
M utati o n s  
N R TIs  
M 4 1 L, K6 5 R/ E/ N, D 6 7 N, 6 9 i nsert, K7 0 E/ R, L 7 4 V, Y1 1 5 F, M 1 8 4 V/I, L 2 1 0 W, 
T 2 1 5 Y/ F, K2 1 9 Q/ E; [ A6 2 V,  V7 5I,  F 7 7 L, F 1 1 6 Y, Q 1 5 1 M]*  
N N R TIs  
L 1 0 0I, K1 0 1 E/ P, K1 0 3 N/ S, V1 0 6 A/ M,  V1 0 8I, E1 3 8/ A/ G/ K/ Q/ R,  V1 7 9 L,  
Y1 8 1 C/I/ V,  Y1 8 8 C/L/ H, G 1 9 0 S/ A, H 2 2 1 Y, P2 2 5 H, F 2 2 7 C, M 2 3 0I/L,  
PIs  
D 3 0 N, V3 2I , M 4 6I/L, I4 7 A/ V,  G 4 8 V, I5 0 V/L, I5 4 V/ M/L,  Q 5 8 E,  T 7 4 P, L 7 6 V,  
V8 2 A/ T/ F/L/ S,  N 8 3 D, I8 4 V,  N 8 8 S,L 9 0 M  
N ote: List g e n erate d fro m I A S_ U S A  G ui d eli n e,  - 2 0 1 9 2 0 1 9 R esista nc e M utati o ns U p d ate Vol u m e 
2 7 Issu e 3, July/ Au g ust  2 0 1 9  
* Q 1 5 1 M C o m pl ex: Q1 5 1 M usu ally occurs in co mbin atio n with t w o or mor e of  th e follo win g fo ur accessory N R TI 
mutatio ns  A6 2 V, V7 5I, F 7 7 L, a n d F 1 1 6 Y  
S u s c e pti bility Sc or e s  
Sta nf or d G e n oty pi c S u s c e pti bility Sc or e ( G S S)  
•  T o esta blish g e n otypic susc e pti bility to A R T tre at m e nt, a g e n otypic se nsitivity  sc ore will b e 
c alc ul ate d. 
•  G e n otypic se nsitivity  to e ac h dru g will b e assesse d usi n g th e HI Vd b,  th e Inte grate d G e n otypic 
R esista nc e Interpretati o n  Syste m  [ Li u , 2 0 0 6 ]. 
•  In th e HI Vd b syste m, e ac h HI V-1  dru g resista nc e m utati o n is assi g n e d a dru g p e n alty sc ore. 
T h e p e n alty  sc ores for  e ac h dru g resista nc e m utati o n are  avail a bl e at  
N N R TI:  https://hivd b.sta nford.e d u/dr -su m m ary/ m ut-sc ores/ N N R TI/ 
N R T I:  https://hivd b.sta nford.e d u/dr -su m m ary/ m ut-sc ores/ N R T I/ 
PI:  https://hivd b.sta nford.e d u/dr -su m m ary/ m ut-sc ores/ PI/ 
I N S T I:   https://hivd b.sta nford.e d u/dr -su m m ary/ m ut-sc ores/I N S T I/.  Sc ores for  p artic ul ar p atterns 
of I N S TIs are also avail a bl e at https://hivd b.sta nford.e d u/dr -su m m ary/p attern-sc ores/I N S T I/ 
•  T h e dru g resista nc e esti m ate is o btai n e d by a d di n g to g eth er th e p e n alty sc ores fro m all 
m utati o ns associ ate d with resista nc e to th at dru g a n d th e n a n u m eric sc ore ( S -G S S) is a p pli e d 
for e ac h dru g as sh o w n b el o w. T h e su m sc ores are titrate d to fall withi n th e foll o wi n g ra n g es: 
susc e pti bl e, p ote nti al l o w-l evel  resista nc e, l o w-l evel resista nc e, i nter m e di ate resista nc e, a n d 
hi g h -l evel resista nc e (se e ta bl e b el o w). 
•  T h e HI Vd b  G S S  will th e n b e  c alc ul ate d for e ac h su bj ect d efi n e d as  th e su m of  th e resista nc e 
sc ores for e ac h of th eir b ac kgro u n d dru gs. 
M o n o gr a m G e n oty pi c S u s c e pti bility Sc or e ( G S S)  
•  M o n o gra m G S S sc ore will b e re p orte d i n a listi n g, b ut will n ot b e use d for su m m ary ta bl es. 
•  G e n otypic se nsitivity  to e ac h dru g will b e assi g n e d usi n g th e M o n o gra m resista nc e sc ore 
for e ac h b ac kgro u n d dru g provi d e d i n th e d ata b ase. 
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 O N FI D E N TI A L  
 
 
 
2 0 4 8 6 2  
1 0 2  
 
G e n oty p e  
A mi n o A ci d C h a n g e s  
•  F or th e D T G  +  3 T C ar m a su bj ect mi g ht h ave a M -G S S sc ore of 0, 1 or 2, a n d i n th e T B R 
ar m a su bj ect mi g ht h ave a M -G S S sc ore of 0, 1, 2, or 3 (si nc e T B R is a 3-dru g re gi m e n). 
 
 
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 O N FI D E N TI A L  
 
 
 
2 0 4 8 6 2  
1 0 3  
 
P h e n oty p e  
P h e n oty pi c S u s c e pti bility  
•  Ph e n otypic susc e pti bility to all lic e nse d a ntiretroviral dru gs a n d D T G will b e d eter mi n e d 
usi n g Ph e n o Se nse HI V  assays fro m M o n o gra m Inc. a n d will b e re p orte d as fol d c h a n g e 
( F C) i n I C 5 0 rel ative to wil d-typ e  c o ntrol virus  N L 4-3, i.e., F C of sa m pl e virus = I C 5 0 of 
sa m pl e virus/I C 5 0  of  c o ntrol virus. 
•  Si nc e th e  m axi m u m assay li mit for F C for e ac h A R T vari es fro m su bj ect to su bj ect, F C 
val u es th at are gre ater th a n th e m axi m u m assay li mit (e.g., ‘ >1 0 0’) will b e i nterprete d as 
h avi n g a val u e e q u al to th e s m all est m axi m u m assay li mit for th at A R T i n th e stu dy 
p o p ul ati o n for  d ata a n alysis.   C e nsore d val u es will b e prese nte d ‘ as is’ i n th e listi n gs.  
•  Ph e n otypic susc e pti biliti es will b e c ate g orise d ac c ordi n g to F C (b ase d o n M o n o gra m 
Ph e n o Se nse assay).  Cli nic al c ut -offs ( w h ere avail a bl e) or bi ol o gic al c ut-offs by 
Ph e n o Se nse will b e use d to d efi n e th e p h e n otypic susc e pti bility of b ac kgro u n d tre at m e nt.  
•  R e plic ati o n c a p acity is g e n erate d as p art of sta n d ard p h e n otypic assays.  
 
•  T o esta blish susc e pti bility to b ac kgro u n d tre at m e nt, a p h e n otypic se nsitivity  sc ore will b e 
c alc ul ate d. Ph e n otypic susc e pti bility to e ac h dru g i n a  su bj ect’s b ac kgro u n d re gi m e n will 
b e d eter mi n e d by a p plyi n g dru g -associ ate d c utoffs as d efi n e d by th e Ph e n o Se nse 
al g orith m to th e p h e n otypic fol d resista nc e to th at dru g at a c ertai n ti m e p oi nt (e.g., 
Scre e ni n g or Baseli n e). A  n u m eric  sc ore will b e assi g n e d to  e ac h b ac kgro u n d dru g usi n g 
t w o differe nt m eth o ds: o n e with full se nsitivity  o nly ( P S Sf) a n d o n e with p arti al se nsitivity 
i ncl u d e d ( P S Sp). 
 
P S S wit h F ull Se nsiti vit y O nl y ( P S Sf)  
 
P S S  wit h  P arti al  Se ns iti vit y I ncl u de d ( P S S p)  
 
•  B oth P S Sf a n d P S Sp will b e c alc ul ate d se p arately for e ac h su bj ect d efi n e d as th e 
su m of th e  resista nc e sc ores for  e ac h b ac kgro u n d dru g. 
 
 
 
 
 
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 - 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 O N FI D E N TI A L  
 
 
 
2 0 4 8 6 2  
1 0 4  
 
Dr u g  
A b br e vi ati o n  
Cl a s s  
P h e n o Se n s e c ut off  
Ab ac avir  
A B C  
N R TI  
(4.5 –  6.5) a 
L a mivu di n e  
3 T C  
N R TI  
3.5  a 
Di d a n osi n e  
d dI 
N R TI  
(1.3 –  2.2)  a 
Stavu di n e  
d 4 T  
N R TI  
1.7  a 
Zi d ovu di n e  
AZ T  ( Z D V)  
N R TI  
1.9  
E mtricita bi n e  
F T C  
N R TI  
3.5  
T e n ofovir  
T D F  
N R TI  
(1.4 –  4)  a 
D el avirdi n e  
D L V  
N N R TI  
6.2  
Efavire nz  
E F V  
N N R TI  
3  
N evira pi n e  
N V P  
N N R TI  
4.5  
Etraviri n e  
E T R  
N N R TI  
(2.9-1 0)  a 
Ril piviri n e  
R P V  
N N R TI  
2.0  
F osa m pre n avir/r  
F P V/r  
PI  
(4-1 1)  a 
Ataza n avir/r  
AT V/r  
PI  
5.2  a 
In di n avir/r 
I D V/r 
PI  
1 0  a 
L o pi n avir/r  
L P V/r  
PI  
(9 –  5 5)  a 
N elfi n avir  
N F V  
PI  
3.6  
Sa q ui n avir/r  
S Q V/r  
PI  
(2.3 –  1 2)  a 
Ti pra n avir/r  
T P V/r  
PI  
(2 –  8)  a 
D aru n avir/r  
D R V/r  
PI  
(1 0 –  9 0)  a 
Rito n avir  
R T V  
PI  
2.5  
Enfuvirti d e  
T 2 0  
FI  
6.4 8  
R alte gravir  
R AL  
I NI 
1.5  
Elvite gravir  
E V G  
I NI 
2.5   
D ol ute gravir  
D T G  
I NI 
(4-1 3)  a 
Bicte gravir  
BI C  
I NI 
(2.5-1 0) 
a.  clinical  cutoff  (lo w er cutoff –  hig h er cutoff)  
 
 
 
 
P h e n oty pi c S u s c e pti bility Sc or e ( P S S)  
N et A s s e s s m e nt a n d O v er all s u s c e pti bility of A R T s  
•  N et assess m e nt is a n assess m e nt of a ntiviral activity  of A R T s usi n g b oth g e n otypic 
a n d p h e n otypic test results i nterprete d thro u g h a pro pri etary  al g orith m (fro m M o n o gra m 
Bi osci e nc es) a n d provi d es th e overall susc e pti bility of th e dru g ( N ote: p arti ally se ns itive 
a n d resista nt c alls are c o nsi d ere d resista nt i n this a n alysis).  
•  F or d eter mi ni n g overall susc e pti bility of A R T s ( O S S), a bi n ary sc ori n g syste m  (0 = 
 1 = 
)  for e ac h a ntiretroviral a g e nt w as use d a n d will b e provi d e d i n th e 
M o n o gra m d at aset. O S S will b e c alc ul ate d as th e su m of th e n et assess m e nt sc ores of 
A R T s c o m prisi n g th e su bj ect’s A R T a n d c ate g orise d as 0, 1, 2, or 3. O S S val u es will 
b e c alc ul ate d o nly for th e ti m e of C V W  w h e n n et assess m e nt is avail a bl e.  
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 4 8 6 2  
1 0 5  
 
D e ci si o n tr e e a p pr o a c h f or  M o n o gra m r e si sta n c e d ata a n al y s e s  
•  We mi g ht h ave resista nc e d ata th at c o m e fro m mixe d d atasets: P S G T, P SI N, G SI N 
(pri m ary assays) vs P S G T +I N (sec o n d ary assay) 
•  If o n e of th e pri m ary assay d o es n ot w ork for a sp ecific ti m e p oi nt, w e mi g ht re p ort th e 
sec o n d ary assay if d ata is avail a bl e. If all pri m ary assays for a sp ecific ti m e p oi nt w ork 
th e n w e re p ort pri m ary. F or exa m pl e, for b aseli n e if th e sa m e assay secti o n ( P S G T, 
P SI N,  G SI N) w orke d th e n w e re p ort  pri m ary. If at l e ast o n e of P S G T or P SI N or G SI N 
di d n’t w ork th e n w e re p ort sec o n d ary P S G T +I N.  
•  Sec o n d ary assay  testi n g results mi g ht n ot al w ays b e avail a bl e.  
B ac k g r o u n d :  
•  D N A G e n o Sure Arc hive –  o nly provi d es g e n o d ata for P R O/ R T a n d Inte grase  
•  P S G T  - provi d es b oth g e n o a n d p h e n o d ata for P R O/ R T ( N R TI a n d N N R TI)  o nly 
•  P SI N - Provi d es p h e n o d ata o n Inte grase o nly  
  
•  G SI N - Provi d es g e n o d ata o n Inte grase o nly  
  
•  P S G T +I N - Sec o n d ary assay  use d if P S G T or G SI N assay  fails; it provi d es b oth g e n o 
a n d p h e n o d ata o n P R O, R T a n d Inte grase  
 
1 3. 6. 8.  
H e alt h O ut c o m e s  
E ur o p e a n Q u ality of Life -5 Di m e n si o ns -5 L e v el s ( E Q -5 D -5 L)  
•  T h e E Q -5 D is a q u ality of life i nstru m e nt th at provi d es a E Q -5 D -5 L Utility Sc ore a n d th e E Q 
Visu al An al o g u e sc al e ( E Q V A S)  
E Q -5 D -5 L  
•  T h e d escri ptive syste m  c o m prises 5 di m e nsi o ns: m o bility,  self -c are, usu al activiti es, 
p ai n/disc o mfort, a n d a nxi ety/d e pressi o n with five l evels for e ac h di m e nsi o n fro m l evel 1 =   
 to l evel 5 = 
.  
•  T h e n u m b er of p ossi bl e h e alth states  is 55 = 3 1 2 5.  
•  T h e h e alth state is d efi n e d by c o m bi ni n g th e l evels of a ns w ers fro m e ac h of th e 5 q u esti o ns.  
•  Eac h h e alth state is referre d to i n ter m s of a 5-di git c o d e. F or exa m pl e, state  1 1 1 1 1 i n dic ates n o 
pro bl e m s o n a ny  of  th e  5 di m e nsi o ns, w hil e state 1 2 3 4 5 i n dic ates n o pro bl e m s with m o bility, 
sli g ht pro bl e m s with w ashi n g or dressi n g, m o d erate pro bl e m s with d oi n g usu al activiti es, severe 
p ai n or disc o mfort a n d extre m e a nxi ety or d e pressi o n. 
•  T h e h e alth state 5-di git c o d e is tra nsl ate d i nto th e utility  sc ore, w hic h is val u e d u p to o n e 
(re prese nti n g p erfect h e alth) with l o w er val u es m e a ni n g w orse state, ac c ordi n g to th e 
m eth o d ol o gy d e scri b e d i n D evli n , 2 0 1 6 , Secti o n 3.4.  T h e U K val u es set d escri b e d i n S ecti o n 
3.4 will b e use d for all su bj ects re g ardl ess of th eir c o u ntry ori gi n. 
•  T h e n u m erals 1 -5 h ave n o arith m etic pro p erti es a n d sh o ul d n ot b e use d as a c ardi n al sc ore.  
•  A m bi g u o us val u es (e.g. 2 b oxes are tic ke d for a si n gl e di m e nsi o n) sh o ul d b e tre ate d as missi n g 
val u es. 
•  Any  missi n g val u es  sh o ul d b e i m p ute d usi n g L O C F.  
•  In L ate s witc h Ph ase, as th ere is d ata c oll ecte d at o nly o n e ti m e p oi nt p ost-s witc h for  T B R ar m, 
th e L O C F m eth o d will n ot b e use d. At  W1 9 6 r esults will b e prese nte d o n o bserve d d ata  
E Q vi s u al A n al o g u e s c al e ( E Q V A S)  ' T h er m o m eter'  
•  Self -rate d  c urre nt h e alth status 
•  R a n g es fro m 0 (
)  to  1 0 0 (
). 
C CI
C CI
C CI
C CI
C CI


 
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13.6.9. 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 
randomised to DTG + 3TC) or CM (for patients randomised to TBR), 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)  
Willingness to switch survey 
• 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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• 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, 96, and 144 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, 
 
13.6.10. PK Data 
Not applicable to analyses post Week 48. 
Below Limit of Quantification (BLQ) concentrations from any of the sparse PK samples 
will be set to missing, regardless of the week of collection. 
13.6.11. 
eCRF Baseline Third Agent Class Determination 
Baseline third agent will be determined as the third agent ingredient: 
• still being taken at randomisation for TBR patients 
• discontinued immediately prior to randomisation for DTG + 3TC patients. 


 
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13.7. 
Appendix 7: Reporting Standards for Missing Data 
13.7.1. 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 Late Switch Phase 
at the Week 200 visit, and did not enter the Continuation Phase; 
 
• Subjects randomised to either treatment group, completed the Randomised 
Late Switch Phase at the Week 200 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 subject no longer derives clinical benefit, or  
o the subject meets a protocol-defined reason for discontinuation, or 
o development of the DTG plus 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. 
13.7.2. 
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 non-responders in the derivation of the 
proportion of subjects with HIV-1 RNA < 50 c/mL (or <400 c/mL). The nature of 
this missing data will be further classified in Snapshot summaries as either 
‘Virologic Failure’ or ‘No Virologic Data at Week X’; see Section 13.11 for full 
details. Further details of missing data as a result of COVID-19 and Snapshot 
sensivity analyses relevant to analyses at Week 96, Week 144 and W196 can 
be seen in Section 13.14.1. 


 
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Element 
Reporting Detail 
LOCF 
• In the LOCF dataset, missing values will be carried forward from the previous, 
non-missing available on-treatment assessment. 
Lipid LOCF 
• If subjects initiate serum lipid-lowering agents Post-baseline, then the last 
available fasted On-treatment lipid values prior to the initiation will be used in 
place of future, observed On-treatment values.  
• Imputation will continue even if the subject discontinues the lipid-lowering agent.  
• Missing assessments will not be imputed.  
• Subjects on lipid-lowering agents at baseline will be excluded from this dataset. 
This dataset will be used for all summaries of lipids data. 
Observed 
Case (OC) 
• This dataset uses only the data that is available at a particular timepoint, with no 
imputation for missing values. 
Lipid W196 
• If subjects initiate serum lipid-lowering agents Post-baseline/LS baseline, then 
the subsequent values will be set to missing.  
• Subjects on lipid-lowering agents at baseline/LS baseline will be excluded from 
this dataset 
• The observed case dataset will be used for all summaries of lipids data. 
 
13.7.2.1. Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in subject listing displays. 
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 study completion date 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 CRFs and TBR treatment is 
recorded on the CONART CRFs. 
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 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, 


 
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Element 
Reporting Detail 
data cut off date or withdrawal date; in this case the earliest of the three 
dates will be used. 
• The recorded partial date will be displayed in listings. 
Concomitant 
Medications 
• Partial dates for any concomitant medications recorded in the CRF 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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13.8. 
Appendix 8: Values of Potential Clinical Importance 
Element 
Reporting Detail 
Laboratory 
Values and 
Adverse 
Events 
• The DAIDS grading for severity of laboratory toxicities and clinical adverse 
events is included in the protocol.  
• The central laboratory will flag lab parameter toxicities directly in the 
provided datasets. 
 
 


 
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13.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Not applicable to analyses post Week 48. 


 
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13.10. 
Appendix 10: Time to Event Details 
13.10.1. TRDF Detailed Steps 
TRDF Detailed steps 
For studies that have a Late Switch or Continuation Phase, ensure only data pertinent to 
the analysis is included, see study RAP for definition of Treatment Phase. 
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.  
Randomised Period denotes period where subjects are still on their randomised treatment, prior 
to late switch of study treatment. This is also irrespective of blinding. Hence, Randomised Period 
also refers to Early Switch Phase.  
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 first 
elevation immediately preceding CVW 
 
 
1.1 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. 
1.2 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. 


 
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TRDF Detailed steps 
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 that is 
considered both: (i) drug related 
(AEREL=Y) and (ii) results 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 domain (for DTG + 3TC subject) 
or Concomitant Medication domain (for 
TBRsubjects)]). 
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 
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 
Exposure domain (for DTG + 3TC subject) 
 
 


 
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TRDF Detailed steps 
or Concomitant Medication domain (for 
TBRsubjects)]). 
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 Visit domain], Study day of 
permanent treatment discontinuation [from 
Exposure domain (for DTG + 3TC subject) 
or Concomitant Medication domain (for 
TBRsubjects)]). 
 
 
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) 
 
 


 
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TRDF Detailed steps 
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 domain (for DTG + 3TC subject) 
or Concomitant Medication domain (for 
TBRsubjects)]). 
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 
i.e tempAVAL ≤ upper bound of the 
analysis visit window 
 
CNSR=1 EVNTDESC=Censored due 
to Study Discontinuation for 
Other Reasons. 
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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13.10.2. 
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 first 
elevation 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 that is 
considered both: (i) drug related 
(AEREL=Y) and (ii) results 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 
Exposure domain]). 
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 Visit domain], Study 
day of permanent treatment 
discontinuation [from 
Exposure domain]). 
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 


 
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TRDF Detailed steps 
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 
Exposure domain]) 
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 
Exposure domain]) 
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 
1. Notes: 
2. Randomised Period = Randomised Early Switch Phase  
3. Efficacy visit windows should be used throughout for the upper bound of the analysis visit window 
4. Subjects are considered to have completed the randomised period if they completed the Early Switch Phase. 
5. 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  
6. EVNTDESC, AVAL & CNSR variables created for the following timepoints:  
7. Week 24, 48, 96, 144 – for the table analysis 
8. Overall – for the Kaplan-Meier plot  
 
13.10.3. ERDF Detailed Steps 
 
Similar algorithm will be applied for ERDF analyses and  Kaplan-Meier figure, where 
condition 2 and 3 in Section 13.10.1 and Section 13.10.2 will not be considered.  
 
 


 
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13.11. 
Appendix 11: Snapshot 
Detailed Algorithm Steps 
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 
• Note: The only protocol-permitted substitutions are as follows: 
- A switch from a PI boosted with RTV to the same PI boosted with cobicistat is allowed. 
- A switch from a PI boosted with cobicistat to the same PI boosted with RTV is allowed. 
Note the same process will be mapped out for Week 24, Week 96, Week 144 and Week 196 
Please refer to Section 13.14.1 for further details of Snapshot modifications in presence of 
COVID-19 missing data (relevant to analyses at Week 96, Week 144 and Week 196). 
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    
 
 
• 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 
• Last on-treatment VL during Week 48 prior 
to/on the date of change <50   c/mL 
HIV1-RNA 
< 50  
 


 
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• 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  
 
 
• Last on-treatment VL during Week 48 ≥ 50 
c/mL 
HIV1-RNA 
≥ 50  
Data in window 
not below 50 
• Last on-treatment VL during Week 48 <50 
c/mL 
HIV1-RNA 
< 50  
 
b. No VL during Week 48    
 
 
i. 
if subjects still on study (i.e. IP has not 
been permanently stopped up to Week 
48) 
No virologic 
data at 
Week 48 
Window  
On study but 
missing data in 
window 
ii. 
If subjects withdraw before/during Week 
48 due to 
 
 
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 
2.  Non-safety 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) 
 
 


 
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• 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 
• Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to Lack of efficacy 
HIV1-RNA 
≥ 50  
Disc. for lack 
of efficacy 
• Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to all other non-safety 
related reasons 
HIV1-RNA 
≥ 50  
Dis. for other 
reason while 
not below 50 
[a]: Excluding permitted change in background therapy where change or decision to 
change is made prior to/on the first on-treatment viral result  
Examples from FDA guidance 
Data in Window 
Virologic outcome should be determined by the last available measurement while the patient is on 
treatment and continued on trial within the time window: 
• HIV-RNA = 580 copies/mL at Day 336, HIV-RNA below 50 copies/mL on Day 350. This 
should be categorized as HIV-RNA below 50 copies/mL. 
No Data in Window 
Discontinued study due to Adverse Event or Death: 
• Any patient who discontinues because of an AE or death before the window should be 
classified as Discontinued due to AE or Death (as appropriate), regardless of the HIV-
RNA result, even if the HIV-RNA is below 50 copies/mL at the time of discontinuation.  
• However, if a patient has an HIV-RNA value in the time window and also discontinues in 
the time window, the viral load data should be used to classify the patient’s response. 
This is the Virology First hierarchy: 
a. HIV-RNA below 50 copies/mL at Day 336 and discontinues because of AE or 
even dies on Day 360 — this person is categorized as having HIV-RNA below 
50 copies/mL.  
b. HIV-RNA is 552 copies/mL on Day 336 and the patient discontinues on Day 
360, the patient is categorized as having HIV-RNA greater than or equal to 50 
copies/mL. 
Discontinued for Other Reasons: 
• Only patients who have achieved virologic suppression can be counted as Discontinued 
for Other Reasons. 
• If a patient discontinues the study before the window because of lack of efficacy then 
the patient should be included in the HIV-RNA greater than or equal to 50 row and not in 
the Discontinued for Other Reasons row. 


 
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• If a patient discontinues because of subject withdrew consent and his or her HIV-1 RNA 
result at the time of discontinuation was equal to or above 50 copies/mL, then he or she 
should be categorized as HIV-RNA greater than or equal to 50 and NOT as 
Discontinued for Other Reasons.  
• If a patient discontinued because of Lost to Follow-Up and the last HIV-RNA result was 
49 copies/mL, then the patient can be categorized as Discontinued for Other Reasons. 
• If patients changed background treatment — not permitted by protocol— they should be 
considered an efficacy failure and captured in the HIV-RNA greater than or equal to 50 
copies/mL row. 
On study but missing data in window: 
• If there are no data during Days 294 to 377, but there is an HIV-RNA below 50 
copies/mL on Day 380, this patient should be considered On Study but Missing Data in 
Window. 
• If there are no data during Days 294 to 377, but there is an HIV-RNA equal to or above 
50 copies/mL on Day 280, this patient also should be classified as On Study but 
Missing Data in Window. 
Optimized Background Therapy Substitutions After Randomisation 
• OBT substitutions (in-class or cross-class) permitted per protocol for documented 
toxicity reasons can be permitted on or before the first trial visit without penalty.  
• If OBT substitutions for toxicity reasons occur after the first trial visit, then patients 
should be categorized as having HIV-RNA greater than or equal to 50 copies/mL if they 
have HIV-RNA above 50 copies/mL at the time of switch. 
 


 
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13.12. 
Appendix 12: Abbreviations & Trade Marks 
13.12.1. Abbreviations 
Abbreviation 
Description 
A&R 
Analysis and Reporting  
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
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 
DOV 
Date of Visit 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
ERDF 
Efficacy Related Discontinuation Failure 
GSK 
GlaxoSmithKline 
GUI 
Guidance 
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 
LOC 
Last Observation Carries Forward 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAMOS 
Randomisation & Medication Ordering System  
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TAF 
Tenofovir alafenamide fumarate 


 
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Abbreviation 
Description 
TBR 
TAF based regimen 
TFL 
Tables, Figures & Listings  
TRDF 
Treatment Related Discontinuation Failure 
 
13.12.2. 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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13.13. 
Appendix 13: Model Checking and Diagnostics for 
Statistical Analyses 
13.13.1. 
Statistical Analysis Assumptions 
Endpoint(s) 
Change from Baseline in bone/renal/inflammatory biomarkers, EQ5D, 
weight, BMI, lipids and HOMA-IR 
Analysis 
      MMRM 
• 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. 
• 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. 
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. 


 
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13.14. 
Appendix 14: COVID-19 Modified Analyses and Supportive 
Sensitivity Analyses 
This section outlines the additional analyses that will be performed at Week 96 onwards 
to account for the effect of COVID-19. 
13.14.1. 
Efficacy Analyses (Snapshot) 
The main efficacy analysis remains that performed on the ITT-E analysis. Study 
Outcomes based on the main Table 2.4-Table 2.6 will be reported in line with the 
Modified Snaphot Algorithm (Section 13.14.1.2) that presents additional subcategories 
related to COVID-19 missing and intercurrent event data (otherwise top-level outcomes 
of >=50 c/mL, <50 c/mL and No Virologic Data remain unaffected). Summary tables to 
test for non-inferiority (Table 2.1-Table 2.3, Table 2.7, Table 2.8 and Table 2.34) will 
remain unchanged. 
A supplemental analysis for study outcomes (Table 2.38) and treatment comparison of 
HIV-1 RNA >=50 c/mL endpoint (Table 2.36) and HIV-1 RNA <50 c/mL endpoint 
(Table 2.37) will be performed on the Efficacy Evaluable Population, which excludes 
subjects with no Week 96 data due to COVID-19. Subjects with no HIV-1 RNA recorded 
within the Week 96 analysis visit window will be excluded either as a result of 
discontinuation from the study due to COVID-19 as recorded on study conclusion page 
or still on-study but no Week 96 data as a result of COVID-19, as recorded in the 
protocol deviations log. (If COVID-19 is not recorded as a reason for discontinuation 
from study on the study conclusion page, then this may be captured from protocol 
deviations and/or AE page.) In the event that there is a higher rate of primary endpoint 
missing data observed than expected, an assessment will be made as to whether this 
analysis will be supplemented or replaced with an imputation-based analysis where 
subjects’ last-on treatment HIV-1 RNA prior to Week 96 will be used in lieu of missing 
Week 96 HIV-1 RNA data as a result of COVID-19. Imputation will only be considered 
for subjects with missing data as a result of COVID-19 (i.e. discontinued due to COVID-
19 or on study but missing data due to COVID-19). Following imputation, the Snapshot 
algorithm will be performed in the same way as described in Section 13.11, and Study 
Outcomes and non-inferority test outputs will be performed. The above supplemental 
analysis on Efficacy Evaluable Population performed at Week 144.The main Study 
Outcomes analyses for subjects with HIV-1 RNA <40 c/mL and HIV-1 RNA <40 c/mL 
and Target Not Detected based on ITT-E population in Table 2.31 and Table 2.35) will 
be reported in line with the Modified Snapshot Algorithm (Section 13.14.1.2, which 
presents additional subcategories related to COVID-19 missing and intercurrent event 
data. The corresponding analyses for the comparison in proportions of subjects with HIV-
1 RNA <40 c/mL and HIV-1 RNA <40 c/mL and Target Not Detected (Table 2.27 and 
Table 2.28, respectively) will remain unchanged. A supplemental analysis for HIV-1 
RNA <40 c/mL and Target Not Detected based on the Evaluable Efficacy Population, 
which excludes subjects with no Week 96 data due to COVID-19 as above. Study 
Outcomes (Table 2.39) and test for comparison (Table 2.40) will be reported.  
Refer to shells document for further details. 


 
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13.14.1.1. Change in Study Treatment 
Given that subjects with any changes in study treatment should be withdrawn from study 
per protocol instructions, it is anticipated that there will be minimal (if any) changes in 
study treatment Snapshot outcomes. However, in the event of any unforeseen change in 
study treatment events then change in study treatment outcomes will be reported by 
COVID-19 and non-COVID-19 subcategories in line with steps 1-4 of the Modified 
Snapshot Algorithm rules as presented in Section 13.14.1.2. 
13.14.1.2. Modified Snapshot Algorithm 
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 13.11, however it 
reports additional subcategories to account for outcomes related to COVID-19. 
Condition  
( ‘Week 48’ indicates Week 48 window) 
Response  
Reasons 
1.  If non-permitted change in background therapy 
prior to Week 48 (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 48 (COVID-19 switch)  
HIV1-RNA ≥ 
50 
 
Change in 
background therapy 
(COVID-19 related) 
2.1    If permitted change (not related to COVID-19) in 
background therapy prior to Week 48 AND the 
latest on-treatment VL prior to/on the date of 
change is ≥ 50 c/mL 
HIV1-RNA ≥ 
50 
 
Change in 
background therapy 
(Non- COVID-19 
related)   
2.2   If permitted change (related to COVID-19) in 
background therapy prior to Week 48 AND the 
latest on-treatment VL prior to/on the date of 
change is ≥ 50 c/mL 
HIV1-RNA ≥ 
50 
 
Change in 
background therapy 
COVID-19 related)  
1. If non-permitted change in background therapy 
during Week 48    
 
 
2.      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.      3.2  Last on-treatment VL during Week 48 prior 
to/on the date of change <50   c/mL 
HIV1-RNA < 
50  
 
4.      3.3.1  No VL during Week 48 prior to/on the date 
of change (non-COVID-19 related)    
HIV1-RNA ≥ 
50  
Change in 
background therapy 
(Non- COVID-19 
related)    
5.      3.3.2  No VL during Week 48 prior to/on the date 
of change (COVID-19 related)     
HIV1-RNA ≥ 
50  
 
Change in 
background therapy 
(COVID-19 related) 


 
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Condition  
( ‘Week 48’ indicates Week 48 window) 
Response  
Reasons 
1. 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 missed visit not 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: 
 
 
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 
No virologic 
data at Week 
48 Window  
Disc. due to 
AE/death 
(Non- COVID-19 
related) 


 
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Condition  
( ‘Week 48’ indicates Week 48 window) 
Response  
Reasons 
recorded in eCRF Conclusion form where 
related to pandemic not equal to ‘Yes’) 
5.3.2.2  COVID-19 safety reasons eCRF (e.g. 
AE/death resulting from COVID-19 as 
recorded in the eCRF Conclusion form 
where related to pandemic=’Yes’) 
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 and pandemic-related not 
equal to ’Yes’) 
 
 
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, lack of efficacy, 
protocol deviation, investigator discretion et 
al. as recorded in eCRF Study Conclusion 
Form and pandemic-related=’Yes’) 
 
 
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 Lack of efficacy  
HIV1-RNA ≥ 
50   
Disc. for lack of 
efficacy 
(COVID-19 related) 
5.3.2.4.3 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 
(COVID-19 related) 
 
 


 
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13.15. 
Appendix 15: List of Data Displays 
13.15.1. 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 
 
13.15.2. Mock Example Shell Referencing 
Non-IDSL specifications will be referenced as indicated and if required example mock-
up displays provided in Appendix 16: 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 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
13.15.3. 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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13.15.4. Study Population Tables 
Note that where the Deliverable column states ‘All’, this refers to all reporting efforts i.e. Weeks 24, 48, 96, 144, and 196. 
Note: For W196 combined outputs (combining Early and Late Switch Phase outputs for DTG+3TC arm and Late Switch Phase for TBR 
arm), population presented in output header will be oveall Safety/ITTE/ CVW/ Viral Genotypic/ Viral Phenotypic but Treatment Lable for 
Early Switch DTG+3TC as ES DTC+3TC and for Late Switch TBR arm as ‘LS DTG+3TC’. For outputs on change from baseline 
summary or post-baseline events, Baseline for LS DTG+3TC should be labelled as ‘LS Baseline’.  
Note: For outputs which uses LS Baseline in the title or template add the footnote “LS Baseline - Baseline for LS DTG/3TC, the latest 
available pre-switch data”. Also in any existing footnote for baseline replace “Baseline” with “Baseline/LS Baseline”. 
Note: For all outputs, Early Switch DTG+3TC and should be labelled as ES DTC+3TC and Late Switch TBR arm as ‘LS DTG+3TC’. 
 
Note: The following footnote should be added for all Listings’ Note: TBR subjects are switched to DTG+3TC in  Late Switch Phase from 
Week 148’ 
Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
 
ITT-E 
ES1  
 
Summary of Subject Disposition for the Subject 
Conclusion Record - Early Switch Phase  
 
Not repeated 
Present the disposition by 
• 
Overall 
• 
Related to COVID-19 
• 
Not Related to COVID-19 
 Weeks 24, 
48, 96 and 
144 
1.101 
ITT-E 
ES1  
 
Summary of Subject Disposition for the Subject 
Conclusion Record - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
Present the disposition by 
• 
Overall 
• 
Related to COVID-19 
• 
Not Related to COVID-19 
Week 196 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.2. 
 
 
 
 
No longer required 
 
1.3. 
 
ITT-E 
ES4 
Summary of Subject Disposition at Each Study Epoch 
 
 
1.4. 
 
All 
Subjects 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
Not repeated 
Weeks 24, 48, 
96, 144 
1.5. 
 
All 
Subjects 
Screened 
NS1 
Summary of Number of Subjects Enrolled by Country and 
Site ID 
Not repeated  
Weeks 24, 48, 
96, 144 
1.6. 
 
ITT-E 
POP_T1 
Summary of Reasons for Withdrawal by Visit- Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96 
1.601 
ITT-E 
POP_T1 
Summary of Reasons for Withdrawal by Visit - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) 
 
Week 196 
(including 
W200) 
Protocol Deviation 
1.7. 
 
ITT-E 
DV1 
Summary of Important Protocol Deviations- Early Switch 
Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
1.701 
ITT-E 
DV1 
Summary of Important Protocol Deviations - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) 
 
Week 196 
(including 
W200) 
1.8. 
 
ITT-E 
DV1 
Summary of Protocol Deviations Leading to Exclusion 
from the Per-Protocol Population- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144  


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Population Analysed 
1.9. 
 
All 
Subjects 
Screened 
SP1 
Summary of Study Populations  
 
All 
1.10. 
 
 
 
 
No longer required 
 
Demographic and Baseline Characteristics 
1.11. 
 
ITT-E 
DM1  
Summary of Demographic Characteristics 
Not repeated 
Weeks 24, 48, 
96, 144 
1.1102 
LS-ITT-E 
DM1  
Summary of Demographic Characteristics - TBR arm – 
Late Switch Phase 
 
Week 196 
1.12. 
 
All 
Subjects 
Screened 
DM11 
Summary of Age Ranges 
Not repeated 
Weeks 24, 48, 
96 
1.13. 
 
ITT-E 
DM5 
Summary of Race and Racial Combinations 
Not repeated 
Weeks 24, 48, 
96 
1.14. 
 
ITT-E 
DM6 
Summary of Race and Racial Combinations Details 
Not repeated 
Weeks 24, 48, 
96, 144 
1.1402 
LS-ITT-E 
DM6 
Summary of Race and Racial Combinations Details - 
TBR arm – Late Switch Phase 
 
Week 196 
1.15. 
 
ITT-E 
POP_T2 
Summary of Hepatitis Status at Entry 
Not repeated 
Weeks 24, 48, 
96, 144 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.1502 
LS-ITT-E 
POP_T2 
Summary of Hepatitis Status at Entry - TBR arm – Late 
Switch Phase 
For Late switch Phase at study entry 
and any new event through W144 
Week 196 
1.16. 
 
ITT-E 
CDC1 
Summary of CDC Classification of HIV Infection at 
Baseline 
Not repeated 
Weeks 24, 48, 
96, 144 
1.1602 
LS-ITT-E 
CDC1 
Summary of CDC Classification of HIV Infection at 
Baseline - TBR arm - Late Switch Phase 
 
Week 196 
1.17. 
 
ITT-E 
RF1 
Summary of HIV Risk Factors 
Not repeated 
Weeks 24, 48, 
96, 144 
1.1702 
LS-ITT-E 
RF1 
Summary of HIV Risk Factors - TBR arm – Late Switch 
Phase 
 
Week 196 
1.18. 
 
ITT-E 
POP_T3 
Summary of Screening  Cardiovascular Risk 
Assessments 
Not repeated 
Weeks 24, 48, 
96, 144 
1.1802 
LS-ITT-E 
POP_T3 
Summary of Screening  Cardiovascular Risk 
Assessments - TBR arm – Late Switch Phase 
Framingham risk score from W144. 
Add footnote to indicate this 
Week 196 
1.19. 
 
ITT-E 
POP_T4 
Summary of Distribution of CD4+ Cell Count (cells/mm^3) 
Results at Screening and Baseline 
Not repeated 
Weeks 24, 48, 
96, 144 
1.1902 
LS-ITT-E 
POP_T4 
Summary of Distribution of CD4+ Cell Count (cells/mm^3) 
Results at LS Baseline - TBR arm – Late Switch Phase 
 
Week 196 
Prior and Concomitant Medications, Medical Conditions 
1.20. 
 
ITT-E 
MH1 
Summary of Current Medical Conditions - Early Switch 
Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.2001 
ITT-E 
MH1 
Summary of Current Medical Conditions - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) 
 
Week 196  
1.21. 
 
ITT-E 
MH1 
Summary of Past Medical Conditions 
Not repeated 
Weeks 24, 48, 
96, 144 
1.2101 
LS-ITT-E 
MH1 
Summary of Past Medical Conditions - TBR arm – Late 
Switch Phase 
 
Week 196 
1.22. 
 
ITT-E 
CM1 
Summary of Concomitant Medications by Ingredient ATC 
Level 1- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
1.2201 
ITT-E 
CM1 
Summary of Concomitant Medications by Ingredient ATC 
Level 1 - DTG + 3TC arm (Early and Late Switch Phase) 
and TBR arm (Late Switch Phase) 
 
Week 196 
(including 
W200) 
1.23. 
 
ITT-E 
CM8 
Summary of Concomitant Medication Ingredient 
Combinations - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
1.2301 
ITT-E 
CM8 
Summary of Concomitant Medication Ingredient 
Combinations - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
 
Week 196 
(including 
W200) 
1.24. 
 
ITT-E 
CM1b 
Summary of Concomitant Medications by Combination 
Term ATC Level 1- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
1.2401 
ITT-E 
CM1b 
Summary of Concomitant Medications by Combination 
Term ATC Level 1 - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
Week 196 
(including 
W200) 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.25. 
 
ITT-E 
POP_T5 
Summary of Antiretroviral Therapy Stopped Prior to 
Screening 
Not repeated 
Weeks 24, 48, 
96, 144 
1.26. 
 
ITT-E 
POP_T5 
Summary of Antiretroviral Therapy Received at 
Screening 
Not repeated 
Weeks 24, 48, 
96, 144 
1.2602 
LS-ITT-E 
POP_T5 
Summary of Antiretroviral Therapy Received at 
Screening - TBR arm – Late Switch Phase 
 
Week 196 
1.27. 
 
ITT-E 
MH4 
Summary of Current Cardiac, Gastrointestinal, 
Metabolism and Nutrition, Psychiatric, Renal and Urinary, 
and Nervous System Conditions 
Not repeated 
Weeks 24, 48, 
96, 144 
1.2701 
ITT-E 
MH4 
Summary of Current Cardiac, Gastrointestinal, 
Metabolism and Nutrition, Psychiatric, Renal and Urinary, 
and Nervous System Conditions - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
Week 196 
(including 
W200) 
1.28. 
 
ITT-E 
MH4 
Summary of Past Cardiac, Gastrointestinal, Metabolism 
and Nutrition, Psychiatric, Renal and Urinary, and 
Nervous System Conditions 
Not repeated 
Weeks 24, 48, 
96, 144 
1.2801 
LS-ITT-E 
MH4 
Summary of Past Cardiac, Gastrointestinal, Metabolism 
and Nutrition, Psychiatric, Renal and Urinary, and 
Nervous System Conditions - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) 
 
Week 196 
1.29. 
 
ITT-E 
POP_T6 
Summary of Lipid Modifying Agent Use at Baseline 
Not repeated 
Weeks 24, 48, 
96, 144 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.2902 
LS-ITT-E 
POP_T6 
Summary of Lipid Modifying Agent Use at LS Baseline - 
TBR arm – Late Switch Phase 
 
Week 196 
1.30. 
 
ITT-E 
POP_T6 
Summary of Lipid Modifying Agent Use Starting Post-
Baseline- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
1.3001 
ITT-E 
POP_T6 
Summary of Lipid Modifying Agent Use Starting Post-
Baseline - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
1.31. 
 
ITT-E 
POP_T7 
Summary of History of Depression and Anxiety at 
Baseline 
Not repeated 
Weeks 24, 48, 
96, 144 
1.3102 
LS-ITT-E 
POP_T7 
Summary of History of Depression and Anxiety at LS 
Baseline - TBR arm – Late Switch Phase 
LS Baseline – at study entry or 
through W144 
Week 196 
1.32. 
 
ITT-E 
POP_T8 
Summary of Baseline Third Agent Class 
Not repeated 
Weeks 24, 48, 
96, 144 
1.3202 
LS-ITT-E 
POP_T8 
Summary of Baseline Third Agent Class - TBR arm - Late 
Switch Phase 
 
Week 196 
1.33. 
 
ITT-E 
NS1 
Summary of Number of Subjects Enrolled by Country and 
Site ID –ITT-E 
Not repeated 
Weeks 24, 48, 
96  
1.3302 
LS-ITT-E 
NS1 
Summary of Number of Subjects Enrolled by Country and 
Site ID – TBR arm - Late Switch Phase 
 
W196 
1.34. 
 
ITT-E 
POP_T9 
Summary of Number of Subjects Attending Nominal and 
Actual Analysis Visits - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 
1.35. 
 
 
 
 
No longer required 
 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.36. 
 
ITT-E 
 POP_T10 
Summary of Antiretroviral Therapy at Screening by 
Regimen 
Not repeated 
Weeks 24, 48, 
96, 144 
1.3602 
LS-ITT-E 
 POP_T10 
Summary of Antiretroviral Therapy at Screening by 
Regimen - TBR arm - Late Switch Phase 
 
W196 
1.37. 
 
ITT-E 
POP_T11 
Summary of Distribution of Quantitative Plasma HIV-1 
RNA Results at Baseline 
Not repeated 
48, 96, 144 
1.3702 
LS-ITT-E 
POP_T11 
Summary of Distribution of Quantitative Plasma HIV-1 
RNA Results at LS Baseline - TBR arm - Late Switch 
Phase 
 
Week 196 
1.38. 
 
ITT-E 
POP_T12 
Summary of Time since First Antiretroviral Therapy until 
Day 1 - Early Switch Phase 
Not repeated 
Week 24, 48, 
96, 144 
1.3802 
LS-ITT-E 
POP_T12 
Summary of Time since First Antiretroviral Therapy until 
Day 1 - TBR arm - Late Switch Phase 
 
W196 
1.39. 
 
ITT-E 
POP_T13 
Summary of Misrandomized Strata or Treatment 
Not required 
48, 96, 144 
1.40. 
 
ITT-E 
POP_T5 
 
Summary of On-Treatment Antiretroviral Therapy Starting 
after Day 1- Early Switch Phase 
Not repeated 
48, 96, 144 
1.4001 
ITT-E 
POP_T5 
 
Summary of On-Treatment Antiretroviral Therapy Starting 
after Day 1 for DTG + 3TC arm (Early and Late Switch 
Phase) and Starting after switch for TBR arm (Late 
Switch Phase) 
 
Week 196 
(including 
W200) 
1.41. 
 
ITT-E 
POP_T5 
 
Summary of Antiretroviral Therapy Starting after 
Treatment Discontinuation- Early Switch Phase 
Not repeated 
48, 96, 144 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.4101 
ITT-E 
POP_T5 
 
Summary of Antiretroviral Therapy Starting after 
Treatment Discontinuation - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) 
 
Week 196 
(including 
W200) 
1.42. 
 
ITT-E 
POP_T10 
 
Summary of On-Treatment Antiretroviral Therapy Starting 
after Screening by Regimen- Early Switch Phase 
Not repeated 
48, 96, 144 
1.4201 
ITT-E 
POP_T10 
 
Summary of On-Treatment Antiretroviral after Day 1 for 
DTG + 3TC arm (Early and Late Switch Phase) and after 
switch for TBR arm (Late Switch Phase) by Regimen 
 
Week 196 
(including 
W200) 
1.43. 
 
ITT-E 
POP_T10 
 
Summary of Antiretroviral Therapy Starting after 
Treatment Discontinuation by Regimen- Early Switch 
Phase 
Not repeated 
48, 96, 144 
1.4301 
ITT-E 
POP_T10 
 
Summary of Antiretroviral Therapy Starting after 
Treatment Discontinuation by Regimen - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
Week 196 
(including 
W200) 
1.44. 
 
ITT-E 
DV1 
Summary of Important COVID-19 Protocol Deviations - 
Early Switch Phase 
Not repeated 
96, 144 
1.4401 
ITT-E 
DV1 
Summary of Important COVID-19 Protocol Deviations - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
 
Week 196 
(including 
W200) 
1.45. 
 
ITT-E 
DV1 
Summary of Important non-COVID-19 Protocol 
Deviations - Early Switch Phase 
Not repeated 
 96, 144 


 
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Study Population Tables 
No. 
Populati
on 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.46. 
 
ITT-E 
PAN4 
Summary of COVID-19 Pandemic Visit Impacts - Early 
Switch Phase  
Not repeated 
144 
1.4601 
ITT-E 
PAN4 
Summary of COVID-19 Pandemic Visit Impacts - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) 
 
Week 196 
(including 
W200) 
 


 
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13.15.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Primary Efficacy Analysis 
2.1. 
ITT-E 
EFF_T1 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA ≥ 50 c/mL at Week X – Snapshot 
Analysis - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.2. 
Per-
Protocol 
EFF_T1 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA ≥ 50 c/mL at Week X – Snapshot 
Analysis - PP - Early Switch Phase  
No longer required 
Weeks 24, 48, 
96 and 144 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
2.3. 
ITT 
EFF_T1 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA ≥ 50 c/mL at Week X – Snapshot 
Analysis – ITT - Early Switch Phase  
No longer required 
Weeks 24, 48, 
96 and 144 
2.4. 
ITT-E 
TBC 
Summary of Study Outcomes (Plasma HIV-1 RNA ≥ / < 50 
c/mL) at Week X – Snapshot Analysis - Early Switch Phase 
See Modified Snapshot in 
Section 13.14.1 
Not repeated 
Weeks 24, 48, 
96 and 144 
2.401 
ITT-E 
TBC 
Summary of Study Outcomes (Plasma HIV-1 RNA ≥ / < 50 
c/mL) at Week X – Snapshot Analysis - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 
2.5. 
Per-
Protocol 
TBC 
Summary of Study Outcomes (Plasma HIV-1 RNA ≥ / < 50 
c/mL) at Week X – Snapshot Analysis - PP - Early Switch 
Phase 
See Modified Snapshot in 
Section 13.14.1 
No longer required 
Weeks 24, 48, 
96 and 144 
2.6. 
ITT 
TBC 
Summary of Study Outcomes (Plasma HIV-1 RNA ≥ / < 50 
c/mL) at Week X – Snapshot Analysis- ITT - Early Switch 
Phase 
See Modified Snapshot in 
Section 13.14.1 
No longer required 
Weeks 24, 48, 
96 and 144 
2.7. 
ITT-E 
EFF_T1 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA ≥ 50 c/mL at Week X – Snapshot 
Analysis (Sparse Data Sensitivity Analysis) - Early Switch 
Phase 
No longer required 
Weeks 24, 48, 
96 and 144 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Secondary Efficacy Analyses 
2.8. 
ITT-E 
EFF_T2 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL at Week X – Snapshot 
Analysis - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.9. 
 
 
 
No longer required 
 
2.10. 
 
 
 
 
No longer required 
 
2.11. 
 
ITT-E 
EFF_T5 
Summary of Proportion of Subjects with Plasma HIV-1 
RNA ≥50 c/mL by Visit – Snapshot Analysis - Early Switch 
Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.12. 
 
ITT-E 
EFF_T5 
Summary of Proportion of Subjects with Plasma HIV-1 
RNA <50 c/mL by Visit – Snapshot Analysis - Early Switch 
Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
2.1201 
ITT-E 
EFF_T5 
Summary of Proportion of Subjects with Plasma HIV-1 
RNA <50 c/mL by Visit – Snapshot Analysis - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) 
 
W196 
2.13. 
 
ITT-E 
EFF_T6 
Summary of Proportion of Subjects with Plasma HIV-1 
RNA <50 c/mL at Week X by Subgroup – Snapshot 
Analysis - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.14. 
 
 
 
 
No longer required 
 
2.15. 
 
ITT-E 
EFF_T3 
Summary of Study Outcomes (Plasma HIV-1 RNA ≥ / < 50 
c/mL) at Week X by Subgroup - Snapshot Analysis - Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
2.16. 
 
ITT-E 
EFF_T8 
Summary of Change from Baseline in Plasma HIV-1 RNA 
(log10 c/mL) by Visit - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 
2.17. 
 
ITT-E 
EFF_T9 
Summary of Change from Baseline in CD4+ count 
(cells/mm3) by Visit - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
2.1701 
ITT-E 
EFF_T9 
Summary of Change from Baseline in CD4+ count 
(cells/mm3) by Visit - DTG + 3TC arm - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
LS baseline for TBR arm 
Week 196 
(including 
W200) 
2.18. 
 
ITT-E 
EFF_T9 
Summary of Change from Baseline in in CD4+/CD8+ count 
ratio (cells/mm3) by Visit - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
2.1801 
ITT-E 
EFF_T9 
Summary of Change from Baseline in in CD4+/CD8+ count 
ratio (cells/mm3) by Visit - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
LS baseline for TBR arm 
W196 
2.19. 
 
ITT-E 
EFF_T10 
Summary of Post-Baseline HIV-1 Associated Conditions 
Including and Excluding Recurrences – Early Switch Phase Not repeated 
Weeks 24, 48, 
96 and 144 
2.1901 
ITT-E 
EFF_T10 
Summary of Post-Baseline HIV-1 Associated Conditions 
Including and Excluding Recurrences - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
LS baseline for TBR arm 
Week 196 
(including 
W200) 
2.20. 
 
 
 
 
No longer required  
 
2.21. 
 
ITT-E 
EFF_T11 
Summary of Post-Baseline HIV-1 Disease Progressions - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
2.2101 
ITT-E 
EFF_T11 
Summary of Post-Baseline HIV-1 Disease Progressions - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS baseline for TBR arm 
Week 196 
(including 
W200) 
2.22. 
 
ITT-E 
EFF_T12 
Cumulative Proportion of Subjects Meeting Confirmed 
Virologic Withdrawal Criteria by Visit - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
2.2201 
ITT-E 
EFF_T12 
Cumulative Proportion of Subjects Meeting Confirmed 
Virologic Withdrawal Criteria by Visit - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 
2.23. 
 
ITT-E 
EFF_T13 
Distribution of Quantitative Plasma HIV-1 RNA Results at 
Suspected and Confirmed Virologic Withdrawal - Early 
Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
2.24. 
 
ITT-E 
EFF_T14 
Summary of Change from Baseline in in CD4+ count 
(cells/mm3) at Week X by Subgroup - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.25. 
 
ITT-E 
EFF_T15 
Summary of Kaplan-Meier Estimates of Proportion of 
Subjects Without Confirmed Virologic Withdrawal at Week 
X - Treatment Related Discontinuation = Failure - Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.26. 
 
ITT-E 
EFF_T15 
Summary of Kaplan-Meier Estimates of Proportion of 
Subjects Without Confirmed Virologic Withdrawal at Week 
X - Efficacy Related Discontinuation = Failure - Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
2.27. 
 
ITT-E 
EFF_T2 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA <40 c/mL at Week X – Snapshot 
Analysis - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.28. 
 
ITT-E 
EFF_T2 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA <40 c/mL and Target Not Detected 
Status at Week X - Snapshot Analysis - Early Switch 
Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.29. 
 
 
 
 
No longer required  
 
2.30. 
 
 
 
 
No longer required  
 
2.31. 
 
ITT-E 
EFF_T3 
Summary of Study Outcomes (<40 c/mL and Target Not 
Detected Status) at Week X – Snapshot - Early Switch 
Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
2.3101 
ITT-E 
EFF_T3 
Summary of Study Outcomes (<40 c/mL and Target Not 
Detected Status) at Week X – Snapshot - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 
2.32. 
 
 
 
 
No longer required 
 
2.33. 
 
ITT-E 
EFF_T6 
Summary of Change from Baseline in CD4+/CD8+ Count 
Ratio (cells/mm3) at Week X by Subgroup - Early Switch 
Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
2.34. 
 
ITT-E 
EFF_T14 
Summary of Analysis for Proportion of Subjects with Plasma 
HIV-1 RNA <50 c/mL at Week X – Snapshot Analysis - 
Withdrawal Bias Sensitvity Analysis - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
2.35. 
 
ITT-E 
EFF_T2 
Summary of Study Outcomes (<40 c/mL) at Week X - 
Snapshot Analysis - Early Switch Phase 
Not repeated 
48, 96 and 
144 
2.3501 
ITT-E 
EFF_T2 
Summary of Study Outcomes (<40 c/mL) at Week X - 
Snapshot Analysis - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
W196 
2.36. 
 
EEP 
EFF_T1 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA ≥ 50 c/mL at Week X – Snapshot 
Analysis (Evaluable Efficacy Population) - Early Switch 
Phase 
No longer required 
96, 144 
2.37. 
 
EEP 
EFF_T1 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA < 50 c/mL at Week X – Snapshot 
Analysis (Evaluable Efficacy Population) - Early Switch 
Phase 
No longer required 
96, 144 
2.38. 
 
EEP 
EFF_T2 
Summary of Study Outcomes (Plasma HIV-1 RNA ≥ / < 50 
c/mL) at Week X – Snapshot Analysis (Evaluable Efficacy 
Population) - Early Switch Phase 
No longer required 
96, 144 
2.39. 
 
EEP 
EFF_T2 
Summary of Study Outcomes (<40 c/mL and Target Not 
Detected Status) at Week X – Snapshot (Evaluable 
Efficacy Population) - Early Switch Phase 
No longer required 
96, 144 
2.40. 
 
EEP 
EFF_T1 
Summary of Analysis for Proportion of Subjects with 
Plasma HIV-1 RNA <40 c/mL and Target Not Detected 
Status at Week X - Snapshot Analysis (Evaluable Efficacy 
Population) - Early Switch Phase 
No longer required 
96, 
 


 
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13.15.6. Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Primary Efficacy Analyses 
2.1
 
 
 
No longer required  
 
Secondary Efficacy Analyses 
2.2. 
 
 
 
No longer required  
 
2.3. 
ITT-E 
EFF_F2 
Unadjusted Treatment Difference in Proportion (95% CI) of 
Subjects with HIV-1 RNA <50 c/mL at Week X by 
Subgroup – Snapshot Analysis - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 
2.4. 
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 - Early 
Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
2.401 
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 - DTG + 
3TC arm - Early and Late Switch Phase 
 
W196 
2.402 
LS-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 - TBR arm 
- Late Switch Phase 
 
W196 
2.5. 
 
 
 
No longer required  
 
2.6. 
ITT-E 
EFF_F4 
Kaplan-Meier Plot of Time to Failure - Treatment Related 
Discontinuation = Failure (TRDF) - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 
2.7. 
ITT-E 
EFF_F4 
Kaplan-Meier Plot of Time to Failure - Efficacy Related 
Discontinuation = Failure (ERDF) - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 
 


 
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13.15.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure 
3.1. 
Safety 
SAFE_T1 
Summary of Extent of Exposure to Investigational Product / 
Study Treatment – Early Switch Phase  
Not repeated 
Weeks 24, 48, 
96 and 144 
3.2. 
Safety 
SAFE_T1 
Summary of Extent of Exposure to Investigational Product / 
Study Treatment - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
 
Week 144, 
W196(includin
g W200 
3.3. 
LS-Safety 
SAFE_T1 
Summary of Extent of Exposure to Investigational Product / 
Study Treatment - TBR - Late Switch Phase  
No longer required 
Week 144 
Adverse Events (AEs) 
3.4. 
Safety 
AE1  
 
Summary of All Adverse Events by System Organ Class 
and Preferred Term - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.401 
Safety 
AE1  
 
Summary of All Adverse Events by System Organ Class 
and Preferred Term - DTG + 3TC  - Early and Late Switch 
Phase 
DTG+3TC arm only 
No longer required 
 Week 144 
3.402 
LS-Safety 
AE1  
 
Summary of All Adverse Events by System Organ Class 
and Preferred Term - TBR - Late Switch Phase 
 
TBR arm which has switched 
over to DTG+3TC only 
No longer required 
Week 144 
3.5. 
 
 
 
No longer required 
 
3.6. 
Safety 
AE5A 
Summary of All Adverse Events by Maximum Grade - Early 
Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.601 
Safety 
AE5A 
Summary of All Adverse Events by System Organ Class 
and Preferred Term and by Maximum Grade - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) 
 
W196(includin
g W200) 
3.7. 
Safety 
AE3 
Summary of Common (>=2%) Adverse Events by Overall 
Frequency- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.701 
Safety 
AE3 
Summary of Common (>=2%) Adverse Events by Overall 
Frequency - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
 
W196 
(including 
W200) 
3.8. 
Safety 
AE3 
Summary of Common (>=2%) Grade 2-5 Adverse Events 
by Overall Frequency- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.801 
Safety 
AE3 
Summary of Common (>=2%) Grade 2-5 Adverse Events 
by Overall Frequency - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
W196 
(including 
W200 
3.9. 
Safety 
AE1  
 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term – Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.10. 
 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.1001 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
 
Week 144, 
W196(includin
g W200 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.1002 
LS-Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade – 
TBR -  Late Switch Phase 
TBR arm which has switched 
over to DTG+3TC only 
No longer required 
Week 144 
3.11. 
 
Safety 
AE15 
Summary of Common (>=2%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subject and Occurrences) - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.1101 
Safety 
AE15 
Summary of Common (>=2%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subject and Occurrences) - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) 
 
W196(includin
g W200 
3.12. 
 
Safety 
AE3 
Summary of Common (>=0.5%) Drug-Related Grade 2-5 
Adverse Events by Overall Frequency- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.1201 
Safety 
AE3 
Summary of Common (>=0.5%) Drug-Related Grade 2-5 
Adverse Events by Overall Frequency - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196(includin
g W200 
3.13. 
 
 
 
 
No longer required  
 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Serious and Other Significant Adverse Events 
3.14. 
 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.1401 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
 
Week 144, 
W196(includin
g W200) 
3.1402 
LS-Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) – TBR - Late Switch Phase 
TBR arm which has switched 
over to DTG+3TC only 
No longer required 
Week 144 
3.15. 
 
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 - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.1501 
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 - DTG + 3TC  - Early and Late Switch 
Phase 
DTG+3TC arm only 
No longer required 
Week 144,  
3.1502 
LS-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 – TBR - Late Switch Phase 
TBR arm which has switched 
over to DTG+3TC only 
No longer required 
Week 144,  


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.16. 
 
Safety 
AE5A 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by Maximum Grade - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.1601 
Safety 
AE5A 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by Maximum Grade - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) 
 
W196(includin
g W200) 
3.17. 
 
 
 
 
No longer required  
 
3.18. 
 
Safety 
AE3 
Summary of Serious Adverse Events by System Organ 
Class - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.1801 
Safety 
AE3 
Summary of Serious Adverse Events by System Organ 
Class - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) 
 
W196(includin
g W200 
3.19. 
 
 
 
 
No longer required  
 
3.20. 
 
Safety 
AE1 
Summary of Drug-Related Serious Adverse Events by 
System Organ Class - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.2001 
Safety 
AE1 
Summary of Drug-Related Serious Adverse Events by 
System Organ Class - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
W196(includin
g W200 
3.21. 
 
 
 
 
No longer required 
 


 
CONFIDENTIAL 
 
 
 
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154 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Chemistry  
3.22. 
 
Safety 
LB1 
Summary of Chemistry Changes from Baseline by Visit - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.2201 
Safety 
LB1 
Summary of Chemistry Changes from Baseline by Visit - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.23. 
 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent Chemistry 
Toxicities - Lipid LOCF - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.2301 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent Chemistry 
Toxicities - DTG + 3TC arm (Early and Late Switch Phase) 
and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 144, 
W196 
(including 
W200) 
3.24. 
 
Safety 
LB1 
Summary of Fasting Lipids by Visit - Lipid LOCF - Early 
Switch Phase 
Not required 
Weeks 24, 48, 
96  
3.25. 
 
 
 
 
No longer required  
 
3.26. 
 
Safety 
LB1 
Summary of Fasting Lipids Percentage Changes from 
Baseline by Visit - Lipid LOCF - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.27. 
 
 
 
 
Not required 
 
3.2601 
Safety 
LB1 
Summary of Fasting Lipids Percentage Changes from 
Baseline by Visit - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 


 
CONFIDENTIAL 
 
 
 
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155 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.28. 
 
 
 
 
No longer required  
 
3.29. 
 
 
 
 
No longer required  
 
3.30. 
 
Safety 
SAFE_T5 
Summary of Changes in NCEP Lipid Baseline Category to 
Week X Category - Lipid LOCF – Early Switch Phase 
Triglycerides, HDL, LDL 
Cholesterol, Total Cholesterol 
(mmol/L) NCEP Categories 
Not repeated 
Weeks 24, 48, 
96, 144 
3.3001 
Safety 
SAFE_T5 
Summary of Changes in NCEP Lipid Baseline Category to 
Week X Category - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
Triglycerides, HDL, LDL 
Cholesterol, Total Cholesterol 
(mmol/L) NCEP Categories 
LS Baseline for TBR arm 
W196 
3.31. 
 
 
 
 
No longer required  
 
3.32. 
 
Safety 
SAFE_T6 
Summary of Changes in Total Cholesterol /HDL Ratio 
Baseline Category to Week X - Lipid LOCF - Early Switch 
Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.3201 
Safety 
SAFE_T6 
Summary of Changes in Total Cholesterol /HDL Ratio 
Baseline Category to Week 196 - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
3.33. 
 
 
 
 
No longer required 
 


 
CONFIDENTIAL 
 
 
 
204862 
 
156 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Hematology 
3.34. 
 
Safety 
LB1 
Summary of Hematology Changes from Baseline - Early 
Switch Phase 
Not repeated 
Weeks 24, 48, 
96,,4 
3.3401 
Safety 
LB1 
Summary of Hematology Changes from Baseline - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.35. 
 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent 
Hematology Toxicities - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.3501 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent 
Hematology Toxicities - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
Laboratory: Urinalysis 
3.36. 
 
 
 
 
No longer required 
 
Biomarkers 
3.37. 
 
Safety 
LB1 
Summary of Change from Baseline in Bone Biomarkers by 
Visit - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.3701 
Safety 
LB1 
Summary of Change from Baseline in Bone Biomarkers by 
Visit - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
3.38. 
 
Safety 
LB1 
Summary of Change from Baseline in Renal Biomarkers by 
Visit - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 


 
CONFIDENTIAL 
 
 
 
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157 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.3801 
Safety 
LB1 
Summary of Change from Baseline in Renal Biomarkers by 
Visit - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
3.39. 
 
Safety 
LB1 
Summary of Change from Baseline in Renal Biomarkers by 
Visit - Loge Transformed Data - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.3901 
Safety 
LB1 
Summary of Change from Baseline in Renal Biomarkers by 
Visit - Loge Transformed Data - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
3.40. 
 
 
 
 
No longer required 
 
3.41. 
 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline Bone 
Biomarkers – MMRM - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96, 144 
3.42. 
 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in Renal 
Biomarkers – MMRM - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96, 144 
3.43. 
 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in Renal 
Biomarkers - Loge Transformed Data - MMRM - Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96, 144 
3.44. 
 
 
 
 
No longer required  
 


 
CONFIDENTIAL 
 
 
 
204862 
 
158 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Hepatobiliary (Liver) 
3.45. 
 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.4501 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
 
W196 
(including 
W200) 
3.46. 
 
Safety 
LIVER10 
Summary of Subjects Meeting Hepatobiliary Abnormality 
Criteria – All Post-Baseline Abnormalities - Early Switch 
Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.4601 
Safety 
LIVER10 
Summary of Subjects Meeting Hepatobiliary Abnormality 
Criteria – All Post-Baseline Abnormalities - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
LS Baseline for TBR arm 
Week 144, 
W196 
(including 
W200) 
Other 
3.47. 
 
Safety 
SAFE_T8 
Summary of True Positive Suicidal Indication Alerts Based 
on eCSSRS by Visit - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.4701 
Safety 
SAFE_T8 
Summary of True Positive Suicidal Indication Alerts Based 
on eCSSRS by Visit - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
W196 
3.48. 
 
Safety 
SAFE_T9 
Summary of Subjects with C-SSRS Suicidal Ideation or 
Behaviour at Baseline - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.49. 
 
Safety 
SAFE_T9 
Summary of Subjects with Post Baseline C-SSRS Suicidal 
Ideation or Behaviour - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 


 
CONFIDENTIAL 
 
 
 
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159 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.4901 
Safety 
SAFE_T9 
Summary of Subjects with Post Baseline C-SSRS Suicidal 
Ideation or Behaviour - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
3.50. 
 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Anxiety 
Adverse Events of Special Interest - Early Switch Phase 
Not repeated 
All 
3.5001 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Anxiety 
Adverse Events of Special Interest - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.51. 
 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Depression 
Adverse Events of Special Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.5101 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Depression 
Adverse Events of Special Interest - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.52. 
 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Suicidality 
and Self Injury Adverse Events of Special Interest - Early 
Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.5201 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Suicidality 
and Self Injury Adverse Events of Special Interest - DTG + 
3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.53. 
 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Insomnia 
Adverse Events of Special Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 


 
CONFIDENTIAL 
 
 
 
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160 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.5301 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Insomnia  
Adverse Events of Special Interest - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.54. 
 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Rash 
Adverse Events of Special Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.5401 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Rash  
Adverse Events of Special Interest - DTG + 3TC arm (Early 
and Late Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.55. 
 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline 
Nightmare/Abnormal Dreams Adverse Events of Special 
Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.5501 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline 
Nightmare/Abnormal Dreams  Adverse Events of Special 
Interest - DTG + 3TC arm (Early and Late Switch Phase) 
and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.56. 
 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Drug 
Hypersensitivity Adverse Events of Special Interest - Early 
Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.5601 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Drug 
Hypersensitivity  Adverse Events of Special Interest - DTG 
+ 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 


 
CONFIDENTIAL 
 
 
 
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161 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.57. 
 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Anxiety Adverse Events of Special Interest - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.5701 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Anxiety Adverse Events of Special Interest - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.58. 
 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Depression Adverse Events of Special 
Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.5801 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Depression Adverse Events of Special 
Interest - DTG + 3TC arm (Early and Late Switch Phase) 
and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.59. 
 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Suicidality and Self Injury Adverse Events of 
Special Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.5901 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Suicidality and Self Injury Adverse Events of 
Special Interest - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.60. 
 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Insomnia Adverse Events of Special Interest 
- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 


 
CONFIDENTIAL 
 
 
 
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162 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.6001 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Insomnia Adverse Events of Special Interest 
- DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.61. 
 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Rash Adverse Events of Special Interest - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.6101 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Rash Adverse Events of Special Interest - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.62. 
 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Nightmare/Abnormal Dreams Adverse 
Events of Special Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.6201 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Nightmare/Abnormal Dreams Adverse 
Events of Special Interest - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.63. 
 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Drug Hypersensitivity Adverse Events of 
Special Interest - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.6301 
Safety 
SAFE_T11 
Summary of Onset and Duration of the First Occurrence of 
Post Baseline Drug Hypersensitivity Adverse Events of 
Special Interest - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
Week 196 
(including 
W200) 
3.64. 
 
 
 
 
No longer required  
 


 
CONFIDENTIAL 
 
 
 
204862 
 
163 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.65. 
 
 
 
 
No longer required 
 
3.66. 
 
 
 
 
No longer required 
 
3.67. 
 
 
 
 
No longer required 
 
3.68. 
 
 
 
 
No longer required 
 
3.69. 
 
 
 
 
No longer required 
 
3.70. 
 
 
 
 
No longer required 
 
3.71. 
 
Safety 
SAFE_T15 
Summary of Post Baseline Depression and Suicidal and 
Self-Injury Adverse Events by AE of Special Interest, 
Maximum DAIDS Toxicity Grade, and Prior History of 
Depression and Anxiety - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.7101 
Safety 
SAFE_T15 
Summary of Post Baseline Depression and Suicidal and 
Self-Injury Adverse Events by AE of Special Interest, 
Maximum DAIDS Toxicity Grade, and Prior History of 
Depression and Anxiety - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196(includin
g W200 
3.72. 
 
 
 
 
No longer required  
 
3.73. 
 
Safety 
LB1 
Summary of Change from Baseline in HOMA-Insulin 
Resistance at Week X - Loge Transformed Data - Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
3.74. 
 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in HOMA-
Insulin Resistance at Week X - Loge Transformed Data – 
MMRM - Early Switch Phase 
No longer required 
48, 96, 144 


 
CONFIDENTIAL 
 
 
 
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164 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.75. 
 
Safety 
LB1 
Summary of Change from Baseline in Weight (kg) by Visit - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.7501 
Safety 
LB1 
Summary of Change from Baseline in Weight (kg) by Visit - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.76. 
 
Safety 
LB1 
Summary of Change from Baseline in BMI (kg/m2) by Visit 
- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.7601 
Safety 
LB1 
Summary of Change from Baseline in BMI (kg/m2) by Visit 
- DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.77. 
 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in Weight (kg) 
– MMRM - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96,,144 
3.78. 
 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in BMI 
(kg/m2) – MMRM - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96, 144 
3.79. 
 
 
 
 
No longer required  
 
3.80. 
 
 
 
 
 
W196 
3.81. 
 
Safety 
SAFE_T16  Summary of HOMA-IR Shifts from Baseline to Week X - 
Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
3.8101 
Safety 
SAFE_T16  Summary of HOMA-IR Shifts from Baseline to Week X - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
3.82. 
 
 
 
 
No longer required 
 


 
CONFIDENTIAL 
 
 
 
204862 
 
165 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.83. 
 
Safety 
New shell 
Sumamry of Chemistry by Visit - Early Switch Phase 
Not required 
All 
3.84. 
 
Safety 
New shell 
Summary of Hematology by Visit - Early Switch Phase 
Not required 
All 
3.85. 
 
Safety 
New shell 
Summary of Weight (kg) by Visit - Early Switch Phase 
Not required 
All 
3.86. 
 
Safety 
New shell 
Summary of BMI (kg/m2) by Visit - Early Switch Phase 
Not required 
All 
3.87. 
 
 
 
 
No longer required 
 
3.88. 
 
 
 
 
No longer required 
 
3.89. 
 
 
 
 
No longer required 
 
3.90. 
 
 
 
 
No longer required 
 
3.91. 
 
 
 
 
No longer required 
 
3.92. 
 
 
 
 
No longer required 
 
3.93. 
 
 
 
 
No longer required 
 
3.94. 
 
 
 
 
No longer required 
 
3.95. 
 
 
 
 
No longer required 
 
3.96. 
 
Safety 
LB1 
Summary of Change from Baseline in Inflammatory 
Biomarkers - Loge Transformed Data - Early Switch Phase 
Not repeated 
48,96,144 
3.9601 
Safety 
LB1 
Summary of Change from Baseline in Inflammatory 
Biomarkers - Loge Transformed Data - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
LS Baseline for TBR arm 
W196 


 
CONFIDENTIAL 
 
 
 
204862 
 
166 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.97. 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in 
Inflammatory Biomarkers at Week X – Loge Transformed 
Data – MMRM – Early Switch Phase 
No longer required 
48,96,144 
3.98. 
Safety 
SAFE_T18 
Summary of Proportion of Subjects with Change from 
Baseline in Weight (>=3%, >=5% and >=10%) at Week X – 
Early Switch Phase 
Not repeated 
48,96,144 
3.9801 
Safety 
SAFE_T18 
Summary of Proportion of Subjects with Change from 
Baseline in Weight (>=3%, >=5% and >=10%) at Week X - 
DTG + 3TC arm (Early and Late Switch Phase) and TBR 
arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.99. 
Safety 
AE1  
 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term up to the End of the 
Week 144 Reporting Window (USPI) - Early Switch Phase 
Not repeated 
48,96,144 
3.9901 
Safety 
AE1  
 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term up to the End of the 
Week 196 Reporting Window (USPI)  - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 
(including 
W200) 
3.100 
Safety 
AE3 
Summary of Common (>=0.5%) Drug-Related Grade 2-5 
Adverse Events by Overall Frequency up to the End of the 
Week X Reporting Window (USPI)  - Early Switch Phase 
Not repeated 
48,96,144 


 
CONFIDENTIAL 
 
 
 
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167 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.10001 
Safety 
AE3 
Summary of Common (>=0.5%) Drug-Related Grade 2-5 
Adverse Events by Overall Frequency up to the End of the 
Week X Reporting Window (USPI)  - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 
(including 
W200) 
3.101 
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 up to the End of the Week X Reporting 
Window (USPI) - Early Switch Phase 
Not repeated 
48,96,144 
3.10101 
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 up to the End of the Week X Reporting 
Window (USPI)  - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
 
W196 
(including 
W200) 
3.102 
Safety 
SAFE_T2 
Summary of Cumulative Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or 
Withdrawal from Study by Visit - Early Switch Phase 
No longer required 
48,96,144 
3.103 
Safety 
SAFE_T14 
Summary of BMI Shifts from Baseline to Week X - Early 
Switch Phase 
No longer required 
48,96 
3.104 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Increase in 
Weight Adverse Events of Special Interest - Early Switch 
Phase 
Not repeated 
48,96,144 


 
CONFIDENTIAL 
 
 
 
204862 
 
168 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.10401 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Increase in 
Weight Adverse Events of Special Interest - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.105 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Decrease in 
Weight Adverse Events of Special Interest - Early Switch 
Phase 
Not repeated 
48,96,144 
3.10501 
Safety 
SAFE_T10 
Summary of Characteristics of Post Baseline Decrease in 
Weight Adverse Events of Special Interest - DTG + 3TC 
arm (Early and Late Switch Phase) and TBR arm (Late 
Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.106 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in Fasting 
Lipids - Loge Transformed Data - MMRM - Lipid LOCF - 
Early Switch Phase 
No longer required 
96, 144 
3.107 
Safety 
SAFE_T7 
Statistical Analysis of Variables Associated with >=2 
HOMA-IR at Week 48 - Logistic Regression - Early Switch 
Phase 
May not be performed depending 
on scope of missing data 
No longer required 
96, 144 
3.108 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent Clinical 
Chemistry Toxicities to the End of the Week X Reporting 
Window (USPI) – LOCF - Early Switch Phase 
Not repeated 
96, 144 
3.10801 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent Clinical 
Chemistry Toxicities to the End of the Week X Reporting 
Window (USPI) – LOCF - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 


 
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No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.109 
 
 
 
No longer required 
96, 144 
3.110 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent 
Hematology Toxicities to the End of the Week X Reporting 
Window (USPI) - Early Switch Phase 
For Week 144: Up to end of 
Week 144 visit window (i.e. 
Week 144 + 4) 
Not repeated 
96, 144 
3.11001 
Safety 
SAFE_T3 
Summary of Maximum Post-Baseline Emergent 
Hematology Toxicities to the End of the Week X Reporting 
Window (USPI) - DTG + 3TC arm (Early and Late Switch 
Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
(including 
W200) 
3.111 
Safety 
PAN1 
Summary of COVID-19 Assessments - Early Switch Phase 
Not repeated 
From week 96 
onwards 
3.11101 
Safety 
PAN1 
Summary of COVID-19 Assessments - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 
3.112 
Safety 
PAN10 
Summary of Exposure Adjusted Adverse Event Incidence 
Rates Over Time Overall and by Country, Gender and Age 
- Early Switch Phase 
No longer required 
96, 144 
3.113 
Safety 
AE5A 
Summary of All Adverse Events by Maximum Grade 
Adverse Events Reported After the End of the Week 48 
Analysis Window - Early Switch Phase 
No longer required 
96, 144 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.114 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade 
Adverse Events Reported After the End of the Week 48 
Analysis Window  - Early Switch Phase 
No longer required 
96, 144 
3.115 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) Adverse Events Reported After the End of 
the Week 48 Analysis Window - Early Switch Phase 
No longer required 
96, 144 
3.116 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by System Organ Class and Preferred Term 
Adverse Events Reported After the End of the Week 48 
Analysis Window - Early Switch Phase 
No longer required 
96, 144 
3.117 
Safety 
SAFE_T7 
Statistical Analysis of Change from Baseline in Weight (kg) 
by Visit - MMRM by Baseline BMI - Early Switch Phase 
By BMI categories 
No longer required 
96, 144 
3.118 
Safety 
New shell 
Summary of Waist to Height Ratio and Waist to Hip Ratio 
at Week 144 
Not repeated 
144 
3.11801 
Safety 
New shell 
Summary of Waist to Height Ratio and Waist to Hip Ratio 
by Visit - DTG + 3TC arm (Early and Late Switch Phase) 
and TBR arm (Late Switch Phase) 
 
W196 
(including 
W200) 
3.11803 
LS-Safety 
New shell 
Summary of Change from LS Baseline in Waist to Height 
Ratio and Waist to Hip Ratio at Week 196 - TBR arm – 
Late Switch Phase 
 
W196 
(including 
W200) 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.119 
Safety 
New shell 
Proportion of Subjects with Metabolic Syndrome at Week 
144 
Refer Table 1.025 in RE 
postcsr_2020_03 for shell 
(overall only) 
Not repeated 
144 
3.11901 
Safety 
New shell 
Proportion of Subjects with Metabolic Syndrome at Week 
196 - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) 
Refer Table 1.025 in RE 
postcsr_2020_03 for shell 
(overall only) 
W196 
(including 
W200) 
3.120 
Safety 
LB1 
Summary of Change from Baseline in Framingham Risk 
Score at Week 144 
Not repeated 
144 
3.12001 
Safety 
LB1 
Summary of Change from Baseline in Framingham Risk 
Score at Week 196 - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
LS Baseline for TBR arm 
W196 
3.121 
Safety 
LB1 
Summary of Change from Baseline in Systolic Blood 
Pressure  and Diastolic Blood Pressure at week 144 
Not repeated 
144 
3.12101 
Safety 
LB1 
Summary of Change from Baseline in Systolic Blood 
Pressure  and Diastolic Blood Pressure at week 196 - DTG 
+ 3TC arm (Early and Late Switch Phase) and TBR arm 
(Late Switch Phase) 
LS Baseline for TBR arm 
W196(includin
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13.15.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1. 
Safety 
AE10 
Plot of Common (>=2%) Adverse Events and Relative 
Risk- Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96, 144 
Laboratory 
3.2. 
Safety 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT - Early 
Switch Phase 
Not required 
Weeks 24, 48, 
96  
3.3. 
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.301 
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin - DTG + 3TC arm - Early and Late Switch Phase 
 
W196 
(including 
W200) 
3.302 
LS-Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin - TBR arm - Late Switch Phase 
 
W196 
(including 
W200) 


 
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Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Other 
3.4. 
Safety 
SAFE_F1 
Heatmap plot of Triglycerides, LDL Cholesterol, Total 
Cholesterol (mmol/L) NCEP Categories and Total 
Cholesterol/HDL Ratio at Week X vs. Baseline –Lipid 
LOCF - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
3.401 
Safety 
SAFE_F1 
Heatmap plot of Triglycerides, LDL Cholesterol, Total 
Cholesterol (mmol/L) NCEP Categories and Total 
Cholesterol/HDL Ratio at Week X vs. Baseline – DTG + 
3TC arm - Early and Late Switch Phase 
 
W196 
3.402 
LS-Safety 
SAFE_F1 
Heatmap plot of Triglycerides, LDL Cholesterol, Total 
Cholesterol (mmol/L) NCEP Categories and Total 
Cholesterol/HDL Ratio at Week X vs. LS Baseline - TBR 
arm - Late Switch Phase 
 
W196 
3.5. 
 
 
 
No longer required 
 
3.6. 
 
 
 
No longer required 
 
3.7. 
Safety 
SAFE_F2 
Line Plot of Adjusted Mean (95% CI) Change from 
Baseline in Renal Biomarkers Over Time — MMRM  - 
Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
3.8. 
Safety 
SAFE_F3 
Line Plot of Ratio of Geometric Means (95% CI) in Renal 
Biomarkers Over Time - Loge Transformed Data – 
MMRM - Early Switch Phase  
No longer required 
Weeks 24, 48, 
96 and 144 


 
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Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.9. 
Safety 
SAFE_F2 
Line Plot of Adjusted Mean (95% CI) of Change from 
Baseline in Bone Biomarkers Over Time — MMRM - 
Early Switch Phase 
No longer required 
Weeks 24, 48, 
96, 144 
3.10. 
 
Safety 
SAFE_F5 
Line Plot of Adjusted Mean (95% CI) of Change from 
Baseline in Weight (kg) Over Time — MMRM - Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96, 144 
3.11. 
 
Safety 
SAFE_F5 
Line Plot of Adjusted Mean (95% CI) of Change from 
Baseline in BMI (kg/m2) Over Time — MMRM - Early 
Switch Phase 
No longer required 
Weeks 24, 48, 
96, 144 
3.12. 
 
Safety 
SAFE_F1 
Bar Chart of Total Cholesterol/HDL Ratio Categories at 
Week X vs. Baseline –Lipid LOCF 
No longer required 
Weeks 24, 48,  
3.13. 
 
 
 
 
No longer required 
 
3.14. 
 
 
 
 
No longer required 
 
3.15. 
 
 
 
 
No longer required 
 
3.16. 
 
Safety 
SAFE_F2 
Line Plot of Ratio of Geometric Means (95% of CI) in 
HOMA-IR Over Time - Loge Transformed Data - MMRM - 
Early Switch Phase 
No longer required 
48, 96, 144 
3.17. 
 
 
 
 
No longer required 
 
3.18. 
 
 
 
 
No longer required 
 


 
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Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.19. 
 
 
 
 
No longer required 
 
3.20. 
 
 
 
 
No longer required 
 
3.21. 
 
 
 
 
No longer required 
 
3.22. 
 
Safety 
SAFE_F2 
Line Plot of Ratio of Geometric Means (95% of CI) in 
Inflammatory Biomarkers Over Time - Loge Transformed 
– MMRM - Early Switch Phase 
No longer required 
48, 96, 144 
3.23. 
 
Safety 
SAFE_F2 
Line Plot of Ratio of Geometric Means (95% CI) in 
Fasting Lipids Over Time - MMRM - Lipid LOCF - Loge 
Transformed Data - Early Switch Phase 
No longer required 
96, 144 
3.24. 
 
Safety 
SAFE_F2 
Line Plot of Adjusted Mean (95% of CI) of Change from 
Baseline in Weight (kg) Over Time - MMRM- by Baseline 
BMI - Early Switch Phase 
No longer required 
96, 144 
3.25. 
 
Safety 
SAFE_T14 
Heatmap plot of BMI at Week X vs. Baseline - Early 
Switch Phase 
Not repeated 
144 
3.2501 
Safety 
SAFE_T14 
Heatmap plot of BMI at Week X vs. Baseline - DTG + 
3TC arm - Early and Late Switch Phase 
 
W196 
(including 
W200) 
3.2502 
LS-Safety 
SAFE_T14 
Heatmap plot of BMI at Week X vs. LS Baseline - TBR 
arm - Late Switch Phase 
 
W196 
(including 
W200) 
 


 
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13.15.9. 
Virology tables  
Virology: Tables 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.1. 
CVW 
VIR_T1 
Summary of INSTI Mutations and Major Mutations of 
NRTI, NNRTI and PI Classes by region at Baseline and 
Time of CVW at or prior to Week X - Early Switch Phase 
Combine 4.1 and 4.2 
Weeks 24, 
48, 96 and 
144 
4.101 
CVW 
VIR_T1 
Summary of INSTI Mutations and Major Mutations of NRTI, 
NNRTI and PI Classes by region at Baseline and Time of 
CVW at or prior to Week X - DTG + 3TC arm (Early and 
Late Switch Phase) and TBR arm (Late Switch Phase) 
Combine 4.1 and 4.2 
 
W196 
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 - Early Switch Phase 
Not Required (Combine with 
4.1) 
Weeks 24, 
48, 96 


 
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4.3. 
CVW 
VIR_T3 
Summary of Genotypi c Susceptibility Score at Baseline 
and Time of CVW by Genotypic Cut-Off at or prior to 
Week X - Early Switch Phase 
Not Required 
All 
4.4.  
CVW 
VIR_T4 
Summary of Phenotype at Baseline and Time of CVW by 
Phenotypic Cut-off at or prior to Week X - Early Switch 
Phase 
Not repeated 
Weeks 24, 
48, 96 and 
144 
4.401 
CVW 
VIR_T4 
Summary of Phenotype at Baseline and Time of CVW by 
Phenotypic Cut-off at or prior to Week X - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 
4.5. 
CVW 
VIR_T5 
Summary of Phenotype at time of CVW by Number of 
Drugs to Which Subject are Resistant at or prior to Week 
X - Early Switch Phase 
Not repeated 
Weeks 24, 
48, 96 and 
144 
4.501 
CVW 
VIR_T5 
Summary of Phenotype at time of CVW by Number of 
Drugs to Which Subject are Resistant at or prior to Week 
X - DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) 
 
W196 
4.6. 
CVW 
VIR_T6 
Summary of Fold Change to DTG, 3TC, TDF and FTC at - 
Time of CVW at or prior to Week X - Early Switch Phase 
 
Not repeated 
Weeks 24, 
48, 96 and 
144 
4.601 
CVW 
VIR_T6 
Summary of Fold Change to DTG, 3TC, TDF and FTC at - 
Time of CVW at or prior to Week X - DTG + 3TC arm 
(Early and Late Switch Phase) and TBR arm (Late Switch 
Phase) 
 
W196 


 
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4.7. 
Viral 
Genotypic 
VIR_T7  
Summary of Subject Accountability: Genotypes Available 
at or prior to Week X - Early Switch Phase 
Not repeated 
Weeks 24, 
48, 96 and 
144 
4.701 
Viral 
Genotypic 
VIR_T7  
Summary of Subject Accountability: Genotypes Available 
at or prior to Week X - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
W196 
4.8. 
Viral 
Phenotypic 
VIR_T8  
Summary of Subject Accountability: Phenotypes Available 
at or prior to Week X - Early Switch Phase 
 
Not repeated 
Weeks 24, 
48, 96 and 
144 
4.801 
Viral 
Phenotypic 
VIR_T8  
Summary of Subject Accountability: Phenotypes Available 
at or prior to Week X - DTG + 3TC arm (Early and Late 
Switch Phase) and TBR arm (Late Switch Phase) 
 
W196 
 
 
 
 
 
 
 
 
 


 
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13.15.10. Pharmacokinetic Tables 
Pharmacokinetic : Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Intensive PK - PK Concentration Data 
5.1
 
 
 
No longer  required 
 
5.2
 
 
 
No longer  required  
 
Intensive PK Derived Parameters 
5.3. 
 
 
 
No longer  required 
 
5.4. 
 
 
 
No longer  required 
 
Sparse PK - PK Concentration Data 
5.5. 
 
 
 
No longer  required 
 
5.6. 
 
 
 
No longer  required 
 
5.7. 
 
 
 
No longer  required 
 
5.8. 
 
 
 
No longer  required 
 


 
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13.15.11. Pharmacokinetic Figures 
Pharmacokinetic : Figures 
No. 
Populatio
n 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Intensive PK - PK Concentration Data 
5.1. 
 
 
 
No longer  required 
 
5.2. 
 
 
 
No longer  required 
 
5.3. 
 
 
 
No longer  required 
 
5.4. 
 
 
 
No longer  required 
 
5.5. 
 
 
 
No longer  required 
 
5.6. 
 
 
 
No longer  required 
 
 


 
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13.15.12. Health Outcomes Tables  
Health Outcomes : Tables 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
EQ-5D-5L 
6.1. 
ITT(E) 
HO_T1 
Summary of EQ-5D Category Scores by visit – LOCF - 
Early Switch Phase 
No longer required 
Weeks 24, 48, 
96  
6.2. 
ITT(E) 
HO_T2 
Summary of EQ-5D Utility and Thermometer Scores by 
visit – LOCF - Early Switch Phase 
Not repeated 
Weeks 24, 48, 
96 and 144 
6.201 
ITT(E) 
HO_T2 
Summary of EQ-5D Utility and Thermometer Scores by 
visit – DTG + 3TC arm (Early and Late Switch Phase) and 
TBR arm (Late Switch Phase) 
Summary on Observed data 
For LS DTG+3TC group, label 
W144 as LS Baseline 
W196 
6.3. 
ITT(E) 
HO_T2 
Summary of Change from Baseline in EQ-5D Utility and 
Thermometer Scores – LOCF - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96  
6.4. 
ITT(E) 
HO_T3 
Statistical Analysis of Change from Baseline in EQ-5D 
Utility Scores – MMRM – LOCF - Early Switch Phase 
No longer required 
Weeks 24, 48, 
96 and 144 
6.5. 
ITT(E) 
HO_T3 
Statistical analysis of Change from Baseline in EQ-5D 
Thermometer Scores – MMRM – LOCF - Early Switch 
Phase 
No longer  required 
Weeks 24, 48, 
96 and 144 
Willingness to switch 
6.6. 
ITT(E) 
HO_T4 
Summary of Reasons for Willingness to Switch – Early 
Switch Phase 
Not repeated 
All 


 
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13.15.13. Health Outcomes Figures 
Health Outcomes : Figures 
No. 
Populatio
n 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
EQ-5D-5L 
6.1. 
ITT(E) 
HO_F1 
Line Plot of Adjusted Mean (95% CI) Change from 
Baseline in EQ-5D  Utility Score Over Time – MMRM - 
LOCF - Early Switch Phase 
No longer required 
Weeks 24, 
48, 96 and 
144 
6.2. 
ITT(E) 
HO_F1 
Line Plot of Adjusted Mean (95% CI) Change from 
Baseline in EQ-5D Thermometer Score Over Time – 
MMRM – LOCF - Early Switch Phase 
No longer required 
Weeks 24, 
48, 96 and 
144 
 
 
 


 
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13.15.14. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
All 
Subjects 
Screened 
ES7 
Listing of Reasons for Screen Failure 
Not repeated 
Weeks 24, 48, 
96, 144 
2.  
ITT-E 
ES2  
Listing of Reasons for Study Withdrawal 
Include period (Early switch 
phase/Late switch phase) in the 
output 
Include “Day Since Switch” in Study 
day column and provide for TBR arm 
All 
3.  
ITT-E 
SD3 
Listing of Reasons for Study Treatment Discontinuation Include “Day Since Switch” in Study 
day column and provide for TBR arm 
All 
4.  
     ITT 
TA1  
Listing of Planned Randomised and Actual Strata and 
Treatment Assignments 
Not repeated 
Weeks 24, 48, 
96 
5.  
     ITT 
POP_L1 
Listing of Subjects Randomised but not Treated 
Not repeated 
Weeks 24, 48, 
96 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviations 
6.  
ITT-E 
DV2 
Listing of Important Protocol Deviations  
Include period (Early switch 
phase/Late switch phase) in the 
output 
Include “Day Since Switch” in Study 
day column and provide for TBR arm 
All 
7.  
ITT-E 
IE4 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
 Not repeated 
Weeks 24, 48, 
96 
Populations Analysed 
8.  
ITT-E 
SP3a 
Listing of Protocol Deviations Leading to Exclusion 
from the Per Protocol Population 
No longer required 
Weeks 24, 48, 
96, 144 
Demographic and Baseline Characteristics 
9.  
ITT-E 
DM4 
Listing of Demographic Characteristics 
Not repeated 
Weeks 24, 48, 
96, 144 
10.  
ITT-E 
DM10 
Listing of Race 
Not repeated 
Weeks 24, 48, 
96, 144 
Efficacy  
11.  
ITTE 
EFF_L1 
Listing of Study Outcome (>= / < 50 c/mL) at Week X – 
Snapshot Analysis 
Please add COVID-19 
Relatedness column (Yes or blank) 
All 
12.  
ITTE 
EFF_L2 
Listing of Quantitative and Qualitative Plasma HIV-1 
RNA Data 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
All 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure and Treatment Compliance 
13.  
Safety 
EX3  
Listing of Exposure Data 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
All 
Adverse Events 
14.  
Safety 
AE8  
Listing of All Adverse Events 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include “Time Since Switch” in ‘Time 
since 1st dose/Time since last dose’ 
column and provide for TBR arm 
All 
15.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse 
Events 
 
All 
16.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text 
 
All 
17.  
Safety 
PSRAE1 
Listing of Possible Suicidality-Related Adverse Event 
Data: Event and Description (Section 1 and Section 2) 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include ‘Time since switch’ in output 
All 
18.  
Safety 
PSRAE3 
Listing of Possible Suicidality-Related Adverse Event 
Data: Possible Cause(s) (Section 3) 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include ‘Time since switch’ in output 
All 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
19.  
Safety 
PSRAE4 
Listing of Possible Suicidality-Related Adverse Event 
Data (Section 4) 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include ‘Time since switch’ in output 
All 
20.  
Safety 
PSRAE5 
Listing of Possible Suicidality-Related Adverse Event 
Data (Section 5 and Section 8) 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include ‘Time since switch’ in output 
All 
Serious and Other Significant Adverse Events 
21.  
Safety 
AE8  
 
Listing of Fatal Adverse Events 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include ‘Time since switch’ in output 
All 
22.  
Safety 
AE8  
Listing of Non-Fatal Serious Adverse Events 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include ‘Time since switch’ in output 
All 
23.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious 
Adverse Event 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
All 
24.  
Safety 
AE8 
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment 
Include study phase (Early switch 
phase/Late switch phase) in the 
output 
Include ‘Time since switch’ in output 
All 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
25.  
 
 
 
No longer required 
 
Hepatobiliary (Liver) 
26.  
Safety 
MH2 
Listing of Medical Conditions for Subjects with Liver 
Stopping Events 
 
All 
27.  
Safety 
SU2 
Listing of Substance Use for Subjects with Liver 
Stopping Events 
 
All 
All Laboratory 
28.  
Safety 
LB5  
Listing of Clinical Chemistry Laboratory Data for 
Subjects with Any Value of Potential Clinical 
Importance 
 
All 
29.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
 
All 
30.  
Safety 
LB5 
Listing of Urinalysis Data for Subjects with Any Value 
of Potential Clinical Importance 
 
All 
Vital Signs 
31.  
Safety 
VS4 
Listing of Vital Signs 
Add waist to height ratio and waist 
to hip ratio also in the listing 
All 
 
 


 
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13.15.15. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Study Population 
32.  
All 
Subjects 
Screened 
POP_L2 
 
 
Listing of Subject Recruitment by Country and Site 
Number 
Not repeated 
Weeks 24, 
48, 96, 144 
33.  
All 
Subjects 
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
Not repeated 
Weeks 24, 
48, 96, 144 
34.  
ITT(E) 
POP_L3 
 
Listing of Visit Dates 
 
All 
35.  
All 
Subjects 
Screened 
POP_L4 
 
Listing of Study Populations 
 
All 
36.  
ITT(E) 
POP_L5 
 
Listing of Hepatitis Test Results at Entry 
Not repeated 
Weeks 24, 
48, 96, 144 
37.  
ITT(E) 
CDC3 
Listing of CDC Classification of HIV Infection at Baseline 
Not repeated 
Weeks 24, 
48, 96 
38.  
ITT(E) 
RF2 
Listing of HIV Risk Factors 
Not repeated 
Weeks 24, 
48, 96 
39.  
ITT(E) 
POP_L6 
 
Listing of Screening Cardiovascular Risk Assessment 
Data 
Not repeated 
Weeks 24, 
48, 96 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
40.  
ITT(E) 
MH2 
Listing of Current and Past Medical Conditions at 
Baseline 
Not repeated 
Weeks 24, 
48, 96, 144 
41.  
ITT(E) 
POP_L7 
 
Listing of Relationship Between Concomitant ATC Level 
1, Ingredient and Verbatim Text  
 
All 
42.  
ITT(E) 
CM2 
Listing of Concomitant Medications 
Include ‘Day since switch’ in the 
output 
All 
43.  
ITT(E) 
CM2 
Listing of Antiretroval Therapy Stopped Prior to Screening Not repeated 
Weeks 24, 
48, 96, 144 
44.  
ITT(E) 
CM2 
Listing of Antiretroval Therapy Received at Screening 
Not repeated 
Weeks 24, 
48, 96, 144 
45.  
ITT(E) 
POP_L8 
 
Listing of Relationship Between Concomitant ATC Level 
4, Ingredient and Verbatim Text  
 
All 
Efficacy 
46.  
ITT(E) 
EFF_L3 
Listing of Plasma HIV-1 RNA data for subjects with 
Confirmed Virologic Withdrawal  
Include study phase (Early 
switch phase/Late switch 
phase) in the output 
Include ‘Day since switch’ in the 
output 
All 
47.  
ITT(E) 
EFF_L4 
Listing of CD4+ Cell Count Data 
Include study phase study 
phase  (Early switch phase/Late 
switch phase) in the output 
All 
48.  
ITT(E) 
EFF_L5 
Listing of CD8+ and CD4+/CD8+ Cell Count Ratio Data 
 
All 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
49.  
ITT(E) 
HIV4 
Listing of Stage 3 HIV-1 Associated Conditions 
Include study phase (Early 
switch phase/Late switch 
phase) in the output 
Include ‘Day since switch’ in the 
output 
All 
50.  
ITT(E) 
EFF_L6 
Listing of Subjects Treatment-related discontinuation = 
Failure (TRDF) and Efficacy-related discontinuation = 
Failure (ERDF) 
No longer required 
Week 24, 48, 
96, 144 
51.  
 
 
 
No longer required 
 
Safety 
52.  
Safety 
EG3  
Listing of ECG Findings 
 
All 
53.  
Safety 
SAFE_L1 
Listing of Post Baseline Maximum AL,  Maximum AST 
and Maximum Bilirubin  
 
All 
54.  
Safety 
SAFE_L2 
Listing of Subjects Meeting Hepatobiliary Abnormality 
Criteria - Post-Baseline Emergent 
 
All 
55.  
Safety 
SAFE_L3 
Listing of C-SSRS Suicidal Ideation and Behaviour Data 
Alerts (4-9) 
Include ‘Day since switch’ in output 
All 
56.  
Safety 
SAFE_L4 
Listing of C-SSRS Suicidal Ideation and Behaviour Data  
Include ‘Day since switch’ in output 
All 
57.  
Safety 
SAFE_L5 
Listing of C-SSRS False Positive Alerts with 
Corresponding Reasons 
Include ‘Day since switch’ in output 
All 
58.  
Safety 
SAFE_L5 
Listing of all C-SSRS True Positives, with Corresponding 
Reasons and AE or SAE status 
Include ‘Day since switch’ in output 
All 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
59.  
Safety 
SAFE_L6 
Listing of Subjects Who Became Pregnant During the 
Study 
Include study phase (Early 
switch phase/Late switch 
phase) in the output 
All 
60.  
Safety 
SAFE_L7 
Patient Profiles for Subjects Meeting Protocol Defined 
Liver Stopping Criteria 
 
All 
61.  
Safety 
SAFE_L7 
Patient Profiles for Subjects Meeting Confirmed Virologic 
Withdrawal Criteria 
 
All 
62.  
Safety 
SAFE_L8 
Listing of Cardiovascular Events  
 
All 
Intensive PK - PK Concentration Data 
63.  
 
 
 
No longer required 
 
64.  
 
 
 
No longer required 
 
Intensive PK Derived Parameters 
65.  
 
 
 
No longer required 
 
66.  
 
 
 
No longer required 
 
Sparse PK - PK Concentration Data 
67.  
 
 
 
No longer required 
 
68.  
 
 
 
No longer required 
 
Virology 
69.  
Viral 
Genotypic 
VIR_L1 
Listing of All Genotypic Data   
 
All 
70.  
 
 
 
No longer required 
 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
71.  
CVW 
VIR_L2 
Listing of Genotype by Genotypic Cut-Off – CVWs 
Add ‘Baseline S-GSS Score’ 
before ‘S-GSS Score’ 
All 
72.  
 
 
 
No longer required 
 
73.  
Viral 
Phenotypic 
VIR_L3 
Listing of All Phenotypic Data  
 
 
All 
74.  
 
 
 
No longer required 
 
75.  
 
 
 
No longer required 
 
76.  
 
 
 
No longer required 
 
77.  
 
 
 
No longer required 
 
78.  
 
 
 
No longer required 
 
79.  
 
 
 
No longer required 
 
80.  
 
 
 
No longer required 
 
81.  
CVW 
VIR_L7 
Listing of Genotypic and Phenotypic Data for Subjects 
with Confirmed Virologic Withdrawal Criteria 
 
All 
82.  
 
 
 
No longer required 
 
Health Outcomes 
83.  
ITT(E) 
HO_L1 
Listing of EQ-5D Category, Utility and Thermometer 
Scores 
Not required 
Weeks 24, 
48, 96 
Other 
84.  
Safety  
SAFE_L9 
Listing of Renal Biomarker Data 
 
Not required 
Weeks 24, 
48, 96 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
85.  
Safety  
SAFE_L9 
Listing of Bone Biomarker Data 
 
Not required 
Weeks 24, 
48, 96 
86.  
 
 
 
 
 
87.  
Safety 
SAFE_L9 
Listing of HOMA-Insulin Resistance Data 
 
All 
88.  
ITT-E 
VIR_L7 
Listing of Genotypic and Phenotypic Data for subjects 
Last on study VL>400 c/ml with resistance testing  
For non-CVW and on-treatment 
patients 
All 
89.  
ITT(E) 
EFF_L3 
Listing of Plasma HIV-1 RNA data for subjects with 
Potential Precautionary Virologic Withdrawal  
Include study phase (Early 
switch phase/Late switch 
phase) in the output 
All 
90.  
Safety 
LB5 
Listing of Hematology Laboratory Data for Subjects with 
Any Value of Potential Clinical Importance 
 
All 
Study Population and Safety 
91.  
ITT(E) 
POP_L9 
Listing of History of Cardiac Therapeutic Procedures 
Not required 
Weeks 24, 
48, 96 
92.  
ITT(E) 
POP_L10 
Listing of Investigational Product Accountability 
 
All 
93.  
 
 
 
No longer required 
 
94.  
Safety 
 
Listing of Inflammatory Biomarker Data 
 
48,96,144, 
196 
95.  
ITT(E) 
POP_L11 
Listing of On-Treatment Antiretroviral Therapy Starting 
after Day 1 
Include “Day Since Switch” in 
Study day column and provide for 
TBR arm 
48,96,144, 
196 
96.  
ITT(E) 
POP_L11 
Listing of Antiretroviral Therapy Starting after Treatment 
Discontinuation 
Include “Day Since Switch” in 
Study day column and provide for 
TBR arm 
48,96,144, 
196 


 
CONFIDENTIAL 
 
 
 
204862 
 
194 
 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
97.  
ITT(E) 
 
Listing of non-Important COVID-19 Protocol Deviations 
Not required 
96 
98.  
Safety 
 
Listing of All COVID-19 Adverse Events  
Mock shell - Refer Listing 98 in 
RE internal 04 
96, 144, 196 
99.  
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom 
Assessments for Subjects with COVID-19 Adverse 
Events  
 
96, 144, 196 
100. 
 
Safety 
 
Listing of Local Laboratory Data  
Mock shell - Refer Listing 100 in 
RE internal 04 
96, 144, 196 
101. 
 
ITT(E) 
 
PAN7 
Listing of All Subjects with Visits and Assessments 
Impacted by the Pandemic 
 
144, 196 
 


 
CONFIDENTIAL 
 
 
 
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13.16. 
Appendix 16: Example Mock Shells for Data Displays 
No mock shells were produced.