Clinical trial NCT02831764
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Keywords: tolerability HIV 1 efficacy treatment naïve two-drug regimen safety non inferiority
Sponsor: ViiV Healthcare
Start date: 2016-07-18; Completion date: 2022-06-29
Enrollment: 722 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will compare safety, efficacy, and tolerability of a two drug regimen of dolutegravir (DTG) plus (+) lamivudine (3TC) administered once daily with DTG plus two nucleoside reverse transcriptase inhibitors (tenofovir disoproxil fumarate \[TDF\]/emtricitabine \[FTC\] fixed dose combination \[FDC\]) administered once daily in human immunodeficiency virus (HIV) 1 infected adult participants that have not previously received antiretroviral therapy. The study is designed to demonstrate the non inferior antiviral activity of DTG + 3TC regimen to that of DTG + TDF/FTC FDC and will characterise the long term antiviral activity, tolerability and safety of DTG plus 3TC through Week 148. Approximately, 700 participants will be randomised 1:1 to receive DTG + 3TC or DTG + TDF/FTC FDC. Participants will be stratified by screening HIV 1 ribonucleotide nucleic acid (RNA) levels and by screening CD4+ (cluster of differentiation 4) cell count.

Detailed description:

Arms: arm 1: Eligible participants will receive one 50 mg tablet of DTG plus one overencapsulated 300 mg 3TC tablet orally once daily upto 96 weeks; thereafter will receive DTG plus 3TC tablet upto Week 148 and will continue to receive this schedule until (i) DTG and 3TC are both locally approved for use as part of a dual regimen, and the single entities of DTG and 3TC are available to patients (e.g. through public health services), or (ii) the DTG/3TC FDC tablet, if required by local regulations, is available, , or (iii) the participant no longer derives clinical benefit, or (iv) the participant meets a protocol defined reason for discontinuation, or (v) development of the DTG plus 3TC dual regimen is terminated. arm 2: Eligible participants will receive one 50 mg tablet of DTG plus one overencapsulated TDF/ FTC FDC (300/200 mg) tablet orally once daily upto 96 weeks; thereafter will receive DTG plus TDF/FTC FDC tablets upto Week 148 (open-label randomised phase).
Interventions: intervention 1: Dolutegravir (DTG) intervention 2: Lamivudine (3TC) intervention 3: Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC)
Intervention descriptions: intervention 1: DTG is available as 50 mg white, round, biconvex, film coated tablet debossed on one side with 'SV 572' and on the other side with '50'. The tablets are packaged into high density polyethylene (HDPE) bottles with induction seals and child resistant closures. Each 45 ml bottle contains 30 tablets and a desiccant. DTG 50 mg tablet will be orally administered once daily with or without food upto 148 weeks. intervention 2: Lamivudine is available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg lamivudine to visually match overencapsulated TDF/FTC FDC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated 3TC 300 mg tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, lamivudine will be dispensed as 300 mg white, diamond shaped, scored, film coated tablets debossed with 'GX CJ7' on both sides, packed in over labelled HDPE bottles with child-resistant closures each containing 30 tablets. intervention 3: Tenofovir disoproxil fumarate and Emtricitabine are available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg TDF and 200 mg FTC to visually match overencapsulated 3TC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated tenofovir disoproxil fumarate/emtricitabine tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, tenofovir disoproxil fumarate/emtricitabine will be dispensed as 300/200 mg white, blue, capsule shaped, film coated tablets debossed with 'GILEAD' on one side and '701' on another side, packed in overlabelled HDPE bottles with polypropylene childresistant closures each containing 30 tablets and a desiccant.

Protocol documents:
SAP_002.pdf: 
CONFIDENTIAL 
ViiV Healthcare group of companies 
 
205543 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan Amendment 3 for ViiV 
Healthcare-sponsored study 205543 (GEMINI-II): A Phase 
III, randomised, double-blind, multicentre, parallel-group, 
non-inferiority study evaluating the efficacy, safety, and 
tolerability of dolutegravir plus lamivudine compared to 
dolutegravir plus tenofovir/emtricitabine in HIV-1-infected 
treatment-naïve adults 
Compound Number  : GSK1349572 + GR109714 (GSK3515864) 
Effective Date  
: 18 Jul 2022 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for Protocol 205543 (GEMINI-II). 
• 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverables for reporting efforts up to Week 
148. 
• 
The planned (futility) and the event-triggered (CVW reviews) IDMC analyses are 
not covered in this RAP. Please refer to SF_1 00 Reporting and Analysis Plan 
(RAP)_D3 IDMC_204861_205543_13th_Dec 2016. 
• 
This version of the RAP amendment 3 (to the originally approved RAP dated 04-
JAN-2018 and RAP amendment 1 dated 08-APR-2019 and RAP amendment 2 
dated 05-MAY-2020) is to provide details on the Final End of Study (EOS) 
analysis. 
 
 
 
 
 
 
 
 


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CONFIDENTIAL 
 
 
205543 
3 
 
The main changes included in RAP Amendment 3 are listed in Section 10.16 Appendix 
16 – End of Study Analysis 
The main changes included in RAP Amendment 2 are 
The following few efficacy tables, safety tables, figures and listings are removed from 
Week 144/148 analyses. Please see Appendix 17 for details. 
• Additional category subgroup analysis of baseline plasma HIV-1 RNA and CD4+ 
cell count - for study outcomes  (< 50 c/mL) and for proportion of subjects with 
plasma HIV-1 RNA < 50 c/mL;  
• Summary of adverse events by system organ class, maximum toxicity and 
subgroups;  
• Summary of adverse events leading to permanent discontinuation of study 
treatment or withdrawal from study by subgroups; 
• Summary of total duration of adverse events of special interests for Anxiety, 
Depression, Drug Hypersensitivity, Insomnia, Nightmare/Abnormal Dreams,  
Rash, Suicidality and Self-Injury; 
• Summary and analysis of change from baseline in bone/renal biomarkers and 
lipids by subgroups;   
• Summary of changes in TC/HDL ratio, NCEP lipid from baseline category to 
maximum (minimum for HDL) post-baseline category; 
• Bar chart of TC/HDL ratio, NCEP lipids at baseline vs. maximum (minimum for 
HDL) post baseline; 
• Summary and listing of subjects meeting hepatobiliary abnormality criteria - all 
post-baseline abnormalities; 
• Summary of weight and BMI by visit; 
Explanation of Week 144 analysis non-inferiority margin added; 
Clarification for Columbia Suicide Severity Rating Scale endpoint derivation added; 
Derivation for analysis windowing edited and added to account for scheduled week 148 
visit; 
For week 148 analysis, a cut-off flag for data exclusion will be derived as:  
• Any assessments done after the upper bound study day 1050 (for parameter without 
scheduled visit at week 148) or 1078 (for event data and parameters with scheduled 
visit at week 148) will be excluded from week 148 analysis (tables and figures only), 
all data will be listed & also plotted in the individual subject plot.  
 
The main changes included in RAP Amendment 1 are: 
In accordance with the new CDC HIV staging categories, only Stage 3 HIV Associated 
Conditions were listed. 


CONFIDENTIAL 
 
 
205543 
4 
 
Statistical Analysis of Kaplan-Meier Estimates of Time to Viral Suppression (including 
figures) will be run Overall and by Baseline HIV-1 RNA and CD4+ Cell Count 
Subgroups   
Statistical Analysis of Kaplan-Meier Estimates of Proportion of Subjects Without 
Confirmed Virologic Withdrawal at Week X - Efficacy Related Discontinuation = Failure 
will be run Overall and by Baseline HIV-1 RNA and CD4+ Cell Count Subgroups     
In Time to Viral Suppression Analysis Subjects who withdraw for any reason without 
being suppressed during on treatment will be censored at earliest of (day of study 
discontinuation, day of withdrawal visit, day of treatment discontinuation) instead of 
withdrawal. 
Due to the nature of the data, the eCSSRS summaries were analysed using nominal visits 
instead of analysis visits based on visit windowing. 
Two additional renal biomarkers were analysed: Urine Beta-2 Microglobulin/Urine 
Creatinine, Urine Retinol Binding Protein/Urine Creatinine and two biomarkers were 
removed: Urine Beta-2 Microglobulin and Urine Retinol Binding Protein. 
Summary of Maximum Post-Baseline Emergent Chemistry Toxicities was updated to 
remove the overall summaries for calcium, glucose, potassium and sodium, and were 
instead summarized by ‘hyper’ and ‘hypo’ categories. 
For AE data, the lag time of 1 day is removed for ‘On-treatment’ derivation. 
New explanation added to 10.6.1 Week 24/48/96/144 cut-off date section how to check if 
the PD occurred prior or at week X viral load date (used for snapshot algorithm) 
Two additional subgroups were analysed: Age (<50, vs ≥50) and Race (White vs. Non-
White). 
Clarification added stating that Multiple imputation (MAR) analyses will be run at week 
24 and 48 only. No MAR analyses after week 48 will be performed. Mixed Model 
Repeated Measures (MMRM) analysis will be considered as the main analyses onwards. 
Clarification added stating that certain subgroups will be summarised and analysed for 
lipids and certain renal biomarkers after week 48.  
The following additional tables were included: 
Number of Subjects Attending Nominal and Actual Analysis Visits 
Summary of changes in total cholesterol/HDL ratio Baseline category to Week X 
Summary of AEs leading to permanent discontinuation of study treatment or withdrawal 
from study by maximum grade 
Summary of drug-related Grade 2-5 AEs 


CONFIDENTIAL 
 
 
205543 
5 
 
Summary of Subjects Meeting Hepatobiliary Abnormality Criteria - All Post- Baseline 
Abnormalities 
Subjects Meeting Hepatobiliary Abnormality Criteria - All Post-Baseline Abnormalities 
Plot of Common (>=2%) Grade 2-5 Adverse Events and Relative Risk 
Plot of Common (>=2%) Drug-Related Adverse Events and Relative Risk  
Plot of Adverse Events Categories and Relative Risk 
Summary of absolute values of fasting lipids by visit  
Summary of CD4+ Cell Count (cells/mm3) by Visit  
Summary of weight (kg) by Visit   
Summary of Change from Baseline in weight (kg) by Visit 
Summary of BMI (kg/m2) by Visit   
Summary of Change from Baseline in BMI (kg/m2) by Visit 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at Week X by Subgroups -  
Snapshot Analysis – Per Protocol population 
Summary of Analysis for Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL at 
Week X - Snapshot Analysis - ITT-E   
Summary of Study Outcomes (<40 c/mL) at Week X - Snapshot Analysis - ITT-E   
Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL by Visit – Snapshot Analysis 
Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL at Week X by Subgroups -
Snapshot Analysis - ITT-E  
Summary of Study Outcomes (<50 c/mL) at Week X by Baseline Plasma HIV-1 RNA 
and CD4+ Cell Count - Snapshot Analysis 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at Week X by Baseline 
Plasma HIV-1 RNA and CD4+ Cell Count - Snapshot Analysis – ITTE 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at Week X by Baseline 
Plasma HIV-1 RNA and CD4+ Cell Count - Snapshot Analysis - PP 


CONFIDENTIAL 
 
 
205543 
6 
 
TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNOPSIS ......................................................... 9 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION ................................................ 12 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan .......................... 12 
2.2. 
Study Objectives and Endpoints ................................................................. 12 
2.3. 
Study Design .............................................................................................. 14 
2.4. 
Statistical Hypotheses................................................................................. 15 
2.4.1. 
Week 144 Statistical Hypotheses ................................................. 15 
2.4.2. 
Rationale for non-inferiority margin at Week 144 ......................... 15 
3. 
PLANNED ANALYSES .......................................................................................... 16 
3.1. 
IDMC Interim Analyses ............................................................................... 16 
3.2. 
Primary Analyses ........................................................................................ 16 
3.3. 
Interim Analyses ......................................................................................... 16 
3.4. 
Final Analyses ............................................................................................ 16 
4. 
ANALYSIS POPULATIONS ................................................................................... 17 
4.1. 
Protocol Deviations ..................................................................................... 18 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 19 
6. 
STUDY POPULATION ANALYSES ....................................................................... 20 
6.1. 
Overview of Planned Study Population Analyses ........................................ 20 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 22 
7.1. 
Efficacy Analyses ........................................................................................ 22 
7.1.1. 
Overview of Planned Efficacy Analyses ....................................... 22 
7.1.2. 
Planned Efficacy Statistical Analyses ........................................... 23 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................. 26 
8.1. 
Efficacy Analyses ........................................................................................ 26 
8.1.1. 
Overview of Planned Efficacy Analyses ....................................... 26 
8.1.2. 
Planned Efficacy Statistical Analyses ........................................... 28 
8.2. 
Safety Analyses .......................................................................................... 31 
8.2.1. 
Overview of Planned Analyses .................................................... 31 
8.2.2. 
Planned Safety Statistical Analyses ............................................. 36 
8.3. 
Virology Analyses ....................................................................................... 42 
8.3.1. 
Overview of planned Virology Analyses ....................................... 42 
8.4. 
Health Outcomes Analyses ......................................................................... 43 
8.4.1. 
Overview of Planned Health Outcomes Analyses ........................ 43 
8.4.2. 
Planned Health Outcomes Statistical Analyses ............................ 44 
9. 
REFERENCES ....................................................................................................... 46 
10. APPENDICES ........................................................................................................ 47 
10.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 48 
10.1.1. 
Exclusions from Per Protocol Population ..................................... 48 


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205543 
7 
 
10.2. 
Appendix 2: Time & Events ......................................................................... 50 
10.2.1. 
Protocol Defined Time & Events .................................................. 50 
10.3. 
Appendix 3: Assessment Windows ............................................................. 55 
10.3.1. 
Definitions of Assessment Windows for Analyses ........................ 55 
10.4. 
Appendix 4: Treatment States and Phases ................................................. 58 
10.4.1. 
Study Phases .............................................................................. 58 
10.4.2. 
Treatment States ......................................................................... 58 
10.4.2.1. Treatment States for Laboratory, HIV 
Associated Conditions, Vital Signs, Health 
Outcomes and Genotypic and Phenotypic Data ......... 58 
10.4.2.2. Treatment States for AE Data ..................................... 58 
10.4.2.3. Treatment States for Prior/Concomitant/Post-
Therapy Medications Data .......................................... 59 
10.4.3. 
Post-treatment Assessments and Phases.................................... 60 
10.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 61 
10.5.1. 
Study Treatment & Sub-group Display Descriptors ...................... 61 
10.5.2. 
Baseline Definition & Derivations ................................................. 61 
10.5.2.1. Baseline Definitions .................................................... 61 
10.5.2.2. Derivations and Handling of Missing Baseline 
Data ........................................................................... 61 
10.5.3. 
Reporting Process & Standards ................................................... 61 
10.6. 
Appendix 6: Derived and Transformed Data ............................................... 64 
10.6.1. 
Week 24/48/96/144 cut off date ................................................... 64 
10.6.1.1. To calculate the total time on treatment prior or 
at week 24 .................................................................. 64 
10.6.1.2. To check if the PD occurred prior or at week 24 
viral load date (used for snapshot algorithm) .............. 64 
10.6.2. 
General ........................................................................................ 65 
10.6.3. 
Study Population .......................................................................... 66 
10.6.4. 
Safety .......................................................................................... 67 
10.6.5. 
Efficacy ........................................................................................ 71 
10.6.6. 
Viral Genotyping and Phenotyping ............................................... 75 
10.6.7. 
Health Outcomes ......................................................................... 80 
10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing Data ............... 81 
10.7.1. 
Premature Withdrawals ................................................................ 81 
10.7.2. 
Handling of Missing Data ............................................................. 81 
10.7.2.1. Handling of Partial and Missing Dates ........................ 81 
10.7.2.2. Handling of Missing Data for Statistical 
Analysis ...................................................................... 82 
10.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 84 
10.9. 
Appendix 9: Snapshot ................................................................................. 85 
10.9.1. 
Snapshot Algorithm Detailed Steps.............................................. 85 
10.10. Appendix 10: Multicenter Studies ................................................................ 87 
10.10.1. Methods for Handling Centres ..................................................... 87 
10.11. Appendix 11: Examination of Covariates, Subgroups & Other Strata .......... 88 
10.11.1. Handling of Covariates, Subgroups & Other Strata ...................... 88 
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses ..................................................................................................... 92 
10.12.1. Statistical Analysis Assumptions .................................................. 92 
10.13. Appendix 13: Time to Event Details ............................................................ 93 
10.13.1. TRDF Detailed Steps ................................................................... 93 
10.13.2. TRDF Detailed Steps for the Kaplan-Meier plot ........................... 96 


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205543 
8 
 
10.13.3. ERDF Detailed Steps ................................................................... 97 
10.13.4. Time to Viral Suppression ............................................................ 98 
10.14. Appendix 14: Q2 Creatinine Assay Accuracy Issue .................................... 99 
10.14.1. Q2 Creatinine Assay Accuracy Issue ........................................... 99 
10.15. Appendix 15: Abbreviations & Trade Marks .............................................. 100 
10.16. Appendix 16: End of Study (Final) Analysis .............................................. 102 
10.16.1. General considerations for data analyses ......................................... 102 
10.16.1.1. Study Phases .............................................................. 102 
10.16.1.2. Analysis Population for the Continuation Phase .............. 103 
10.16.2. Study Population .......................................................................... 103 
10.16.3. Efficacy Analysis ......................................................................... 104 
10.16.4. Safety Analysis ............................................................................ 104 
10.16.5. Virology analysis ......................................................................... 105 
10.16.6. COVID - 19 analysis .................................................................... 106 
10.16.7. List of Data Displays for End of Study (EOS) Final Report ............... 107 
10.17. Appendix 17: List of Data Displays............................................................ 115 
10.17.1. Data Display Numbering ............................................................ 115 
10.17.2. Mock Example Shell Referencing .............................................. 115 
10.17.3. Deliverables ............................................................................... 115 
10.17.4. Study Population Tables ............................................................ 116 
10.17.5. Efficacy Tables .......................................................................... 119 
10.17.6. Efficacy Figures ......................................................................... 124 
10.17.7. Safety Tables ............................................................................. 125 
10.17.8. Safety Figures ........................................................................... 134 
10.17.9. Virology tables ........................................................................... 136 
10.17.10. Health Outcomes Tables ........................................................... 137 
10.17.11. Health Outcomes Figures .......................................................... 137 
10.17.12. ICH Listings ............................................................................... 138 
10.17.13. Non-ICH Listings ........................................................................ 140 
10.18. Appendix 18: Example Mock Shells for Data Displays .............................. 145 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
 
205543 
9 
 
1. 
REPORTING & ANALYSIS PLAN SYNOPSIS 
Overview 
Key Elements of the RAP 
Purpose 
• 
This RAP describes the planned analyses and outputs required for the Clinical 
Study Reports for protocols 204861 (GEMINI-I) and 205543 (GEMINI-II). 
• 
The planned (futility) and the event-triggered (CVW reviews) IDMC analyses 
are not covered in this RAP. Please refer to SF_1 00 Reporting and Analysis 
Plan (RAP)_D3 IDMC_204861_205543_13th_Dec 2016. 
Protocol 
 
• 
This RAP is based on the protocol amendment 2 of study 205543 (Dated: 14-
JUN-2018, GSK Document No.: 2015N263962_02) and eCRF Version 
10.0 (Dated: 20-APR-2020). 
Primary 
Objective  
• 
To demonstrate non-inferior antiviral activity of DTG + 3TC versus DTG + 
TDF/FTC at 48 weeks in HIV-1-infected, ART-naïve subjects. 
Primary 
Endpoint 
• 
Proportion of subjects with plasma HIV-1 RNA <50 copies/mL (c/mL) at Week 
48 using the FDA Snapshot algorithm for the intent-to-treat exposed (ITT-E) 
population. 
Study 
Design 
• 
205543 and 204861 are two identical Phase III, randomised, double-blind, 
active-controlled, multicentre, parallel-group, non-inferiority studies. 
• 
Each sister study will be conducted in approximately 700 (350 subjects per 
arm) HIV-1 infected ART-naïve adults with screening plasma HIV-1 RNA of 
1,000 to ≤ 500,000 c/mL. 
• 
Subjects will be randomized 1:1 to receive a two-drug regimen of DTG plus 
3TC once daily or the three-drug regimen of DTG plus the FDC tablet of 
TDF/FTC once daily. Randomization will be stratified by screening plasma 
HIV-1 RNA (≤ or > 100,000 c/mL) and screening CD4+ cell count (≤ or > 200 
cells/mm3). 
• 
Both studies will comprise a 28-day screening phase (which may be extended 
to 35 days to allow receipt of all screening assessment results), a double-blind 
randomised phase (96 weeks), an open-label randomised phase (between 
Wee 96 and Week 148) and a continuation phase. 
• 
 No dose reductions, modifications in dosage, or changes in the frequency of 
dosing of any components of each regimen will be allowed in these studies. 
Planned 
Analyses 
• 
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. 


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205543 
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Overview 
Key Elements of the RAP 
 
• 
Further interim analyses may be conducted to support regulatory submissions 
and publications and pricing reimbursement dossiers. In particular, the 
following analyses will take place: secondary analysis at Week 24 (when the 
last subject has had their Week 24 viral load assessed, including a retest if 
required), secondary analysis at Week 96 (when the last subject has had their 
Week 96 viral load assessed, including a retest if required) and secondary 
analysis at Week 144 (when the last subject has had their Week 144 viral load 
assessed, including a retest if required). 
Analysis 
Populations 
• 
The ‘All subject screened’ population consisting of all subjects screened, 
including screen-failures. 
• 
The ‘Intent-to-Treat Exposed’ (ITT-E) population consisting of all randomised 
subjects who receive at least one dose of study medication, assessed 
according to their randomised treatment regardless of the treatment they 
receive. Unless otherwise stated, the ITT-E population will be used for the 
efficacy analyses. 
• 
The ‘Intent-to-Treat’ (ITT) population comprise of all randomised subjects. 
Subjects will be assessed according to their randomised treatment even if no 
study treatment was taken or the wrong treatment was received. 
• 
The ‘Per-Protocol Population’ consisting of subjects in the ITT-E population 
with the exception of significant protocol deviators, e.g. deviations that could 
affect the assessment of antiviral activity. Unless otherwise stated, the PP 
population will be used for the sensitivity analyses of the primary efficacy 
endpoint. 
• 
The ‘Safety’ population consisting of all subjects who receive at least one dose 
of study medication, assessed according to their actual treatment they 
received. Unless otherwise stated, this population will be used for the safety 
analyses. 
• 
‘CVW’ comprise of all subjects in the ITT-E population who have met the 
derived CVW criteria.  
• 
 ‘Viral Genotypic’ comprise of all subjects in the ITT-E population who have 
available On-treatment genotypic resistance data.  
• 
‘Viral Phenotypic’ comprise of all subjects in the ITT-E population who have 
available On-treatment phenotypic resistance data.  
Hypothesis 
• 
This study is designed to show that the antiviral effect of a simplified two-drug 
regimen of DTG plus 3TC once-daily is not inferior to a standard three-drug 
regimen of DTG plus TDF/FTC FDC once daily in HIV-1 infected ART-naïve 
adult subjects. Non-inferiority will be concluded if the lower bound of a two-
sided 95% confidence interval for the difference in response rates between the 
two treatment arms is greater than -10%. 


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Overview 
Key Elements of the RAP 
Primary 
Analyses 
• 
The primary endpoint will be analysed using a Cochran-Mantel-Haenszel 
stratified analysis, adjusting for baseline stratification factors.  A point estimate 
and corresponding 95% confidence interval will be constructed for the adjusted 
difference in response rates between DTG + 3TC and DTG + TDF/FTC 
treatment groups. 
Secondary 
Analyses 
• 
Secondary analyses will be conducted for additional efficacy, safety, health 
outcomes, and virologic endpoints. 
Sensitivity 
Analyses  
• 
At Weeks 24, 48, 96, and 144, 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 plus 3TC is superior to treatment with DTG plus TDF/FTC FDC will be 
tested using the same level of significance as for the tests of non-inferiority. 
Superiority will be declared if the lower end of the confidence internal is above 
0%. The primary comparison will also be performed using the ITT population 
and will be compared for consistency with the results from the ITT-E and PP 
populations. 
• 
The time to Confirmed Virologic Withdrawal (CVW) or treatment related 
(TRDF)/efficacy (ERDF) related discontinuation (i.e., drug-related AE, protocol 
defined safety stopping criteria, or lack of efficacy) will be calculated. This 
analysis censors subjects who have not met CVW criteria and are ongoing in 
the study, or who have discontinued for reasons other than those related to 
treatment/lack of efficacy. 
• 
At Week 48 a sensitivity analysis will be performed to assess whether bias was 
introduced by the unblinded analysis performed at Week 24. The Week 48 
Snapshot results of the subjects who reached Week 48 prior to the Week 24 
unblinding will be compared to the Week 48 results in the subjects who 
reached Week 48 after the Week 24 unblinding. 
 


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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis specified 
in the protocol amendment 2 of study 205543 (Dated: 14-JUN-2018, GSK Document No.: 
2015N263962_02). Please note that these two studies are identical in terms of study design 
and analysis plan. 
2.2. 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To 
demonstrate 
non-inferior 
antiviral activity of DTG + 3TC 
versus DTG + TDF/FTC FDC at 
48 weeks in HIV-1-infected, ART-
naïve subjects 
• 
Proportion of subjects with plasma HIV-1 RNA <50 
copies/mL (c/mL) at Week 48 using the FDA 
Snapshot algorithm for the intent-to-treat exposed 
(ITT-E) population 
Secondary Objectives 
Secondary Endpoints 
• 
To demonstrate the antiviral 
activity of DTG + 3TC versus DTG 
+ TDF/FTC FDC at 24, 96 and 
144 weeks 
• 
Proportion of subjects with plasma HIV-1 RNA <50 
c/mL at Weeks 24, 96 and 144 using the FDA 
Snapshot algorithm for the ITT-E population 
• 
To evaluate the antiviral activity, 
immunological 
effects, 
and 
incidence of disease progression 
(HIV-associated conditions, AIDS 
and death) of DTG + 3TC 
compared to DTG + TDF/FTC 
FDC over time 
• 
Time to viral suppression (HIV-1 RNA <50 c/mL); 
• 
Absolute values and changes from baseline in 
CD4+ cell counts at Weeks 24, 48, 96 and 144; 
• 
Incidence of disease progression (HIV associated 
conditions, AIDS and death). 
• 
To assess viral resistance in 
subjects 
meeting 
confirmed 
virologic 
withdrawal 
(CVW) 
criteria 
• 
Incidence of treatment-emergent genotypic and 
phenotypic resistance to DTG and 3TC or TDF/FTC 
FDC in subjects meeting CVW criteria 
• 
To evaluate the safety and 
tolerability of DTG + 3TC 
compared to DTG + TDF/FTC 
FDC  over time 
• 
Incidence and severity of adverse events (AEs) and 
laboratory abnormalities; 
• 
Proportion of subjects who discontinue treatment 
due to AEs over 24, 48, 96 and 144 weeks 
• 
To evaluate renal biomarkers (in 
urine and blood) and bone 
biomarkers (in blood) in subjects 
treated 
with 
DTG 
+ 
3TC 
compared to DTG + TDF/FTC 
FDC 
• 
Change from Baseline in renal and bone 
biomarkers at Weeks 24, 48, 96 and 144 


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Objectives 
Endpoints 
• 
To evaluate the effects of DTG + 
3TC on fasting lipids compared to 
DTG + TDF/FTC over time 
 
• 
Change from Baseline in fasting lipids at Weeks 24, 
48, 96, and 144; 
• 
The incidence of Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Weeks 
24, 48, 96, and 144; 
• 
To evaluate the effect of patient 
demographics 
and 
baseline 
characteristics (e.g. demographic 
factors, HIV-1 subtype, baseline 
CD4+ cell count) on response to 
DTG + 3TC compared to DTG + 
TDF/FTC over time 
• 
Proportion of subjects by patient subgroup(s) (e.g. 
by age, gender, Baseline CD4+ cell count) with 
plasma HIV-1 RNA <50 c/mL at Weeks 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 and 144 by patient subgroups 
• 
To assess change in health-
related quality-of-life for subjects 
treated with DTG plus 3TC 
compared to DTG + TDF/FTC 
• 
Change from Baseline in health related quality of 
life using EQ-5D-5L at Weeks 4, 24, 48, 96, and 
144  
Exploratory Objectives 
Endpoint 
• To evaluate inflammation 
biomarkers in subjects treated 
with DTG+ 3TC compared to DTG 
+ TDF/FTC 
• Change from Baseline in inflammation biomarkers at 
Week 48, 96 and 144 (data will be collected at Day 
1, Week 48 and 144, but results will be available for 
analysis at Week 96 and 144.) 
• To evaluate telomere length in 
subjects treated with DTG + 3TC 
compared to DTG + TDF/FTC 
• Change from Baseline in telomere length at Week 
96 and 144 (telomere length results will not be 
available until EOS) 
 


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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• Phase III, randomised, double-blind, active-controlled, multicentre, parallel-
group, non-inferiority study. This study comprises a 28-day Screening Phase 
(which may be extended to 35 days to allow receipt of all Screening 
assessment results), a Double-blind Randomized Phase (Day 1 to Week 96), 
an Open-Label Randomized Phase (Week 96 to Week 148) and a 
Continuation Phase (Post-Week 148). 
Dosing 
• Patients are randomized to receive DTG (50mg) + 3TC (300mg) once daily or 
DTG (50mg) + TDF (300mg) / FTC (200 mg) FDC once daily 
Treatment 
Assignment 
• In each study, approximately N=700 subjects will be randomized 1:1 to 
DTG+3TC or DTG+TDF/FTC FDC 
• Stratified randomisation by Baseline HIV-1 RNA (≤ vs. >100,000c/mL) and 
Baseline CD4+ cell count (≤ vs. >200 cells/mm3) 
• The study initially enrolled subjects with a Screening HIV-1 RNA of 1000 to 
≤100,000 c/mL. Accumulated data from other clinical trials investigating the 
DTG + 3TC dual regimen underwent independent review (Dated: 4-NOV-
2016), which was supportive of evaluating the dual regimen’s efficacy in 
subjects with a Screening viral load of up to 500,000 c/mL, and allowing 
recruitment to open to subjects with a Screening HIV-1 RNA of 1000 to 
≤500,000 c/mL. 
Interim 
Analyses 
• Four planned analyses will be conducted to evaluate primary and secondary 
objectives of the protocol. Further data cuts and analyses may be conducted 
in order to support regulatory submissions and publications. The Week 48 
analysis will be primary. No adjustment for multiplicity caused by repeated 
evaluation of the primary endpoint will be made as the Week 24, Week 96 and 
Week 144 analyses will be secondary. 
Final 
Analysis 
• A final End-of-Study analysis will be conducted when all subjects have 
completed the study. 


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2.4. 
Statistical Hypotheses 
This study is designed to show that the antiviral effect of a simplified two-drug regimen of 
DTG + 3TC once-daily is non-inferior to a standard three-drug regimen of DTG + 
TDF/FTC FDC once daily in HIV-1 infected ART-naïve adult subjects. 
Non-inferiority can be concluded if the lower bound of a two-sided 95% confidence 
interval for the difference in response rates between the two treatment arms is greater than 
-10%. If rd is the response rate on DTG + 3TC and rf is the response rate on DTG + 
TDF/FTC FDC, then the hypotheses can be written as follows: 
H0: rd - rf ≤ -10%  
 
H1: rd - rf > -10% 
2.4.1. 
Week 144 Statistical Hypotheses 
Though the confirmatory non-inferiority test is designated at Week 48, it is planned to do 
non-inferiority test and report results at some other key timepoints (Weeks 24, 96 and 
144) even if these analyses are exploratory in nature.  For the Week 24 and 96 analysis, 
the same non-inferiority margin was used as specified in the protocol for the primary 
endpoint analysis at Week 48.  
For the purpose of the Week 144 analysis, a non-inferiority margin of 12% will be used. 
Using a non-inferiority margin of 12%, non-inferiority can be concluded if the lower 
bound of a two-sided 95% confidence interval for the difference in response rates 
between the two treatment arms is greater than -12%. If rd is the response rate on DTG + 
3TC and rf is the response rate on DTG + TDF/FTC FDC, then the hypotheses can be 
written as follows: 
H02: rd - rf ≤ -12%      H12: rd - rf > -12% 
Additionally, if non-inferiority is met with this margin, non-inferiority will be assessed in 
a closed testing procedure against a non-inferiority margin of 10% without multiplicity 
adjustment. 
2.4.2. 
Rationale for non-inferiority margin at Week 144 
With longer follow-up duration it is expected to have lower response rates as more 
subjects withdraw from the study.  Lower response rates are being associated with larger 
binomial variance. As such, the primary non-inferiority margin for the Week 144 analysis 
is 12%. 


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3. 
PLANNED ANALYSES 
3.1. 
IDMC Interim Analyses 
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 both studies (204861 and 205543). An ad-hoc review of 
data by the IDMC will be triggered whenever the number of CVWs exceeds thresholds 
pre-specified in the IDMC charter. Further, an interim futility analysis will be performed 
for the IDMC to evaluate the efficacy and safety of DTG plus 3TC when approximately 
50% of subjects have completed their visit at Week 24; the sponsor will remain blinded to 
this analysis. Full details of the methods, timing, decision criteria and operating 
characteristics will be pre-specified in the IDMC Charter and IDMC RAP. 
3.2. 
Primary Analyses 
The primary analysis at Week 48 will be conducted to evaluate primary and secondary 
objectives of the protocol. 
The planned analyses at Week 48 will be performed after the completion of the following 
sequential steps: 
1. All subjects have completed their week 48 visit as defined in the protocol, including 
a retest if required. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
3.3. 
Interim Analyses 
At least three other analyses will be conducted to evaluate primary and secondary 
objectives of the protocol, when all subjects have completed their visits at Week 24, at 
Week 96, and at Week 144. Further data cuts and analyses may be conducted as 
necessary after Week 144 in order to support regulatory submissions and publications.  
The planned analyses at Weeks 24, 96 and 144 will be performed after the completion of 
the same steps specified in Section 3.2. 
ViiV Healthcare/GSK will unblind the study for the purpose of the Week 24 analysis; 
however, the PPD (except IVRS personnel), subjects and investigators will remain blinded 
to treatment allocation until each subject has reached their Week 96 visit. 
3.4. 
Final Analyses 
A final End-of-Study analysis will be conducted when all subjects have completed the 
study. 


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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses 
Evaluated 
All subject 
screened 
• 
Comprise of all subjects screened for inclusion in 
the study, including screen-failures. 
• 
This population will be based on the treatment to 
which the subject was randomized. Screen-failures 
will be categorised as “Non-randomised”. 
• 
Study 
Population 
Randomized 
• 
The Randomized population will consist of all 
subjects who are randomized in the study 
• 
Study 
Population 
Intent-To-Treat 
Exposed (ITT-E) 
• 
Comprise of all randomized subjects who receive at 
least one dose of study treatment. 
• 
This population will be based on the treatment to 
which the subject was randomized. 
• 
Any subject who receives at least one dose of study 
medication and randomization number  
• 
Study 
Population 
• 
Efficacy 
Intent-To-Treat 
(ITT) 
• 
Comprise of all randomised subjects. 
• 
Subjects will be assessed according to their 
randomised treatment even if no study treatment 
was taken or the wrong treatment was received. 
• 
Efficacy 
(Sensitivity 
analyses) 
Per-Protocol 
(PP) 
• 
Comprise of all subjects of the ITT-E population 
who have no significant protocol deviation that 
could affect the assessment of antiviral activity. 
• 
Protocol deviations that would exclude subjects 
from the PP population are defined in Section 4.1 
(Protocol Deviations) and Section  10.1 (Protocol 
Deviation Management and Definition for Per-
Protocol Population). 
• 
Efficacy 
(Sensitivity 
Analysis) 


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Population 
Definition / Criteria 
Analyses 
Evaluated 
Safety 
• 
Comprise of all subjects who receive at least one 
dose of study treatment. 
• 
This population will be based on the treatment the 
subject actually received. 
• 
Safety 
CVW 
• 
Comprise of all subjects in the ITT-E population 
who have met the derived CVW criteria 
 
Viral Genotypic  
 
• 
Comprise of all subjects in the ITT-E population 
who have available On-treatment genotypic 
resistance data. Assessed according to their 
randomised treatment regardless of the treatment 
they receive.   
• 
Virology 
Viral Phenotypic 
 
• 
Comprise of all subjects in the ITT-E population 
who have available On-treatment phenotypic 
resistance data. Assessed according to their 
randomised treatment regardless of the treatment 
they receive.   
• 
Virology 
NOTES :  
• 
Refer to Appendix 17: List of Data Displays which details the population to be used for each displays being 
generated. 
• 
Refer to Appendix 6 which describes how CVW is derived. 
 
4.1. 
Protocol Deviations 
• 
Important 
protocol 
deviations 
(including 
deviations 
related 
to 
study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed. 
• 
Important deviations which result in exclusion from the per protocol analysis 
population will also be summarised and listed. (Please refer to Appendix 1: Protocol 
Deviation Management and Definitions for Per Protocol Population). 
• 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the ViiV-GSK 204861-205543 Study Deviation Rules 
Document. 
o Data will be reviewed prior to unblinding and freezing the database to ensure 
all important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. Note: 
It will not be possible to identify whether subjects received a different treatment 
to the one they were randomised to until post unblinding, hence this protocol 
deviation will be identified after unblinding the database. 
o This dataset will be the basis for the summaries and listings of protocol deviations. 
• 
A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF. 


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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
• There are no planned adjustments made for multiple centres in this study. 
• There are no planned adjustments for multiple comparisons or multiplicity. 
• There are no Pharmacokinetic and Pharmacodynamic analyses planned in this 
study. 
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 1 
Overview of Appendices 
Section 
Component 
Section 10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
Section 10.2 
Appendix 2: Time & Events 
Section 10.3 
Appendix 3: Assessment Windows 
Section 10.4 
Appendix 4: Treatment States and Phases 
Section 10.5 
Appendix 5: Data Display Standards & Handling Conventions 
 Section 10.6 
Appendix 6: Derived and Transformed Data 
Section 10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
Section 10.8 
Appendix 8: Values of Potential Clinical Importance 
Section 10.9 
Appendix 9: FDA Snapshot Algorithm 
Section 10.10 
Appendix 10: Multicenter Studies 
Section 10.11 
Appendix 11: Examination of Covariates, Subgroups & Other Strata 
Section 10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
Section 10.13 
Appendix 13: Time to Event Details 
Section 10.14 
Appendix 14: Q2 Creatinine Assay Accuracy Issue 
Section 10.15 
Appendix 15: Abbreviations & Trade Marks 
Section 10.16 
Appendix 16: End of Study (Final) Analysis 
Section 10.17 
Appendix 17: List of Data Displays 
 


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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the ITT-E population, unless otherwise 
specified.  
Table 2 provides an overview of the planned study population analyses, with full details of 
data displays being presented in Appendix 17: List of Data Displays. 
Table 2 
Overview of Planned Study Population Analyses 
Display Type 
Data Display’s 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 
Subjects for Whom the Treatment Blind was Broken 
 
Y 
Subject Disposition 
Y [3,4] 
 
Reasons for Withdrawal by Visit 
Y 
Y 
Study Visit Dates   
 
Y 
Populations Analysed 
Study Populations [2] 
Y 
Y 
Protocol deviations 
Important Protocol Deviations 
Y 
Y 
Deviations leading to exclusion from PP 
Y 
Y 
Inclusion and Exclusion Criteria Deviations 
 
Y 
Demography 
Demographic Characteristics[5] 
Y 
Y 
Subgroups  
 
Y 
Summary of Age Ranges 
Y 
 
Race & Racial Combinations[6] 
Y  
Y 
Hepatitis C Status 
Y 
Y 
CDC Classification of HIV infection at Baseline 
Y 
Y 
HIV Risk Factor 
Y 
Y 
Cardiovascular Risk Assessments at Baseline 
Y 
Y 
Distribution of Quantitative Plasma HIV-1 RNA 
Y 
 
Distribution of CD4+ Cell Counts 
Y 
 


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Display Type 
Data Display’s Generated 
Table 
Listing 
History of Cardiac Therapeutic Procedures 
 
Y 
Medical Conditions, Concomitant  Medications & Antiretroviral Therapy 
Medical Conditions (Current and Past)  
Y  
Y[7] 
Medical Conditions: Sub-conditions  (Current/Past)  
Y  
 
Concomitant Medications (non-ART) 
Y[8] 
Y[7,9] 
Prior and Concomitant ART Medications 
 
Y[7,10]  
Lipid Modifying agents (Baseline and Post-Baseline) 
Y 
 
Other  
IP Accountability [11] 
 
Y 
History of Depression and Anxiety at Baseline 
Y 
 
Subjects attending Nominal and Actual Analysis 
Visits 
Y 
 
NOTES : 
• 
Y = Display Generated, T = Tables, L = Listings, IP = Investigational Product 
1. 
Randomized population. One listing of subjects randomised but not treated, and one listing of planned and actual 
treatment strata. 
2. 
All Subjects screened population. 
3. 
Subject  Accountability by Phase (Overall, Double Blind Phase, Open Label Phase) 
4. 
Subjects who have not been recorded as either completing or 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 and BMI (kg/m^2) 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. 
Repeated for subjects at sites in Mexico who experienced an adverse event, at End of Study reporting only. 
8. 
Three separate tables, summarised by Ingredient ATC Level 1, Ingredient combinations and 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).) 
9. 
One listing for all concomitant medications and one listing showing the relationship between verbatim text, 
ingredient and ATC Level 1. 
10. One listing for Prior ART, one listing for concomitant ART and one listing showing the relationship between 
verbatim text, ingredient, combination and ATC Level 4. 
11. Dispensation information (dates and number of tablets dispensed and returned) 
 


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7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Efficacy Analyses 
The primary efficacy analyses will be based on the “Intent-To-Treat Exposed” population, 
unless otherwise specified. Summaries will be presented by treatment group with no total 
column. Primary and secondary efficacy Tables/Figures/Listings will be performed for 
each reporting effort, i.e., outputs from Section 7.1.1 and Section 8.1.1 will be produced 
for week 24, 48, 96 and 144 analysis. 
7.1.1. 
Overview of Planned Efficacy Analyses 
Table 3 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 17: List of Data Displays.  
Table 3 
Overview of Planned Efficacy Analyses 
[Endpoint / Parameter/ Display 
Type] 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL – Snapshot  
Week 48 (ITT-E population) 
Y[1] 
 
 
 
Y[2] 
 
Y 
Study Outcomes  
 
 
 
Y[1] 
 
 
Y 
Sensitivity Analyses 
Treatment Heterogeneity across 
randomization strata  
Y 
 
 
 
 
 
 
Proportion of subjects without 
virologic or virologic/tolerability 
failure[3] 
Y[6] 
Y[4] 
 
 
 
 
Y 
Week 24 to Week 48 Bias 
Assessment[5] 
 
 
 
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. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
1. 
Generated using the ‘Intent-to-Treat Exposed’ (primary), ‘Per-Protocol’ (sensitivity) and ‘Intent-to-Treat’ 
(sensitivity) populations.  
2. 
Line plots, with 95% confidence intervals, for the proportion of subjects <50 c/mL by treatment group at each visit. 
3. 
Outputs will be produced for Efficacy related discontinuation = Failure (ERDF) and Treatment related 
discontinuation = Failure (TRDF). 
4. 
Kaplan-Meier Plot of Time to Failure – ERDF/TRDF 
5. 
Required for the Week 48 reporting effort only. 
6. 
 By subgroup 
 


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7.1.2. 
Planned Efficacy Statistical Analyses 
Primary Statistical Analyses 
Endpoint(s) 
• Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot 
algorithm for the ITT-E population 
Snapshot Dataset 
• 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, as 
well as subjects who switch their concomitant ART prior to the visit of interest in certain 
scenarios. Since changes in ART are not permitted in this protocol, all such subjects who 
change ART will be considered non-responders. 
• Otherwise, virologic response or virologic non-response 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 10.3). 
• Full details of the Snapshot algorithm are in Appendix 9.  
Model Specification 
• The primary endpoint will be analysed using a stratified analysis with Cochran-Mantel-
Haenszel (CMH) weights, adjusting for Baseline plasma HIV-1 RNA ( ≤ vs. >100,000 c/mL) 
and CD4+ cell count (≤200 cells/mm3 or >200 cells/mm3).  
• 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 four Baseline analysis strata: 
o Plasma HIV-1 RNA ≤ 100,000 c/mL AND CD4+ ≤ 200 cells/mm3 
o Plasma HIV-1 RNA ≤ 100,000 c/mL AND CD4+ > 200cells/mm3 
o Plasma HIV-1 RNA > 100,000 c/mL AND CD4+ ≤ 200cells/mm3 
o Plasma HIV-1 RNA > 100,000 c/mL AND CD4+ > 200 cells/mm3 
• If nk is the number of DTG+3TC treated subjects, mk is the number of DTG+TDF/FTC FDC 
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 dk are estimates of the differences in response proportions between 
the two treatment arms, rd-rf, for the kth strata. 
∑
∑
=
k
k
k
cmh
W
d
W
d
ˆ
ˆ
 


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Primary Statistical Analyses 
• 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.  The full equation for this variance estimate is provided in 
Section 10.6.5. 
• Non-inferiority will be concluded if the lower bound of the two-sided 95% confidence interval 
(CI) for the CMH adjusted difference in the proportion of patients who respond in the DTG 
+3TC group minus the proportion of patients who respond in the DTG + TDF/FTC FDC 
group is greater than -10%.   
Model Results Presentation 
• Adjusted CMH estimate of the difference in the proportion of responders between the 
two treatment groups (DTG + 3TC – DTG + TDF/FTC FDC) and corresponding 95% 
confidence interval. 
• Figures: Line plots, with 95% confidence intervals, for the proportion of subjects below 
50 c/mL by treatment group at each visit 
 
Sensitivity and Supportive Statistical 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 DTG+TDF/FTC will be tested at the two-sided 5% level of significance.  
Superiority will be declared if the lower end of the 95% confidence interval in the ITT-E 
analysis is above 0%. If superiority is declared the p-value for superiority will also be 
calculated. 
2. Intent-to-Treat population analysis: 
• Statistical analysis will be repeated using the Intent-to-Treat population and compared 
for consistency with the results from the ITT-E and PP populations. 
• In this analysis, subjects randomized but not exposed to study treatment will be 
classified as non-responders. 
3.  Treatment Heterogeneity across randomization strata: 
• 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-rf are zero or one, and tests will be one-
sided.  
• Any heterogeneity found to be statistically significant will be explored and if necessary 
results will be reported for each level of the categorical variable. Tests of homogeneity 
will be assessed at the one-sided 10% level of significance. 
)
ˆ
r(
aˆ
v
96
.1
ˆ
cmh
cmh
d
d
×
±


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205543 
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Sensitivity and Supportive Statistical Analyses 
 
 
 
4. 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/efficacy related 
discontinuation (i.e., drug-related AE, protocol defined safety stopping criteria, or lack of 
efficacy).  
• The detailed algorithm for TRDF are listed in Section 10.13. 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 48 will be 
presented by treatment group, along with estimated difference in proportions between 
treatment groups and its associated two-sided 95% CI.  
• Kaplan-Meier Plot of Time to Failure – Treatment/Efficacy related discontinuation = 
Failure  
5. Bias sensitivity analysis 
• A sensitivity analysis will be performed at Week 48 to assess whether bias was 
introduced by the unblinded analysis performed at Week 24.  
• Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm will be compared between subjects who reached Week 48 results 
prior and after the Week 24 unblinding 
• No formal statistical hypothesis testing will be performed 


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8. 
SECONDARY STATISTICAL ANALYSES 
8.1. 
Efficacy Analyses 
8.1.1. 
Overview of Planned Efficacy Analyses 
The secondary efficacy analyses will be based on the Intent-To-Treat-Exposed population, unless 
otherwise specified. Week X represents each reporting effort (at Week 24/48/96/144).  
Table 4 provides an overview of the planned efficacy analyses, with further details of data displays 
being presented in Appendix 17: List of Data Displays. 
Similarly to the plasma HIV-1 RNA <50 c/mL cut off, the following cut off will be derived and 
analysed: 
• Plasma HIV-1 RNA<40 c/mL; 


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Table 4 
Overview of Planned 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 
By Visit 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
By subgroup  
 
 
 
Y[2] 
Y[1] 
 
 
 
 
 
 
 
 
 
Study Outcomes by 
subgroup  
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Proportion of Subjects with Plasma HIV-1 RNA <40 copies/mL –  Snapshot 
At Week X 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Outcomes  
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
By Visit 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
By subgroup  
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 RNA over time –  Observed[6]  
By Visit  
 
 
 
 
Y[4] 
 
 
 
 
 
Y[9] 
 
 
 
Subjects with Plasma HIV-1 RNA <50 c/mL by HIV-1 RNA and CD4+ Cell Counts subgroup 
Snapshot outcomes 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Proportion of Subjects 
Y[2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan - Meier  
Time to viral 
suppression 
Y 
Y[5] 
 
 
 
 
 
 
 
 
 
 
 
 
By Subgroup 
Y 
Y[5] 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmed Virologic Withdrawal (CVW) 
By Visit 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA distribution 
at time of suspected 
and confirmed Virologic 
withdrawal 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
CD4+ Cell Counts  
At Week X 
 
 
 
 
 
 
 
Y[3] 
Y[7] 
 
 
 
 
 
By Visit 
 
 
 
Y 
Y[4] 
 
Y 
 
 
 
Y 
 
 
Y 
By subgroup 
 
 
 
 
 
 
 
Y 
 
 
Y 
 
 
 
Post-baseline HIV-1 Disease Progression[8] 
HIV Conditions 
including Recurrences 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
HIV Conditions 
excluding Recurrences 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
HIV Disease 
Progressions 
 
 
 
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. 


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• 
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. 
Repeat for Per Protocol population. 
3. 
Primary analysis method is multiple imputation MAR. Repeated for additional analyses using MMRM.  
4. 
Individual plasma HIV-1 RNA and CD4+ profiles for subjects with at least one SVW visit.  
5. 
Overall and by Baseline HIV-1 RNA and CD4+ Cell Count Subgroups. 
6. 
Using observed case (OC) data which contains the data that is available at a particular time point, with no 
imputation for missing values. 
7. 
Line plots, with 95% confidence intervals for Adjusted Mean Change From Baseline in CD4+ Cell Count by 
treatment group at each visit.  
8. 
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. 
9. 
Descriptive summary of the log10 change from baseline HIV-1 RNA by visit presented 
8.1.2. 
Planned Efficacy Statistical Analyses 
Secondary Statistical Analyses 
Endpoint(s) 
• The time to viral suppression 
Model Specification 
• Nonparametric Kaplan-Meier method will be performed Overall and by Baseline HIV-1 
RNA Subgroup. 
• Time of event will be the first viral load value <50 copies/mL  
• Subjects who withdraw for any reason without being suppressed will be censored at 
earliest of (day of study discontinuation, day of withdrawal visit, day of treatment 
discontinuation or study day 1050). 
• Subjects who have not been withdrawn and have not had viral suppression at time of 
the analysis will be censored at the earliest of (last viral load date or study day 1050).  
• Subjects who have completed the Double Blind and Open Label phases and have not 
had viral suppression will be censored at date of completion 
• CIs for Quartiles of time to viral suppression (including median) will be estimated using 
the Brookmeyer Crowley Method. 
• Cox proportional hazards model will be used to estimate the hazard ratio (DTG +3TC 
vs. DTG+TDF/FTC) and 95% confidence interval. 
• The generalised Wilcoxon procedure will be used to estimate a p-value for detecting a 
difference in cumulative incidence curves between treatment groups 
o Note: In general, the logrank test tends to be sensitive to distributional 
differences which are most evident late in time. In comparison, the generalised 
Wilcoxon test tends to be more powerful in detecting differences early in time 
(when the proportional hazard assumption are not met). 
Model Results Presentation 
• 
Number and percentage of subjects with event or censored at analysis week 
• 
Quartiles of time to viral suppression (including median) and 95% CI 
• 
Hazard ratio for viral suppression (DTG +3TC vs. DTG+TDF/FTC) and 95% CI 
• 
A p-value from Generalised Wilcoxon procedure 
• Figures: Kaplan-Meier Plots of Time to Viral Suppression 


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Secondary Statistical Analyses 
Secondary Statistical Analyses 
Statistical Analyses 
Endpoints 
• Change from baseline in CD4+ cell counts 
Covariates & Factors 
• Baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL) 
• Note: Baseline CD4+ cell count will be used as continuous covariate as specified below.  
Data Handling 
• A multiple imputation technique will be used to deal with the missing data. (Multiple 
imputation (MAR) analyses are run at week 24 and 48 only.) 
Model Specification 
• Multiple imputation (MAR) analyses are run at week 24 and 48 only. 
• Using the OC dataset as a starting point, multiple imputations will be drawn from a 
multivariate normal imputation model (taking into account scheduled measurements 
prior to analysis Week X) with a Markov Chain Monte Carlo (MCMC) approach used to 
estimate posterior distributions. The MCMC method in the MI procedure in SAS will be 
used with multiple chains, 500 burn-in iterations, and a non-informative prior. A random 
seed number of 1349572 will be used in the SAS program.  Where a subject has a 
monotone or non-monotone pattern of missingness, all of their missing observations can 
be imputed under this approach. The absolute value will be imputed before the change 
value is calculated. Imputations will be drawn separately for subsets of subjects 
according to their treatment group, i.e., based on means and variance-covariances from 
the same treatment group (Missing At Random (MAR) approach) conditioning on 
observed covariates (see above).  
• The imputations will be carried out 1,000 times. An ANCOVA, using the observed 
margins (OM) option, will be performed on each dataset produced adjusting for the 
covariates (listed above), treatment, and baseline value for the endpoint as a covariate, 
regardless of their significance. Rubin’s imputation rules through PROC MIANALYZE in 
SAS will be used to combine the 1,000 estimated least squares means and difference to 
produce one estimated mean with 95% CI and associated p-value for the adjusted mean 
difference between each treatment group at Week X. 
• Interactions between treatment and each of the covariates will not be assessed. 
Model Checking & Diagnostics 
• Refer to Appendix 12: 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 – DTG+TDF/FTC FDC) and corresponding 95% confidence interval 
and p-value. 
Additional Analyses 
• Based on the OC dataset, the Mixed Model Repeated Measures (MMRM), using the 
observed margins (OM) option, will adjust for treatment, covariates (listed above) and 
baseline CD4+ cell count value as a covariate, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations between a subject’s 
score (the correlation matrix for within-subject errors will be unstructured). 


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Secondary Statistical Analyses 
• 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 score for the endpoint can vary between visits (ie. CD4+ cell count 
baseline score*visit interaction will be included in the model) 
• 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 
• 
Change from baseline in CD4+ cell count by each subgroup listed in Section 10.11. will 
be analyzed by an ANCOVA model, using the observed margins (OM) option, adjusting 
for the covariates (listed above), treatment, baseline value as a covariate, subgroup and 
treatment*subgroup interaction term regardless of their significance, using an OC 
dataset. 
• Results will be presented as adjusted point estimates, 95% confidence intervals. 
 
Secondary Statistical Analyses 
Endpoint(s) 
• Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot 
algorithm by subgroup 
Subgroups 
• 
See table in Section 10.11 for list of subgroups 
Model Specification 
• The proportion of subjects with plasma HIV-1 RNA <50 c/mL based on the Snapshot 
algorithm at analysis week will be summarized by treatment group and subgroup. 
•  If the basic summary suggests an interaction, then a corresponding summary of study 
outcomes by subgroup will be produced. 
Note: These subgroup analyses will be exploratory and likely underpowered so that 
interpretation may therefore focus on point estimates as well as the lower bounds of 95% 
CIs for the treatment differences and response rates. Additionally, multiple comparisons are 
being made which inflates the risk of false positive findings. Therefore, if consistent findings 
across the multiple comparisons were observed then these analyses would still be 
suggestive of a generalizable finding of non-inferiority. 
Model Results Presentation 
• Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL and unadjusted difference in 
proportions between treatment groups and corresponding two-sided 95% CI will be 
presented by subgroup 
• Figures: Plot of 95% confidence intervals for the difference in proportion of subjects below 
50 c/mL by subgroup. 
 


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8.2. 
Safety Analyses 
8.2.1. 
Overview of Planned Analyses 
The safety analyses will be based on the Safety population, unless otherwise specified. 
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.  
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 17: List of Data Displays. 


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Table 5 
Overview of Planned Safety Analyses 
Endpoint  
Absolute 
Change from Baseline 
Max Post BL 
Summary 
Individual 
Stats Analysis 
Summary 
Summary 
T 
F 
F 
L 
T 
F 
L 
T 
F 
T 
F 
L 
Exposure 
Extent of Exposure 
Y 
 
 
Y [1,2] 
 
 
 
 
 
 
 
 
Adverse Events (AEs) 
All AEs by SOC 
and PT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
All AEs by 
Maximum Grade [3]  
Y 
 
 
 
 
 
 
 
 
 
 
 
Drug-Related AEs 
by SOC and PT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
Drug-Related AEs 
by SOC and 
Maximum Grade [3] 
Y 
 
 
 
 
 
 
 
 
 
 
 
AEs of Mexican 
Subjects   
 
 
 
Y [4] 
 
 
 
 
 
 
 
 
Common AEs by 
Frequency [5] 
Y 
Y [6] 
 
 
 
 
 
 
 
 
 
 
Common Grade 2-
5 AEs by 
Frequency [5] 
Y 
Y 
 
 
 
 
 
 
 
 
 
 
Common Drug-
Related Adverse 
Events  
Y 
Y 
 
 
 
 
 
 
 
 
 
 
Various AE 
categories  
 
Y 
 
 
 
 
 
 
 
 
 
 
Common Non-
Serious AEs by 
SOC and PT 
(Subjects & No. of 
Occurrences) 
Y 
 
 
 
 
 
 
 
 
 
 
 
Common Drug-
Related Grade 2-5 
AEs [24] 
Y 
 
 
 
 
 
 
 
 
 
 
 
Subject Numbers 
for Individual AEs 
 
 
 
Y 
 
 
 
 
 
 
 
 
Relationship 
Between AE SOCs, 
PT and Verbatim 
Text 
 
 
 
Y 
 
 
 
 
 
 
 
 
Post Baseline AE 
by Maximum 
Toxicity and 
Subgroups 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Post-treatment AE 
by SOC and 
Maximum Toxicity 
Y 
 
 
 
 
 
 
 
 
 
 
 
Serious and Other Significant AEs 
 
Fatal AEs 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
Non-Fatal Serious 
AEs 
 
 
 
Y 
 
 
 
 
 
 
 
 
Drug-Related Fatal 
AEs 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
Serious AEs by 
SOC 
Y 
 
 
 
 
 
 
 
 
 
 
 
Serious AEs for 
Mexicans 
 
 
 
Y[4] 
 
 
 
 
 
 
 
 
Serious AEs for 
non-Mexicans 
 
 
 
Y[4] 
 
 
 
 
 
 
 
 
Reasons for 
Considering as a 
Serious AE 
 
 
 
Y 
 
 
 
 
 
 
 
 
Drug-Related 
Serious AEs by 
SOC 
Y 
 
 
 
 
 
 
 
 
 
 
 
Drug-Related Non 
Fatal Serious AEs 
 
 
 
Y 
 
 
 
 
 
 
 
 
Serious AEs by 
SOC and PT 
(Subjects & No. of 
Occurrences) 
Y 
 
 
 
 
 
 
 
 
 
 
 
Drug-Related AE 
leading to 
withdrawal from 
study 
Y 
 
 
 
 
 
 
 
 
 
 
 
AEs Leading to 
Withdrawal from 
Study / Permanent 
Discontinuation of 
Study Treatment 
and by Maximum 
Grade [3] 
Y[18] 
 
 
Y 
 
 
 
 
 
 
 
 
Individual Adverse 
Events 
 
 
 
Y 
 
 
 
 
 
 
 
 
Possible 
Suicidality-Related 
Adverse Event 
(PSRAE) 
 
 
 
Y[7] 
 
 
 
 
 
 
 
 
Cardiovascular 
events 
 
 
 
Y 
 
 
 
 
 
 
 
 


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Laboratory Values  
 
Clinical Chemistry  
 
 
 
Y[8] 
 
 
 
Y 
 
 
 
 
Lipids 
Y 
 
 
 
 
 
 
Y 
 
 
 
 
Fasted Lipid 
(Triglycerides, LDL, 
HDL and TC and 
TC/HDL) analysis 
Y 
 
 
 
Y[9,18] 
 
 
 
 
 
 
 
TC/HDL ratio 
 
 
 
 
 
 
 
 
 
Y 
 
 
Hematology  
 
 
 
Y [8] 
 
 
 
Y 
 
 
 
 
Urine Dipstick 
 
 
 
Y [8] 
 
 
 
 
 
 
 
 
Urine 
Concentration 
 
 
 
Y [8] 
 
 
 
Y 
 
 
 
 
Liver Chemistries 
 
 
 
 
 
 
 
 
 
 
Y 
[10] 
Y 
NCEP shifts in 
lipids (LDL, HDL, 
TC, Triglycerides) 
 
 
 
 
 
 
 
 
 
Y 
Y[12] 
 
NCEP shifts in 
lipids (LDL, HDL, 
TC, Triglycerides) 
and TC/HDL ratio 
 
 
 
 
 
 
 
Y[25] 
 
 
 
 
Biomarkers 
 
Bone biomarkers 
 
 
 
Y 
Y[18] 
Y[19] 
 
Y[18] 
 
 
 
 
Bone biomarkers 
(%) 
 
 
 
 
 
 
 
Y 
 
 
 
 
Renal biomarkers 
 
 
 
Y 
Y[18] 
Y[19] 
 
Y[18] 
 
 
 
 
Renal biomarkers 
(%) 
 
 
 
 
 
 
 
Y 
 
 
 
 
Inflammation 
Biomarkers 
 
 
 
Y 
 
 
 
Y 
 
 
 
 
Telomere length 
 
 
 
Y 
 
 
 
Y 
 
 
 
 
Emergent Laboratory Toxicities[13] 
 
Clinical Chemistry 
 
 
 
 
 
 
 
 
 
Y 
 
 
Hematology 
 
 
 
 
 
 
 
 
 
Y 
 
 
Fasting LDL 
Cholesterol 
Abnormalities of 
Grade 2 or Greater 
 
 
 
 
 
 
 
 
 
Y[21] 
 
 
AST, ALT and Total 
Bilirubin Maximum 
Post-Baseline 
Emergent Toxicity 
By Baseline 
Hepatitis C Status 
 
 
 
 
 
 
 
 
 
Y 
 
 
 
 


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Other 
 
ECG [14] 
 
 
 
Y 
 
 
 
 
 
 
 
 
Vital Signs at 
Screening 
 
 
 
Y 
 
 
 
 
 
 
 
 
Liver Assessment 
Y[23] 
 
 
Y[15] 
 
 
 
 
 
 
 
 
Hepatobiliary 
Abnormality criteria 
– All post baseline 
and Treatment 
Emergent 
Y  
 
 
Y 
 
 
 
 
 
 
 
 
Columbia 
suicidality  
Y 
 
 
Y[16,20] 
 
 
 
 
 
 
 
 
Subjects who 
became Pregnant 
 
 
 
Y 
 
 
 
 
 
 
 
 
Patient Profiles 
 
 
 
Y[17] 
 
 
 
 
 
 
 
 
Characteristics of 
Post Baseline 
AESI[22] 
Y 
 
 
 
 
 
 
 
 
 
 
 
Onset and Duration 
of the First 
Occurrence of Post 
Baseline AESI[22] 
Y 
 
 
 
 
 
 
 
 
 
 
 
Total Duration of 
Post Baseline 
AESI[22] 
Y 
 
 
 
 
 
 
 
 
 
 
 
Post Baseline 
Depression, 
Suicidal and Self-
Injury Adverse 
Events by 
System Organ 
Class, Maximum 
Toxicity, and Prior 
History of 
Depression and 
Anxiety 
Y 
 
 
 
 
 
 
 
 
 
 
 
PK  
 
 
 
Y 
 
 
 
 
 
 
 
 
Weight 
Y 
 
 
 
 
 
 
Y 
 
 
 
 
BMI 
Y 
 
 
 
 
 
 
Y 
 
 
 
 


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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. Includes reason for any dose change/interruption. 
2. Repeated for subjects at sites in Mexico at End of Study reporting only. 
3. For AEs reported more than once by a subject, the most severe intensity will be included. 
4. Only for End of Study reporting 
5. Common AEs are those with >=2% incidence in either treatment group summarised by frequency. 
6. Plots of incidence rates and relative risk with 95% CI for DTG + 3TC vs. DTG + TDF/FTC. 
7. Four PSRAE listings: Event and Description (Section 1-Section 2), Possible Cause (Section 3), Section 4 and 
Section 5-Section8. 
8. Listings for laboratory parameters with abnormalities for potential clinical concern, defined as any Grade1-4 
toxicity.  
9. Primary analysis method is multiple imputation MAR. Repeated for aditional analyses using MMRM. Lipids LOCF 
dataset will be used for all lipids summaries and analyses except for the analysis using multiple imputation 
methodology. 
10. Scatter plot of baseline vs. maximum post-baseline for ALT. Scatter plot of maximum ALT vs. maximum 
Bilirubin.  
11. Shift table summarising baseline vs. maximum post-baseline result  
12. Bar chart for LDL, HDL, TC, Triglycerides and HDL/TC ratio. 
13. Emergent Laboratory Toxicities - See protocol Appendix 6, Section 12.6). 
14. Only collected at Screening or when a Cardiovascular event occurs. 
15. Separate listings for Liver Event Results and Time of Event Relative to Treatment, RUCAM score, biopsy, 
imaging, past/ current conditions and FU. 
16. Includes Baseline and lists all visits for a subject who reports any ideation or behaviour at any visit. 
17. Patient profiles for subjects meeting protocol defined liver stopping criteria and for patients with CVW. Patient 
profiles can also be provided for any other subjects, as necessary for medical review. 
18. Overall and by subgroup (listed in Section 10.11). 
19. Line Plot of Adjusted Mean (95% CI) Change from Baseline 
20. Separate outputs: Listing of False Positive Alerts with Corresponding Reasons and Listing of True Positives but 
not AES with Corresponding Reasons 
21. Fisher’s exact test Statistical analysis  
22. AESI: Depression, Anxiety, Suicidality and Self injury, Drug Hypersensitivity, Rash, Insomnia, and 
Nightmare/abnormal dreams.  
23. Summary of Liver Monitoring/Stopping Event Reporting 
24. AEs those with >=1% incidence in either treatment group 
25. Shit tables at Baseline to Week X 
8.2.2. 
Planned Safety Statistical Analyses 
Statistical Analyses 
Endpoints 
• Change from Baseline in Fasting Lipids (Triglycerides, LDL cholesterol, HDL cholesterol, Total 
Cholesterol and TC/HDL ratio) 
Covariates & Factors 
• Baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL) 
• Baseline CD4+ cell count (≤ vs. >200 cells/mm3) 
• Age  
Data Handling 
• Use the observed case dataset as a starting point. 
• If a subject has a non-fasting value, that visit will be set to missing. 


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Statistical Analyses 
• If a subject initiates serum lipid-lowering therapy (as defined by ATC level 2=’Lipid Modifying 
Agents’) at Baseline, they will be excluded from the analysis.  
• If a subject initiates lipid-lowering therapy during the study, all visits after that date will be set 
to missing.  
Model Specification 
• If some Fasting Lipids 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. 
• A multiple imputation technique will be used to deal with the missing data (Multiple 
imputation (MAR) analyses are run at week 24 and 48 only). 
• Multiple imputations will be drawn from a multivariate normal imputation model (taking into 
account scheduled measurements prior to analysis Week X) with a Markov Chain Monte 
Carlo (MCMC) approach used to estimate posterior distributions. The MCMC method in the 
MI procedure in SAS will be used with multiple chains, 500 burn-in iterations, and a non-
informative prior. A random seed number of 1349572 will be used in the SAS program.  
Where a subject has a monotone or non-monotone pattern of missingness, all of their 
missing observations can be imputed under this approach. The absolute value will be 
imputed before the change value is calculated. Imputations will be drawn separately for 
subsets of subjects according to their treatment group, i.e., based on means and variance-
covariances from the same treatment group (Missing At Random (MAR) approach) 
conditioning on observed covariates (see above).  
• The imputations will be carried out 1,000 times. An ANCOVA, using the observed margins 
(OM) option, will be performed on each datasets produced adjusting for the covariates 
(listed above), treatment, and baseline value as a covariate, regardless of their significance. 
Rubin’s imputation rules through PROC MIANALYZE in SAS will be used to combine the 
1,000 estimated least squares means and difference to produce one estimated mean with 
95% CI and associated p-value for the adjusted mean difference between each treatment 
group at Week X. 
• Interactions between treatment and each of the covariates will not be assessed. 
Model Checking & Diagnostics 
• Refer to Appendix 12: 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 – DTG+TDF/FTC FDC) and corresponding 95% confidence interval 
and p-value. 
• Note: For Fasting Lipids 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. 
Additional Analyses 
• With lipids LOCF dataset (Section 10.7.2.2), Mixed Model Repeated Measures (MMRM), 
using the observed margins (OM) option, will adjust for treatment, covariates (listed above) 
and baseline fasting lipid value as a covariate, with visit as the repeated factor. 
• The model will make no further assumptions about the correlations between a subject’s 
score (the correlation matrix for within-subject errors will be unstructured). 


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Statistical Analyses 
• 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). 
Subgroup Analyses 
• Subgroup Analyses are run at week 24, 48 and 96 only. 
• Only Age (<50, vs ≥50) subgroup after week 48 will be analysed.  
• Change from baseline in fasting lipids by each subgroup listed in Section 10.11. will be 
analyzed by an ANCOVA model, using the observed margins (OM) option, adjusting for 
the covariates (listed above), treatment, baseline value as a covariate, subgroup and 
treatment*subgroup interaction term regardless of their significance, using an Lipid 
LOCF dataset. 
• Results will be presented as adjusted point estimates and 95% confidence intervals. 
 
Endpoints 
• The incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol 
Data Handling 
• The observed case (OC) dataset uses only the data that is available at a particular 
timepoint, with no imputation for subjects that have no post baseline values.  
Model Specification/ Analysis Methodology 
• Endpoints will be analysed for the comparison between DTG+3TC and DTG+TDF/FTC FDC 
by Fisher’s exact test using the Safety Population  
Model Results Presentation 
• Incidence for each treatment group and a p-value for the difference in incidence between 
treatment groups. 
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) 
Covariates & Factors 
• Baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL) 
• Baseline CD4+ cell count (≤ vs. >200 cells/mm3) 
• Age  
• Sex (Female vs. Male) 
• Race (White, African American/African Heritage, Asian, Other) 
• BMI (<vs. ≥ 25 kg/m2) 
• Smoking status (Never vs. Former vs. Current Smoker) 
• Current Vitamin D use (Yes vs. No) 
Data Handling 
• A multiple imputation technique will be used to deal with the missing data (Multiple 
imputation (MAR) analyses are run at week 24 and 48 only). 


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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 analyzed for each bone biomarker for the comparison between 
DTG+3TC and DTG+TDF/FTC. 
• Multiple imputation (MAR) analyses are run at week 24 and 48 only. 
• Using the OC dataset as a starting point, multiple imputations will be drawn from a 
multivariate normal imputation model (taking into account scheduled measurements prior to 
analysis Week X) with a Markov Chain Monte Carlo (MCMC) approach used to estimate 
posterior distributions. The MCMC method in the MI procedure in SAS will be used with 
multiple chains, 500 burn-in iterations, and a non-informative prior. A random seed number 
of 1349572 will be used in the SAS program Where a subject has a monotone or non-
monotone pattern of missingness, all of their missing observations can be imputed under 
this approach. The absolute value will be imputed before the change value is calculated. 
Imputations will be drawn separately for subsets of subjects according to their treatment 
group, i.e., based on means and variance-covariances from the same treatment group 
(Missing At Random (MAR) approach) conditioning on observed covariates (see above). 
• The imputations will be carried out 1,000 times. An ANCOVA, using the observed margins 
(OM) option, will be performed on each datasets produced adjusting for the covariates 
(listed above), treatment, and baseline value as a covariate, regardless of their significance. 
Rubin’s imputation rules through PROC MIANALYZE in SAS will be used to combine the 
1,000 estimated least squares means and difference to produce one estimated mean with 
95% CI and associated p-value for the adjusted mean difference between each treatment 
group at Week X. 
• Interactions between treatment and each of the covariates will not be assessed. 
Model Checking & Diagnostics 
• Refer to Appendix 12: 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 – DTG+TDF/FTC FDC) 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. 
Additional Analyses 
• 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 
score (the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (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 


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the effect of baseline score for the endpoint can vary between visits (i.e. baseline score*visit 
interaction will be included in the model). 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change From 
Baseline will be generated for each treatment group by visit 
Subgroup Analyses 
• Subgroup Analyses are run at week 24, 48 and 96 only. 
• 
Change from baseline in bone biomarkers by each subgroup listed in Section 10.11. will 
be analyzed by an ANCOVA model, using the observed margins (OM) option, adjusting 
for the covariates (listed above), treatment, baseline value as a covariate, subgroup and 
treatment*subgroup interaction term regardless of their significance, using an OC 
dataset. 
• Results will be presented as adjusted point estimates and 95% confidence intervals. 
Statistical Analyses 
Endpoints 
• Change from baseline in renal biomarkers (serum Cystatin C, urine albumin/creatinine 
ratio, urine protein/creatinine ratio, urine phosphate, eGFR (based on CKD-EPI-
creatinine and CKD-EPI-cystatin C), serum creatinine, Urine Beta-2 Microglobulin/Urine 
Creatinine ratio and Urine Retinol Binding Protein/Urine Creatinine ratio).  
Covariates & Factors 
• Baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL) 
• Baseline CD4+ cell count (≤ vs. >200 cells/mm3)  
• Age  
• Sex (Female vs. Male) 
• Race (White, African American/African Heritage, Asian, Other) 
• Presence of diabetes mellitus (DM) (Yes vs. No) 
• Presence of hypertension (Yes vs. No) 
Data Handling 
• A multiple imputation technique will be used to deal with the missing data (Multiple 
imputation (MAR) analyses are run at week 24 and 48 only). 
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 analyzed for each renal biomarker for the comparison between 
DTG+3TC and DTG+TDF/FTC. 
• Multiple imputation (MAR) analyses are run at week 24 and 48 only. 
• Using the OC dataset as a starting point, multiple imputations will be drawn from a 
multivariate normal imputation model (taking into account scheduled measurements prior to 
analysis Week X) with a Markov Chain Monte Carlo (MCMC) approach used to estimate 
posterior distributions. The MCMC method in the MI procedure in SAS will be used with 
multiple chains, 500 burn-in iterations, and a non-informative prior. A random seed number 
of 1349572 will be used in the SAS program.  Where a subject has a monotone or non-
monotone pattern of missingness, all of their missing observations can be imputed under 
this approach. The absolute value will be imputed before the change value is calculated. 
Imputations will be drawn separately for subsets of subjects according to their treatment 


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group, i.e., based on means and variance-covariances from the same treatment group 
(Missing At Random (MAR) approach) conditioning on observed covariates (see above).  
• The imputations will be carried out 1,000 times. An ANCOVA, using the observed margins 
(OM) option, will be performed on each datasets produced adjusting for the covariates 
(listed above), treatment, and baseline value as a covariate, regardless of their significance. 
Rubin’s imputation rules through PROC MIANALYZE in SAS will be used to combine the 
1,000 estimated least squares means and difference to produce one estimated mean with 
95% CI and associated p-value for the adjusted mean difference between each treatment 
group at Week X. 
• Interactions between treatment and each of the covariates will not be assessed.  
Model Checking & Diagnostics 
• Refer to Appendix 12: 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 – DTG+TDF/FTC FDC) 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. 
Additional 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 
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 
score (the correlation matrix for within-subject errors will be unstructured). 
• The repeated measures analysis will assume that the treatment difference can vary between 
visits (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 score for the endpoint can vary between visits (ie. baseline score*visit 
interaction will be included in the model). 
• Line plots of LS means with 95% confidence intervals for Adjusted Mean Change From 
Baseline will be generated for each treatment group by visit 
Subgroup Analyses 
• Subgroup Analyses are run at week 24, 48 and 96 only. 
• Only baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL), baseline CD4+ cell count (≤ 
vs. >200 cells/mm3), Age (<50, vs ≥50) and presence of hypertension subgroups after 
week 48 will be analysed. 
• Only Serum Cystatin C, eGFR (based on CKD-EPI-creatinine and CKD-EPI-cystatin C), 
Urine Beta-2 Microglobulin/Urine Creatinine ratio and Urine Retinol Binding 
Protein/Urine Creatinine ratio after week 48 will be analysed. 
• Change from baseline in renal biomarkers by each subgroup listed in Section 10.11. will 
be analyzed by an ANCOVA model, using the observed margins (OM) option, adjusting 
for the covariates (listed above), treatment, baseline value as a covariate, subgroup and 
treatment*subgroup interaction term regardless of their significance, using an OC 
dataset. 
• Results will be presented as adjusted point estimates and 95% confidence intervals. 


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8.3. 
Virology Analyses 
8.3.1. 
Overview of planned Virology Analyses 
The virology analyses will be based on the Viral Genotypic and Phenotypic population, 
unless otherwise specified. 
Table 6 provides an overview of the planned analyses, with full details being presented in 
Appendix 17: List of Data Displays.  


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Table 6 
Overview of Planned Virology Analyses 
Endpoint  
Absolute 
Summary 
Individual 
T 
F 
F 
L 
Summary of Subject Accountability 
Genotypes Available 
Y 
 
 
 
Phenotypes Available 
Y 
 
 
 
Genotypic Resistance 
Genotypic results at Baseline and CVW[1] 
Y[2] 
 
 
Y[3] 
Incidence of treatment-emergent genotype at time of 
CVW[1] 
Y[2] 
 
 
 
Stanford Genotypic Susceptibility Score (S-GSS) 
Genotype at Baseline and Time of CVW by Genotypic 
Cut-Off 
Y 
 
 
Y 
Phenotypic Resistance 
Incidence of treatment-emergent phenotype at time of 
CVW[1] 
Y[4] 
 
 
Y 
Replication capacity 
 
 
 
Y 
Fold Change at Baseline and CVW   
Y 
 
 
 
Net Assessment for Overall Susceptibility Score 
Overall Susceptibility Score (OSS) 
 
 
 
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. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.    
1. 
Sample used for resistance testing is taken at the suspected visit date, and only tested once a subject confirms 
virological failure at a subsequent visit.   
2. 
Separate outputs for INI and NRTI/NNRTI/PI mutations 
3. 
All and Treatment Emergent 
4. 
Separate outputs by phenotypic cut-off and by number of drugs to which subjects are resistant. 
 
8.4. 
Health Outcomes Analyses 
8.4.1. 
Overview of Planned Health Outcomes Analyses 
The Health Outcomes analyses will be based on the Intent-To-Treat (Exposed) 
population, unless otherwise specified. 
Table 7 provides an overview of the planned Health Outcomes analyses, with full details 
of data displays being presented in Appendix 17: List of Data Displays. 


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Table 7 
Overview of Planned Health Outcomes 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 
Quality of Life  
 EQ-5D-5L Utility 
Score/ EQ Visual 
Analogue scale 
(EQ VAS)  - LOCF 
 
 
 
Y 
 
 
Y  
Y 
Y[1] 
 
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 (descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.   
1. 
 Line plot of Adjusted Mean (95% CI) Change From Baseline. 
8.4.2. 
Planned Health Outcomes Statistical Analyses 
Statistical Analyses 
Endpoint(s) 
• Change from baseline in EQ-5D-5L Utility Score  
• Change from baseline in EQ Visual Analogue Scale (VAS)  
Covariates & Factors 
• Baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL) 
• Baseline CD4+ cell count (≤ vs. >200 cells/mm3) 
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 – DTG+TDF/FTC FDC) 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.   


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9. 
REFERENCES 
Brookmeyer, R. and Crowley, J. (1982), “A Confidence Interval for the Median Survival 
Time”, Biometrics, 38, 29-41. 
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  
GSK Document No.: 2015N263962_02. 205543 Protocol Amendment 02.  A Phase III, 
randomised, double-blind, multicentre, parallel-group, non-inferiority study evaluating 
the efficacy, safety, and tolerability of dolutegravir plus lamivudine compared to 
dolutegravir plus tenofovir/emtricitabine in HIV-1-infected treatment-naïve adults. 
Effective Date: 14-JUN-2018. 
Kalbfleisch J.D., Prentice R.L. The Statistical Analysis of Failure Time Data. 1st ed. New 
York:John Wiley & Sons; 1980 
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. 
Sato T. On the variance estimator for the Mantel-Haenszel risk difference. Biometrics. 
1989;42:311-323.  
Wensing AM, Calvez V, Ceccherini-Silberstein F, Charpentier C, Günthard HF, Paredes 
R, Shafer RW, Richman DD. 2019 update of the drug resistance mutations in HIV-1. Top 
Antivir Med. 2019 Sep;27(3):111-121. PMID: 31634862; PMCID: PMC6892618. 
 


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10. 
APPENDICES 
Section 
Component 
Section 10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
Section 10.2 
Appendix 2: Time & Events 
Section 10.3 
Appendix 3: Assessment Windows 
Section 10.4 
Appendix 4: Treatment States and Phases 
Section 10.5 
Appendix 5: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 10.6 
Appendix 6 : Derived and Transformed Data 
• Week 24/48/96/144 cut off date 
• General 
• Study Population 
• Safety 
• Efficacy 
• Viral Genotypic and Phenotypic 
• Health Outcomes 
Section 10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
• Premature Withdrawals 
• Handling of Missing Data 
Section 10.8 
Appendix 8: Values of Potential Clinical Importance 
Section 10.9 
Appendix 9: FDA Snapshot Algorithm 
Section 10.10 
Appendix 10: Multicenter Studies 
Section 10.11 
Appendix 11: Examination of Covariates, Subgroups & Other Strata 
Section 10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
Section 10.13 
Appendix 13: Time to Event Details 
Section 10.14 
Appendix 14: Q2 Creatinine Assay Accuracy Issue 
Section 10.15 
Appendix 15: Abbreviations & Trade Marks 
Section 10.16 
Appendix 16: End of Study (Final) Analysis 
Section 10.17 
Appendix 17: List of Data Displays 
 
 


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10.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
10.1.1. 
Exclusions from Per Protocol Population 
Presented below are the criteria for subject exclusion from the Per Protocol population. 
Note: these are based on the ViiV-GSK 204861-205543 Study Deviation Rules 
Document v3.0-01Dec2017. Refer to the latest version of the rules document prior to 
finalisation of the per protocol population. 
Subjects considered to have other significant protocol deviations, i.e., deviations which 
could affect the assessment of antiviral activity, could be flagged as excluded from the 
per-protocol population in the PD log based on clinical review of protocol deviations. 
The following criteria define the protocol deviations which, if they occur prior or at an 
analysis timepoint of interest, will lead to exclusion of a subject from the Per-Protocol 
population for that analysis. Potential protocol deviations leading to exclusion from PP 
population will be reviewed by the study team to confirm that they meet these criteria.  
This review will occur before the clinical database has been frozen for analysis. Note: for 
significant protocol deviation ‘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’ it 
will not be possible to identify whether subjects received a different treatment to the one 
they were randomised to until post unblinding. 
Additional Statistical Programming Check: 
In addition to the rules described below, subjects will also be excluded from the per 
protocol population for the following: 
• 
Permanent discontinuation of IP/withdrawal due to a reason of “Protocol Deviation” 
(as recorded in the eCRF). 
Ensure that the actual reason for the protocol deviation leading to permanent 
discontinuation is categorised under a rule specified in the rules document that results in 
exclusion from the per-protocol population.  
The main categories are listed: 
Significant Protocol Deviation Category 
Deviation source  
• 
Study treatment was unblinded prior to completion of the 
Week X visit 
PPD 
• 
Subject deviates from any inclusion or exclusion criteria, as 
recorded in the eCRF 
PPD 
• 
Subject took/received incorrect study treatment, for greater 
than 10% of the total time On-treatment; as evaluated at the 
time of the Week X analysis. 
PAREXEL 


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Significant Protocol Deviation Category 
Deviation source  
• 
Interruption of study treatment 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; as evaluated at the time of the Week X 
analysis  
PAREXEL 
• 
Use of prohibited medication 
PPD 
• 
Subject's change (i.e. substitution or dose modification) of 
DTG, 3TC, TDF or FTC, but was not withdrawn from the 
study 
PPD 
• 
Subject became pregnant while on study 
PPD 
 


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10.2. 
Appendix 2: Time & Events 
10.2.1. 
Protocol Defined Time & Events 
Procedures 
Screening Visita 
Double-blind Randomised Phase 
Open-label Randomised Phase 
Continuation 
Phasec 
Withdrawal 
Follow-upd 
Baseline / Day 1 
Week 
Every 12 
weeks after 
Week 148 
4 
8 
12 
16 
24 
28b 
36 
48 
52b 
60 
72 
84 
96 
100b 
108 
120 
132 
144 
148 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
X 
X 
X 
X 
X 
 


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Procedures 
Screening Visita 
Double-blind Randomised Phase 
Open-label Randomised Phase 
Continuation 
Phasec 
Withdrawal 
Follow-upd 
Baseline / Day 1 
Week 
Every 12 
weeks after 
Week 148 
4 
8 
12 
16 
24 
28b 
36 
48 
52b 
60 
72 
84 
96 
100b 
108 
120 
132 
144 
148 
Columbia Suicidality 
Severity Rating 
Scale 
 
Xh 
X 
X 
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 
X 
X 
X 
X 
X 
Symptom Directed 
Physical 
Exam/Medical 
Decision Makingi 
X 
X 
X 
X 
X 
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 
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 
X 
X 
X 
X 
X 
EQ-5D-5Ll 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Laboratory Assessments 
Plasma for HIV 
genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative plasma 
HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
X 
X 
 
Lymphocyte subset  
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Plasma for 
storage/inflammation 
biomarkersn 
X 
X 
X 
X 
X 
X 
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 
 
X 
X 
Haematology 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedures 
Screening Visita 
Double-blind Randomised Phase 
Open-label Randomised Phase 
Continuation 
Phasec 
Withdrawal 
Follow-upd 
Baseline / Day 1 
Week 
Every 12 
weeks after 
Week 148 
4 
8 
12 
16 
24 
28b 
36 
48 
52b 
60 
72 
84 
96 
100b 
108 
120 
132 
144 
148 
Fasting lipids and 
glucoseo 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Xp 
 
Urinalysis and spot 
urine for protein 
analysisq 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Pregnancy testr 
S 
U 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
HBsAg, anti-HBc, 
anti-HBs, and HBV 
DNAs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal and bone 
marker analytes 
(blood/urine)t 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Whole blood for 
virology/telomere 
lengthu 
 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
Xu 
 
Whole blood for 
telomere lengthv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Study Treatment 
IVRS/IWRSw 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
 
 
Study treatment 
accountability (pill 
counts) 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 


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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, ECG = electrocardiograph, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus type 1, INR = international 
normalised ratio, IVRS = interactive voice recognition system, IWRS = interactive web recognition system, PT = prothrombin time, RNA = ribonucleic acid, RPR = rapid plasma 
reagin 
a. 
Randomisation may occur as soon as all Screening results are available. 
b. 
Subjects with plasma HIV-1 RNA levels ≥50 c/mL at Week 24, Week 48 and Week 96 must have HIV-1 levels re-assessed by a second measurement performed four weeks later 
at the Week 28, Week 52 visit and Week 100 visit, respectively. Subjects should have received full doses of study treatment for at least 2 weeks at the time of HIV-1 RNA re-
assessment for any HIV-1 RNA level ≥50 c/mL.  Subjects with plasma HIV-1 RNA levels <50 c/mL at Week 24, Week 48 and Week 96 should not attend the Week 28 visit,  Week 
52 visit and Week 100 visit, respectively. 
c. 
Subjects randomised to DTG plus 3TC who complete through Week 148 may 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. 
f. 
Full medical history will be conducted prior to randomisation 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. 
At screening, 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. Body mass index (BMI) will be calculated within the eCRF.  At Week 96 and Week 144, only weight will be 
measured. 
h. 
On Day 1, the electronic Columbia Suicidality Severity Rating Scale (eC-SSRS) is to be administered prior to randomisation.  
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 Healthcare/GSK product will be collected between obtaining informed consent and administration 
of study drug at Day 1. 
l. 
The questionnaire is recommended to be administered at the beginning of the visit before any other assessments are conducted.  Only conduct the questionnaire at Withdrawal if 
occurring prior to Week 144.  
m. At Week 148, repeat HIV-1 RNA testing will only be performed for subjects with HIV-1 RNA ≥50 c/mL at Week 144.  
n. 
Plasma samples for storage will be collected at each visit, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  Additionally, these samples will 
be used when needed such as when samples are lost or arrive at the laboratory unevaluable or as a priority need for genotypic and/or phenotypic analyses when subjects meet 
CVW criteria.  Additionally, inflammation biomarkers (IL-6, hs-CRP) will be measured at Day 1, Week 48, Week 96 and Week 144 using stored plasma samples. 
o. 
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable. 
p. 
Only collect fasting lipids and glucose if the Withdrawal visit occurs at Week 24, Week 48, Week 96 or Week 144. 
q. 
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate. 


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r. 
Pregnancy testing will be conducted (females of reproductive potential only) on serum (S) samples with the exception of Day 1, which must be a urine (U) test to confirm status 
prior to administration of study treatment. 
s. 
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. 
t. 
Blood samples for renal and bone biomarker assessments: Renal: Cystatin C; Beta-2 Microglobulin; Retinol Binding Protein (RBP); Bone: bone specific alkaline phosphatase, 
procollagen type I N-terminal propeptide, type I collagen cross-linked C-telopeptide, osteocalcin, 25-hydroxyvitamin D. Urine sample for renal biomarker assessments: RBP and 
Beta-2-Microglobulin.  Only collect at the Withdrawal visit if it occurs at Week 24, Week 48, Week 96 or Week 144. 
u. 
Whole blood samples may be used for virologic analyses as described in the protocol.  A sample at Day 1 and a second sample at either Week 148 or at Withdrawal (if a subject 
is withdrawn prior to Week 148 will be taken for all subjects.  Additionally, where possible, stored whole blood from Day 1 will be used for telomere length evaluation (while 
telomere length evaluation at Week 96 and Week 144 require a separate whole blood sample). 
v. 
Whole blood samples for telomere length evaluation will be taken at Week 96 and Week 144 (where possible, the Day 1 evaluation will be done from the stored whole blood 
‘virology/telomere length’ sample in footnote ‘u’) 
w. At Screening, a subject number will be generated.  
 


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10.3. 
Appendix 3: Assessment Windows 
Laboratory data, health outcomes (except for eCSSRS, which will use nominal visit 
labels as recorded on the eCRF) 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. The CVW algorithm will be derived 
using nominal CRF visit rather than using the assessment window defined below. 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. 
10.3.1. 
Definitions of Assessment Windows for Analyses 
Analysis Set / 
Domain 
Parameter      (if 
applicable) 
Target  
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy/HO/lab  Snapshot 
endpoints/lipids, 
glucose, renal 
(serum 
creatinine, GFR 
BSA adj follow 
safety chem), 
bone, telomere, 
urinalysis, EQ5D 
& CSSRS 
-28 
≤-4 
≤-4 
Screen 
 
 
1 
-3  
1 
Day 1 
 
 
29 
2 
42 
Week 4 
 
 
57 
43 
70 
Week 8 
 
 
85 
71 
98 
Week 12 
 
 
113 
99 
126 
Week 16 
 
 
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,… 144 
 
 
Forcing snapshot window to be ±6 weeks, Week 148 nominal visit 
will be counted under Week 144 analysis window for HIV-1 RNA 
 
 
1121 
1051 
1162 
Week 160 (7*w-69d, 
7*w+42d) 
 
 
1205 
1163 
1246 
Week 172 (7*w-41, 
7*W+42) 
 
 
Study 
Day of 
last 
dose + 
28 
> (Study 
Day of last 
dose + 1) 
> (Study 
Day of last 
dose + 1) 
Follow-up 


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NOTES : 
• 
For key scheduled timepoints at Week 24/48/96/144, the windows have been defined to cover ± 6 weeks, 
regardless of the midpoint between adjacent target Study Days.  The windows for the adjacent periods are 
adjusted accordingly. 
• 
For parameters that are not scheduled to be assessed at particular visits, such as unscheduled visits or 
parameters measured at the wrong visit, the all-inclusive windows defined above will still be used; data 
summaries will be reported by scheduled visits. Assessments at unscheduled visits will be included in data 
summaries, and for ‘any time On-treatment’ time points and in data listings, as well any algorithms that make 
use of additional data (e.g. snapshot,). 
• 
See Section 10.6.2 for how to handle multiple assessments within a time window. 
Analysis Set / 
Domain 
Parameter      (if 
applicable) 
Target  
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy/ 
Safety/Virology 
CD4+ cell count, 
safety lab (chem, 
hema) observed 
case for non-
snapshot 
efficacy 
-28 
≤-4 
≤-4 
Screen 
 
 
1 
-3  
1 
Day 1 
 
 
29 
2 
42 
Week 4 
 
 
57 
43 
70 
Week 8 
 
 
85 
71 
98 
Week 12 
 
 
113 
99 
126 
Week 16 
 
 
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,… 
 
 
1009 
967 
1022 
Week 144 (7*w-41d, 
7*w+14d) 
 
 
1037 
1023 
1078  
Week 148 (7*w-13d, 
7*w+42d) 
 
 
1121 
1079 
1162 
Week 160 (7*w-41, 
7*w+42d) 
 
 
Study 
Day of 
last 
dose + 
28 
> (Study 
Day of last 
dose + 1) 
> (Study 
Day of last 
dose + 1) 
Follow-up 


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NOTES : 
• 
For key scheduled timepoints at Week 24/48/96/144/148, the windows have been defined to allow analysis visits 
at week144 and week 148. 
• 
For parameters that are not scheduled to be assessed at particular visits, such as unscheduled visits or 
parameters measured at the wrong visit, the all-inclusive windows defined above will still be used; data 
summaries will be reported by scheduled visits. Assessments at unscheduled visits will be included in data 
summaries, and for ‘any time On-treatment’ time points and in data listings, as well any algorithms that make 
use of additional data (e.g. snapshot,). 
• 
See Section 10.6.2 for how to handle multiple assessments within a time window. 
 
 


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10.4. 
Appendix 4: Treatment States and Phases 
10.4.1. 
Study Phases 
All displays are for the Double Blind and Open Label phases combined, unless specified 
otherwise. All data collected up to the point of DBF will be included in summary statistics 
hence, for example, data collected beyond week 24 will be included in the week 24 
reporting effort. In other words, all data collected up to the point of DBF will be included 
in summary statistics, which could be past week 24 for subjects enrolled early in the study. 
However, at the Week 144 analysis, summary statistics will include data up to Week 148 
for both arms. 
Data collected after Week 148 will be considered to be during the Continuation Phase of 
the study and will be not included in the table summaries for Week 144/148 reporting. 
Treatment Phase 
Definition* 
Screening 
Date < Day 1 
Double Blind 
Day 1 ≤ Date ≤ Week 96 
Open Label 
Week 96 < Date ≤ Week 148 
Continuation Phase 
Date > Week 148  
*based on analysis windowing. For parameters without scheduled visit at week 148, data will be cut at 
Week 144 analysis visit, i.e. at upper analysis window bound, i.e. study day 1050. 
All available data will be listed in listings with no cut-off for WK148 applied.  
10.4.2. 
Treatment States 
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment. 
10.4.2.1. 
Treatment States 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:  
• 
If the study treatment stop date is missing then the assessment will be considered to be On-Treatment 
 
10.4.2.2. 
Treatment States for AE Data 
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. 


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Treatment State 
Definition 
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.  
NOTES:  
• 
Partial AE start date will use imputation as described in Section 10.7 
• 
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. 
 
10.4.2.3. 
Treatment States for Prior/Concomitant/Post-Therapy Medications Data 
• 
Prior medications are those taken (i.e., started) before the start date of 
investigational product.  
• 
Concomitant medications are those taken (i.e., started or continued) at any time 
between the start date and stop date of IP, inclusive. Prior medications that were 
continued during this period are also considered as concomitant medications.  
• 
Post-treatment medications are those started after the stop date of IP. 
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.  Also, for any medication starting on the same date as IP, it will be 
assumed that the medication was taken after the subject started taking IP. 
ART medications will also be classified as prior, concomitant and/or post-treatment 
according with the following modifications: 
• ART starting on study treatment stop date will be considered as only post-
treatment and not concomitant.  It is expected that after discontinuation of study 
treatment, a subject may immediately begin taking another ART.  (Note: this is 
different to concomitant medications which are considered concomitant and post-
treatment if they start on the IP stop date). 
• ART stopping on study treatment start date will only be considered as prior and 
not concomitant. (Note: this is different to concomitant medications which are 
considered concomitant and post-treatment if they start on the IP stop date).  
The table below is for concomitant medications 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 
 
x = start/stop date of medication 
? = missing start/stop date of medication 
* 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 
** 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 
*** 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 
 
10.4.3. 
Post-treatment Assessments and Phases 
On-treatment and Post-treatment assessments and events will be classified as occurring 
during the Double Blind, Open Label or the Continuation Phase of the study as follows: 
• 
If a subject did not enter the Open Label Phase, then any Post-treatment data will be 
assigned to Double Blind Phase.  
• 
If a subject did not enter the Continuation Phase, then any Post-treatment data will be 
assigned to the Open Label Phase.  
• 
For subjects who did enter the Continuation Phase, any Post-treatment data will be 
assigned to the Continuation Phase. 


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10.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
10.5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
PPD Randomization System 
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
1 
DTG + 3TC once daily 
DTG + 3TC 
1 
2 
DTG + TDF/FTC FDC once daily 
DTG + TDF/FTC FDC 
2 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
 
10.5.2. 
Baseline Definition & Derivations 
10.5.2.1. 
Baseline Definitions 
For all endpoints (unless stated otherwise) the baseline value will be the latest pre-dose 
assessment. This is generally expected to be from the Day 1 visit, although such values 
may be missing or unscheduled assessments may be performed before treatment start.  
10.5.2.2. 
Derivations and Handling of Missing Baseline Data 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
NOTES : 
• 
Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 Baseline Definitions will be 
used for derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing. 
 
10.5.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• The currently supported versions of SAS software and TSCG will be used. 
Reporting Area 
HARP Server 
: uk1salx00175 
HARP Area 
: \ARPROD\GSK3515864\mid204861\ 
: \ARPROD\GSK3515864\mid205543\ 
QC Spreadsheet 
: \ARPROD\GSK3515864\ mid204861\<REPORTING_EFFORT>\documents 
: \ARPROD\GSK3515864\ mid205543\<REPORTING_EFFORT>\documents 


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Reporting Process 
Analysis Datasets  
• Analysis datasets will be created according to 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 each reporting effort. 
 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, 
unless otherwise stated: 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics 
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. 
• 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. 
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. 
• Reporting for Data Listings:  
•  Actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).   Relative time, relative to a reference date, is 
provided in listings where a date of an event or assessment is available. These 
reference dates will typically be the start date of treatment. 
• 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 10.3.  
• However, data summaries will only report visits that are planned assessment time points 
for each parameter (according to the T&E table). 
• Assessments at unscheduled visits will be included in data listings 


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Reporting Standards 
Invalid Laboratory Assessments 
• Certain laboratory endpoints are required to be collected in a fasting state, i.e., glucose and 
lipids (triglycerides, total cholesterol, HDL, LDL). If these endpoints are collected in a non-
fasting state, then the results will be excluded from summaries; such results will be included 
in data listings with the fasting status noted. 
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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10.6. 
Appendix 6: Derived and Transformed Data 
10.6.1. 
Week 24/48/96/144 cut off date 
10.6.1.1. 
To calculate the total time on treatment prior or at week 24 
For the week 24 interim, it is necessary to define a cut-off for the calculation of total time 
on treatment during the Week 24 time period. This is for purpose of significant protocol 
deviation identification only for deviations that are being identified by PAREXEL. 
The cut-off date is defined as follows: 
• For subjects who have a Week 24 visit -> cut-off = Week 24 end date from Visit 
dataset (SV). 
• For subjects who have withdrawn before Week 24 visit -> cut-off = 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 who have not withdrawn but no IP stop date or week24 visit date yet 
-> cut-off = IP start date + 210* - 1   
  *upper bound of week24 window 
 
The last exposure data should use both Start Date of Treatment and End Date of 
Treatment in case the IP was interrupted and re-started. 
This cut-off date applies for the calculation of total on treatment during Week 
 24, such as for denominator of dose interruption percentage. 
A similar approach will be used for the Week 48/96/144 cut-off. 
10.6.1.2. 
To check if the PD occurred prior or at week 24 viral load date (used for 
snapshot algorithm) 
• For subjects who have Week 24 viral load date -> cut-off = Week 24 viral load 
date (used for snapshot algorithm) from LB dataset. 
• For subjects who do not have a Week 24 viral load date: 
− 
if withdrawn before Week 24 Snapshot HIVRNA sample taken -> cut-off = the 
earliest of (Day of Study Discontinuation from DS, date of Withdrawal Visit 
from SV) 
− 
If missing data during week 24 window but on study-> cut-off = IP start date + 
210* - 1   
       *upper bound of week24 window 
A similar approach will be used for the Week 48/96/144 cut-off. 
 


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10.6.2. 
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 
• If after window assignment (see Section 10.3), there are multiple valid assessments of a 
parameter within the same on-treatment 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 (ie 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 treatment start date: 
• Ref Date = Missing                        → Study Day = Missing  
• Ref Date < Treatment start Date   → Study Day = Ref Date – treatment start Date     
• Ref Date ≥ 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: Double-Blind, Open-
Label and Continuation. 
Emergent  
• Emergent refers to AE Severity/ Lab toxicity that develops or increases in intensity after 
baseline 
Study Drug 
• Study Drug refers to either Investigation Product DTG + 3TC or DTG + TDF/FTC FDC. 
 


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10.6.3. 
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.   
• For the purpose of calculating age the ‘30th June’ is imputed as the date and month of birth 
for all subjects. 
• 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, 𝑝𝑝̂, of having a cardiovascular disease (CVD) within the next 10-
years according to the Framingham formula [D’Agostino et al. 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
 
 


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Demographics 
• A subject will be considered as treated for high blood pressure if during screening it has 
specified that is suffering from hypertension. 
• A subject is classified as diabetic if current or past is indicated in the medical conditions 
eCRF for Type 1 or Type 2 diabetes mellitus, or diabetes mellitus.  
• 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. 
• 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, but will be counted in the highest category of risk in the 
summary by category. 
 
10.6.4. 
Safety 
Extent of Exposure 
• Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• If DTG and blinded background are not started on the same day, the earliest start date and 
latest stop date of the two will be used.  
• Subjects who were randomized but did not report a treatment start date 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 duration of interruptions 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%). 
Refer to Section 10.6.1 for details. 
Adverse Events 
AE Severity – DAIDS Grading 
• The DAIDS grading (VERSION 2.0, November 2014) 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 


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Extent of Exposure 
Depression 
Drug Hypersensitivity 
Insomnia 
Nightmare/Abnormal Dreams 
Rash 
Suicidality and self-injury 
 
Laboratory Parameters 
• 
Additional non-protocol specified laboratory assessments performed at the institution’s local 
laboratory that are databased will not be included in the listings or analyses/summaries. All 
analyses will be based on central laboratory assessments only. If a laboratory value which is 
expected to have a numeric value for summary purposes, has a non-detectable level 
reported in the database, where the numeric value is missing, but typically a character value 
starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine 
how much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
Lab Toxicities – DAIDS Grading  
• Toxicities will be based on the Division of AIDS (DAIDS) grading system, as specified in the 
protocol.  
• Toxicity grades provided by the central laboratory do not distinguish between abnormally 
high or low criteria, when both are relevant for a particular parameter. 
• When summarising toxicity grades for such parameters, they will be categorised as to 
whether they are above or below the midpoint of normal range. 
Parameter 
Below Midpoint 
Above Midpoint 
Fasted glucose 
Hypoglycaemia 
Hyperglycaemia 
Sodium 
Hyponatremia 
Hypernatremia 
Potassium 
Hypokalemia 
Hyperkalemia 
Calcium 
Hypocalcaemia  
Hypercalcaemia 
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 


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Laboratory Parameters 
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 
Glomerular Filtration Rate (GFR) 
• Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [Levey et al. 2009] 
will be used by the central laboratory to provide an estimate of GFR, in mL/min per 1.73 m2, 
as follows: 
 
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.  
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 or during the conduct of the study.  
• If both antibody and virus RNA assessments are available, then the latter will take 
precedence and positive/negative status will be based on whether HCV RNA is detectable 
(i.e., ≥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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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.  
 The exception to this is where an investigator’s assessment of true positive 
alert (recorded in the eCRF) relates only to an earlier duplicate call.  In 
such situations the earlier ‘positive’ alert will be selected over the later 
‘negative’ assessment thus ensuring both the positive alert and the 
resulting true positive assessment by the investigator are selected for 
summary.   
• Relevant CRF pages will be completed based on the latest entry (if it was a positive alert). 
• Baseline evaluation includes 'Lifetime' and 'Current History' data on ideation and/or 
behaviour. Subjects with timing of assessment not done per protocol are noted and their 
Lifetime' and 'Current History' data are included in the baseline summary despite being 
performed at post baseline.  
• Post-baseline evaluation includes 'Since Last Assessment' data on ideation and/or 
behaviour. Subjects with timing of assessment done not per protocol are noted and their 
'Since Last Assessment' data are included in the post-baseline summary despite their 
assessments being performed on Study Day 1.  
• Positive Alerts with a status of 'Not Applicable' contribute to counts of positive alerts but not 
to counts of either true or false positive alerts.  
• A true positive alert is defined as an eCSSRS positive alert (any question 4 to 9 with a 
response of 'yes') where the eCSSRS positive alert is consistent with clinical judgement.  
• Subjects may have more than one type of suicidal ideation or behaviour. 
 


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10.6.5. 
Efficacy 
HIV-1 RNA 
Snapshot 
• The Snapshot algorithm 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 10.9) 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: 
Snapshot Rate = Number of responders in that analysis window
Number of subjects in the analysis population 
• Full details of the algorithm, including the handling of special cases, are included in Section 
10.9. 
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. 


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HIV-1 RNA 
Target Detected / Target Non Detected 
• 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. 
Variance Estimator of Cochran Mantel-Haenszel Risk Difference 
(
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where 
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CVW Derivation 
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 5.4.1.2) 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 value. Note: study drug interruptions will not be taken into 
account when programmatically identifying CVW. 
• Additional guidelines specified in the protocol related to patient management only and 
will not be taken into account when programmatically identifying CVW. 
 
There are 3 parts to the derivation of CVW. 
 
Virologic Non-response (Parts 1 &2) 
• A decrease in plasma HIV-1 RNA of less than 1 log10 c/mL at Week 12 or Week 16, 
with subsequent confirmation, unless plasma HIV-1 RNA is <200 c/mL. 
• Confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24. 
Virologic Rebound (Part 3) 
• Confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL at any time (not 
necessarily immediately) after prior confirmed suppression to <200 c/mL. 
 


C O N FI D E N TI A L  
 
 
2 0 5 5 4 3  
 
7 3  
 
HI V -1 R N A  
If t he c alc ul ati o n res ults i n bot h r eb o un d a nd no n-r es pons e, it wo ul d b e r ep ort ed as a r e bo u nd. 
P art 1.  A d e cre as e i n Pl as m a HI V -1 R N A of l es s t h a n 1 l o g 1 0 c/ m L o nly at wee k 12 or 
W e e k 16, wit h s u b s e q u e nt c o nfir m ati o n, u nl es s Pl as m a  HI V -1 R N A is < 20 0 c/ m L  
- 
T his a p pli es t o W eek 12 and W e ek 1 6 d at a o nly  (pr o gra m mi n g n ote:  incl u de 
u nsc he d ul ed visits as a p art of a c o nfir m ati o n)  
- 
If t her e is a d ecr eas e < 1 l og 1 0 fr o m B aseli n e at W e ek 1 2 or W eek 16 an d HI V-1 R N A 
> = 2 0 0 c/ m L, th en -> s usp ect e d vir ol ogic wit h dr a w al  
- 
If t her e is a co nfir m atory s a m pl e, t he n ch eck if th er e is a d ecr eas e <1 l og 1 0 fr o m 
B as eli n e a nd th e HI V -1 R N A > = 2 00 c/ m L t h en -> c onfir m e d vir ol o gic wit hdr a w al  
- 
Ex a m pl e: P art 1, s ubj ect   – c onfir m e d vir ol o gic wit hdra w al o n 1 8-J un-1 5  
 
P art 2: C o nfir m e d Pl a s m a HI V -1 R N A l e vel s > = 2 00 c/ m L o n or aft er W e ek 24  
- 
If p ati e nt is n ot alr e ady a confir m e d V F d u e t o th e rul es i n P art 1, w e ca n t h en c ontin u e 
t o c heck t he r es ults fr o m W e ek 24 on w ar ds 
- 
If a p ati ent has a s a m pl e o n/ aft er W eek 24 and th e r esult is > = 2 00 c/ m L th en -> 
s us p ecte d vir ol ogic wit h dr a w al. 
- 
If a p ati ent, th en has a 2 nd c o ns ecutiv e s a mpl e > = 20 0 c/ m L t h en -> c onfir m e d vir olo gic 
wit h dr a w al.  
- 
Ex a m pl e: P art 2, s ubj ect 1 06 4 - c onfir m e d vir ol o gic withdr a w al o n 0 6- Oct-1 5  
  
P art 3: C o nfir m e d re b o u n d i n pl a s ma HI V -1 R N A l e vel s t o > =2 0 0 c/ m L aft er pri or 
c o nfir m e d s u p pr es si o n t o < 2 0 0 c/ m L  
− P ati e nt m ust h av e 2 co ns ecutiv e v al ues <2 0 0 c/ m L, foll o w e d at any ti m e ( not 
n ec essarily i m m e di at ely) by 2 c ons ec utive v al ues > =2 00 c/ m L.  
− O nc e a pati e nt h as 2 co ns ec utiv e v al ues <2 0 0 c/ m L, if a ny foll o wi n g  v alu e is > =2 00 
c/ m L t h en -> s usp ecte d r ebo u nd  
− If a p ati ent, th en has a 2 nd c o ns ecutiv e s a mpl e > = 20 0 c/ m L t h en th e n -> c o nfir m e d 
r e b o un d 
− Ex a m pl e: P art 3, s ubj ect   – c onfir m e d r e bo un d o n 26- A u g -1 5  
 
E x a m ple:  P art 1, su bj ect 
 
 
s u bj e ct vi sit 
vi sit d at e  c/ m L 
l o g 1 0 
c/ m L 
l o g 1 0 
d e cr ea s e 
fr o m B L 
C V 
o ut c o m e  
c o m m e nt s  
B as eli n e  
1 6 -F e b -
1 5  
3 3 98  
3. 5 3    
  
  
W e ek 4  
3 9  
1. 5 9  
1. 9 4    
  
W e ek 8  
2 3 54  
3. 3 7  
0. 1 6    
  
W e ek 1 2  
3 6 87 4 2  
5. 5 6  
-2. 0 3  
S us p ect e d 
vir ol o gic 
wit h dr a w al   
< 1 l o g 1 0 
d ecr e ase 
fr o m 
b as eli ne, 
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L  
 
 
2 0 5 5 4 3  
 
7 4  
 
HI V -1 R N A  
a n d val u e 
> 2 0 0 c/ m L  
W e ek 1 2 
r et est  
1 7 29 3  
4. 2 4  
-0. 7 1  
C o nfir m e d 
vir ol o gic 
wit h dr a w al  
< 1 l o g 1 0 
d ecr e ase 
fr o m 
b as eli ne, 
a n d val u e 
> 2 0 0 c/ m L  
 
E x a m ple:  P art 2, su bj ect 
 
 
s u bj e ct vi sit 
vi sit d at e  
c/ m L 
l o g 1 0 
c/ m L 
l o g 1 0 
d e cr ea s e 
fr o m B L 
C V 
o ut c o m e  
c o m m e nt s  
B as eli n e  
2 8 -M ar -1 5  3 8 28 6  
4. 5 8    
  
  
W e ek 4  
3 3 2  
2. 5 2  
2. 0 6    
  
W e ek 8  
4 0 0  
2. 6 0  
1. 9 8    
  
W e ek 1 2  
< 5 0  
< 1. 7 0  
2. 9 9    
  
W e ek 2 4  
8 7 39 4  
4. 9 4  
-0. 3 6  
S us p ect e d 
vir ol o gic 
wit h dr a w al   
v al u e >2 0 0 
o n/ aft er 
w e ek 24  
W e ek 2 4 
r et est 
2 1 3  
2. 6 2  
1. 9 7  
C o nfir m e d 
vir ol o gic 
wit h dr a w al  
C o ns ec utiv e 
v al u e >2 0 0 
o n/ aft er 
w e ek 24  
 
E x a m ple:  P art 3, su bj ect 
 
 
s u bj e ct vi sit 
vi sit 
d at e  
c/ m L 
l o g 1 0 
c/ m L 
l o g 1 0 
d e cr ea s e 
fr o m B L 
C V 
o ut c o m e  
c o m m e nt s  
B as eli n e  
0 2 -A pr -
1 5  3 0 30 0 7  
5. 4 8  
 
 
 
W e ek 4  
1 7 0  
2. 2 3  
3. 2 5    
  
W e ek 8  
1 4 0  
2. 1 5  
3. 3 3    
  
W e ek 1 2  
1 6 6  
2. 2 2  
3. 2 6   
 
W e ek 1 6  
2 9 15 3  
4. 4 6  
1. 0 2  
S us p ect e d 
r e b o un d 
2 
c o ns ecutiv e 
 v al u es 
< 2 0 0,  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L  
 
 
2 0 5 5 4 3  
 
7 5  
 
HI V -1 R N A  
 f oll o w e d by 
a n i niti al 
v al u e > =2 0 0 
w e ek 16 
r et est 
4 5 4  
2. 6 6  
2. 8 2  
C o nfir m e d 
r e b o un d 
2 n d 
c o ns ecutiv e 
s a m pl e 
> = 2 0 0  
Wit h dr a w al  
1 7 -S ep -
1 5  < 4 0  
1. 5 9  
3. 8 9    
  
  
  
 
  
 
 
 
1 0. 6. 6.  
Vir al G e n ot y pi n g a n d P h e n ot y pi n g  
G e n ot y p e  
G e n er al c o n si d er ati o n s  
•  N o mi n al a nd an alysis wi n d o w will b e i ncl u d ed i n t h e listi n gs.  
•  F or s u m m ary p ur p oses an alysis wi n d o w will b e use d.  
•  N ot e: R esista nc e t estin g will b e perf or m e d o n sa m pl es c oll ect e d at th e S V W ti m e poi nt (i. e. 
t h e ti m ep oi nt of t h e i niti al HI V-1 R N A r es ult whic h m e ets o n e of t h e Vir ol o gic Wit hdr a w al 
crit eri a a n d will be s ubs e que ntly c onfir m e d i n a r e pe at HI V-1 R N A t est.  T he S V W ti m e p oi nt 
is n ot ed as t h e C V W ti m e p oi nt i n listi ngs a nd s u m m ari es.  
A mi n o A ci d C h a n g e s  
•  A m ut atio n is c onsi d er ed pres e nt w h en ev er th e e nco d ed a mi n o aci d r esi du e diff ers fr o m t h e 
a mi n o aci d t hat w oul d hav e b e en enc o de d by t he wil d -typ e ( e.g., H X B 2, NL 4 3) co m p ar at or 
g e ne; e. g., Q 1 48 K.  
•  If t he enc o de d a mi n o aci d is s e e n as a mixt ur e of wil d-ty p e an d m ut a nt a mi n o aci d, e. g., 
Q 1 4 8 Q/ K, t h e m ut ate d a mi no aci d is co nsi der e d pr es ent at th e co d on of i nt erest.  
•  If t he enc o de d a mi n o aci d is s e e n as a mixt ur e of t w o or m or e a mi n o aci ds, whic h may or 
m ay n ot incl u de wil d ty pe, e. g., Q1 84 K/ H or Q 1 84 K/ H/ Q, etc., f or th e p ur p oses of c alc ul ati n g 
t h e n u m b er of m utat ed a min o acids, only o ne m utati o n is c o nsi d er ed to be pr ese nt at t he 
c o d on of i nt er est. 
•  Tr e at m e nt e m er g ent m utatio ns:   n ee d to m e et bel o w t hr e e crit eri a:  
1. N e w m utati o n:   obs erv ed d uri n g tre at m ent c o m pari n g t o bas eli n e at t h e s a m e cod o n 
wit h t h e cl ass/r e gio n.  
2. M ut ati o ns ar e bas ed on pr es p ecifi e d lists us ually i d e ntifi e d i n t h e R A P.   
a. I nt egr as e:  m ay use a list ge n er ate d by Vir ol ogy th at may i ncl u de no n-I A S 
g ui d anc e m ut ati ons deriv e d usi n g t h e St anf or d d at a base ( e. g., m utati o ns with 
p e nalty sc or e > = 1 5; htt ps://hiv d b.sta nfor d. ed u/dr -s u m m ary/ m ut-sc or es/I N S TI/), 
or ot her r eli a bl e so urc es.  Not e th e list m ay c h an g e ov er ti m e. Us u ally t he m aj or 
m ut ati o ns ar e th e o nes wit h evi d enc e of str on g r esista nc e t o t h e A R T dr ug.   
b. All ot h er cl asses:  d efin e d by t h e I nter n ati on al Antivir al S oci ety -U S A (I A S -U S A).  
3. A R T Dr u g class r el ate d: b as ed on t he cl ass of th e A R T t h e s ubj ects ar e taki n g duri n g 
t h e tr eat m ent an d th e n e w m aj or m ut ati on wit hi n t h at cl ass will b e c onsi d er ed.  
P P D
P P D


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Genotype 
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' 
Prespecified Lists – Resistance Associated Mutations 
1. Known INI (INSTI) mutations associated with the development of resistance to RAL, EVG 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*, V151I*, G193E* 
INI (INSTI) Prespecified List  
NOTES:   
• 
Current listing may be modified in case of additional substantive data availability.    
• 
Most INI mutations listed taken from Stanford HIV Resistance Database 
(http://hivdb.stanford.edu/DR/cgi-bin/rules_scores_hivdb.cgi?class=INI cited 28 Feb 2014) and 
accessed on Oct 27th 2016.   
• 
Most INI mutation listed had a score of ≥15; and INI substitutions listed above in bold had a score of 
=60.    
*Mutations denotes additional INI mutations added as they were identified during in vitro passage of DTG or 
seen in a previous DTG study in INI-experienced subjects (ING112574). 
2. 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.  Note that NRTIs A62V, V75I, F77L, 
and F116Y all need to be present together with Q151M to be resistant, so are not major 
mutations alone. 
Class 
Mutations 
NRTIs 
M41L, K65R/E/N, D67N, 69 insert, K70E/R, L74V, Y115F, M184V/I, L210W, 
T215Y/F, K219Q/E;  [A62V, V75I, F77L, F116Y, Q151M] 
NNRTIs 
L100I, K101E/P, K103N/S, V106A/M, V108I, E138/A/G/K/Q/R, V179L, 
Y181C/I/V, Y188C/L/H, G190S/A, H221Y, P225H, F227C, M230I/L, 
PIs 
D30N,V32I , M46I/L, I47A/V, G48V, I50V/L, I54M/L, Q58E, T74P, L76V, 
V82A/T/F/L/S, N83D, I84V, N88S, L90M 
3. Note: 2017 Drug Resistance Mutations Update Volume 24, Issue 4, December 
2016/January 2017 
Susceptibility Scores 
Stanford Genotypic Susceptibility Score (GSS) 


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Genotype 
• To establish genotypic susceptibility to ART treatment, a genotypic sensitivity score will be 
calculated. 
• Genotypic sensitivity to each drug will be assessed using the HIVdb, the Integrated 
Genotypic Resistance Interpretation System [Liu, 2006]. 
• In the HIVdb system, each HIV-1 drug resistance mutation is assigned a drug penalty score. 
The penalty scores for each drug resistance mutation are available at 
NNRTI: https://hivdb.stanford.edu/dr-summary/mut-scores/NNRTI/ 
NRTI:  https://hivdb.stanford.edu/dr-summary/mut-scores/NRTI/ 
PI:  https://hivdb.stanford.edu/dr-summary/mut-scores/PI/ 
INSTI:   https://hivdb.stanford.edu/dr-summary/mut-scores/INSTI/. Scores for particular 
patterns of INSTIs are also available at https://hivdb.stanford.edu/dr-summary/pattern-
scores/INSTI/ 
• The drug resistance estimate is obtained by adding together the penalty scores from all 
mutations associated with resistance to that drug and then a numeric score (S-GSS) is 
applied for each drug as shown below. The sum scores are titrated to fall within the following 
ranges: susceptible, potential low-level resistance, low-level resistance, intermediate 
resistance, and high-level resistance (see table below). 
Resistance 
Estimate 
S-GSS Score Sensitivity 
0 – 9 
1 
Susceptible 
10 – 14 
0.75 
Potential low-level resistance 
15 – 29 
0.5 
Low-level resistance 
30 – 59 
0.25 
Intermediate resistance 
≥60 
0 
High-level resistance 
 
 
 
• The HIVdb GSS will then be calculated for each subject defined as the sum of the resistance 
scores for each of their background drugs. 
Phenotype 
Monogram Genotypic Susceptibility Score (GSS) 
• Monogram GSS score will be reported in a listing, but will not be used for summary tables. 
• Genotypic sensitivity to each drug will be assigned using the Monogram resistance score for 
each background drug provided in the database. 
Score 
Sensitivity 
1 
Sensitive 
0 
Resistant  
 
 
Phenotypic Susceptibility Score (PSS) 
Net Assessment and Overall susceptibility of ARTs 
• Net assessment is an assessment of antiviral activity of ARTs using both genotypic and 
phenotypic test results interpreted through a proprietary algorithm (from Monogram 
Biosciences) and provides the overall susceptibility of the drug (Note: partially sensitive 
and resistant calls are considered resistant in this analysis).  


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Genotype 
• For determining overall susceptibility of ARTs (OSS), a binary scoring system (0= 
resistant, 1=sensitive) for each antiretroviral agent was used and will be provided in the 
Monogram dataset. OSS will be calculated as the sum of the net assessment scores of 
ARTs comprising the subject’s ART and categorised as 0, 1, 2, or 3. OSS values will be 
calculated only for the time of CVW when net assessment is available. 
Decision tree for Monogram resistance data analyses 
• We might have resistance data that come from mixed datasets: PSGT, PSIN, GSIN 
(primary assays) vs PSGT+IN (secondary assay) 
• If one of the primary assay does not work for a specific timepoint, we might report the 
secondary assay if data is available. If all primary assays for a specific timepoint work 
then we report primary. For example, for baseline if the same assay section (PSGT, 
PSIN, GSIN) worked then we report. If at least one of PSGT or PSIN or GSIN didn’t 
work then we report secondary PSGT+IN.  
• Secondary assay testing results might not always be available. 
• For examples please refer to decision tree below. 
Background:  
• PSGT - provides both geno and pheno data for PRO/RT (NRTI and NNRTI) only 
• PSIN - Provides pheno data on Integrase only  
• GSIN - Provides geno data on Integrase only  
• PSGT+IN - Secondary assay used if PSGT or GSIN assay fails; it provides both geno 
and pheno data on PRO, RT and Integrase  
Table Symbol Key: 
y = assay test successful 
n = assay test failure 
2nd  = back up test performed 
bold = assay to use for analysis 
 
How to make decisions:  
Scenario 1: if primary PSGT, PSIN and GSIN assays all work) for both baseline and 
CVW samples, then PSGT+IN assay will not be performed, no PSGT+IN data should 
be generated.  
 
Assays  
Baseline  CVW 
PSGT 
y 
y 
PSIN 
y 
y 
GSIN  
y 
y 
 


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Genotype 
Scenario 2: If PSGT works for baseline, but PSIN and GSIN fail, then secondary 
PSGT+IN assay will be performed on baseline sample; similarly, if PSGT works for 
CVW sample but PSIN and GSIN  fail to work, in this scenario, use data generated 
from PSGT+IN assay on both Baseline and CVW sample for analyses, regardless of 
obtained PSGT assay data.  
Assays  
Baseline  
CVW 
PSGT 
y 
y 
PSIN 
n 
n 
GSIN  
n  
n 
2nd PSGT+IN  
Y 
Y 
 
Scenario 3:  If PSGT, PSIN and GSIN all work for baseline samples; PSGT works for 
CVW but PSIN and GSIN fail, while PSGT+IN on CVW sample works, then use 
CVW PSGT+IN (PR, RT and INSTI) to do comparison with PSGT, PSIN and GSIN 
baseline data (do not use PSGT at CVW data vs. PSGT at Baseline) 
Assays  
Baseline  CVW 
PSGT 
y 
y 
PSIN 
y 
n 
GSIN  
y 
n 
2nd PSGT+IN 
- 
Y 
 
Scenario 4: If PSGT works but GSIN and PSIN both fail on baseline sample, then 2nd 
PSGT+IN assay might be performed. And if PSGT, PSIN and GSIN all work for CVW 
sample, then use Baseline PSGT+IN data to do comparison with CVW Primary assay 
data, regardless of PSGT Baseline data. In other words, don’t use PSGT Baseline to do 
comparison of PSGT part of  PSGT+IN assay data for CVW sample 
Assays  
Baseline  CVW 
PSGT 
y 
y 
PSIN 
n 
y 
GSIN  
n  
y 
2nd PSGT+IN  
Y 
- 


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10.6.7. 
Health Outcomes 
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) 
• The EQ-5D is a quality of life instrument that provides a EQ-5D-5L Utility Score and the EQ 
Visual Analogue scale (EQ VAS)  
EQ-5D-5L 
• The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression with five levels for each dimension from level 1 = no 
problem to level 5 = extreme problems.  
• The number of possible health states is 55 = 3125. 
• The health state is defined by combining the levels of answers from each of the 5 questions. 
• Each health state is referred to in terms of a 5 digit code. For example, state 11111 indicates no 
problems on any of the 5 dimensions, while state 12345 indicates no problems with mobility, 
slight problems with washing or dressing, moderate problems with doing usual activities, severe 
pain or discomfort and extreme anxiety or depression. 
• The health state 5 digit code is translated into the utility score, which is valued up to one 
(representing perfect health) with lower values meaning worse state, according to the 
methodology described in Devlin,.2016, Section 3.4. The UK values set described in, Section 
3.4 will be used for all subjects regardless of their country origin. 
• The numerals 1-5 have no arithmetic properties and should not be used as a cardinal score. 
• Ambiguous values (e.g. 2 boxes are ticked for a single dimension) should be treated as missing  
values. 
• Observed values will be used in listing. 
EQ visual Analogue scale (EQ VAS) 'Thermometer' 
• Self-rated current health status 
• Ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). 
 


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10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing 
Data 
10.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subjects are considered to have completed the study if they satisfy one of the 
following: 
o Randomly assigned to either treatment arm, completed the Open-
label Randomised Phase including the Week 148 visit, and did not 
enter the Continuation Phase; 
o Randomly assigned to DTG plus 3TC, completed the Open-label 
Randomised Phase including the Week 148 visit, entered and 
completed the Continuation Phase (defined as remaining on study 
until DTG and 3TC are both locally approved for use as part of a dual 
regimen and the single entities of DTG and 3TC are available to 
patients (e.g. through public health services) or the DTG/3TC FDC 
tablet, if required by local regulations, is available or 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. 
 
10.7.2. 
Handling of Missing Data 
10.7.2.1. 
Handling of Partial and Missing 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 stop date of study treatment or 
withdrawal date; in this case the earliest of the two dates will be used. 
Adverse 
Events 
• The eCRF allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may 
be missing.  
• 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: 
o 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 


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Element 
Reporting Detail 
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 or 
withdrawal date; in this case the earliest of the two 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. 
 
10.7.2.2. 
Handling of Missing Data for Statistical Analysis 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
• Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should 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. 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 10.9 for full 
details 
Lipids 
LOCF 
• If subjects initiate 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.  
• If the missing data was due to other reasons, no data will 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. 


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Element 
Reporting Detail 
LOCF 
• This dataset will be used for all summaries of health outcomes data. 
• 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.  
Observed 
Case (OC) 
• This dataset uses only the data that is available at a particular timepoint, with 
no imputation for missing values. 
 
 
 


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10.8. 
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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10.9. 
Appendix 9: Snapshot 
10.9.1. 
Snapshot Algorithm Detailed Steps 
Please note that no change in the background ART is permitted for this protocol. 
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. 
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 ART 
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 ART 
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 
and HIV-1 RNA 
>= 50 copies/mL 
• Last on-treatment VL during Week 48 prior to/on 
the date of change <50   c/mL 
HIV1-RNA < 
50  
 
• No VL during Week 48 prior to/on the date of 
change     
HIV1-RNA ≥ 
50  
Change in ART 
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 ART 
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 
and HIV-1 RNA 


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Condition 
(‘Week 48’ indicates Week 48 window) 
Response  
Reasons 
>= 50 copies/mL 
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 
and HIV-1 RNA 
>= 50 copies/mL 
• 
Last on-treatment VL during Week 48 <50 c/mL 
HIV1-RNA < 
50  
 
5.2 No VL during Week 48    
 
 
5.2.1 if subjects still on study (i.e. IP has not been 
permanently stopped up to Week 48) 
No virologic 
data at Week 
48 Window  
On study but 
missing data in 
window 
5.2.2 If subjects withdraw before/during Week 48 due
to 
 
 
5.2.2.1 Safety reasons (e.g. AE/death, liver 
chemistry stopping criteria, renal toxicity 
withdrawal criteria, QTc withdrawal criteria et al,
as recorded in eCRF Conclusion form) 
No virologic 
data at Week 
48 Window 
Disc due to 
AE/death 
5.2.2.2  Non-safety related reasons (e.g. Lack of 
efficacy, protocol deviation, withdrew consent, 
loss to follow-up, study closed/terminated, 
investigator discretion et al, as recorded in 
eCRF Conclusion Form) 
 
 
• 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 and HIV-1 
RNA >= 50 
copies/mL 
[a]: Excluding permitted change in background therapy where change or decision to 
change is made prior to/on the first on-treatment viral result  
 
 


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10.10. 
Appendix 10: Multicenter Studies 
10.10.1. 
Methods for Handling Centres 
Data will be summarised for all centres combined. Country will be treated as an 
exploratory subgroup for analyses of the secondary efficacy endpoint as described in 
Section 8.1. 
 
 


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10.11. 
Appendix 11: Examination of Covariates, Subgroups & 
Other Strata 
10.11.1. 
Handling of Covariates, Subgroups & Other Strata 
• 
The following is a table of covariates that may be used in descriptive summaries, 
statistical analyses and analyses by subgroup. 
• 
Model terms that are categorical in nature or expressed as categorical terms will be 
included as ‘factors’ (e.g., ‘Baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL)’); 
otherwise model terms will be included as continuous scale ‘covariates’ (e.g., ‘Age’).  
• 
Additional covariates of clinical interest may also be considered.  
• 
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial, i.e. the race subgroup (African 
American/African Heritage; Non-African American/African;) might be used if 
percentage of subjects is small within a particular subgroup in other race categories. 
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. 
Randomization Strata using Baseline 
Values 
• 
Baseline plasma HIV-1 RNA (≤ vs. >100,000 
c/mL); 
• 
Baseline CD4+ cell count: (≤ vs. > 200 cells/mm3) 
 
Baseline data is used to derive actual strata regardless 
of how they were allocated at day 1 based on 
screening data 
 
Additional covariates and factors for inclusion in specific statistical models are defined as 
follows: 
• 
 
Age (continuous covariate) 
• 
 
Sex (Female vs. Male) 
• 
 
Race (White, African American/African Heritage, Asian, Other) 
• 
 
BMI (<25 vs. ≥ 25 kg/m2)) 
• 
Smoking status (Never vs. Former vs. Current Smoker) 
• 
Current Vitamin D use (Yes vs. No) 
• 
Presence of diabetes mellitus (DM) (Yes vs. No) 
• 
Presence of hypertension (Yes vs. No) 
• 
     HIV subtype (categories will be defined from Q2 Screening lab reports): HIV 
subtype will have its own category if it is reported by at least 10% of subjects overall 
in ITT-E, the remaining subtypes will be combined into ‘Others’. 
 


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Subgroups for statistical analyses and summaries by subgroup   
Endpoint 
 
 
 
 
 
Covariates and 
subgroups 
• 
Proportion of subjects with 
plasma HIV-1 RNA <50 c/mL 
at week X - Snapshot algorithm 
by subgroup 
• 
Study Outcomes using the 
Snapshot algorithm by 
subgroup 
• 
Proportion of Subjects with 
Plasma HIV-1 RNA <40 c/mL - 
Snapshot Analysis 
• 
Statistical analysis of 
Change from 
baseline in CD4+ cell 
counts by subgroup 
• 
Summary of Change 
from baseline in 
CD4+ cell counts by 
subgroup 
 
• Statistical 
analysis of 
Change from 
Baseline in 
Fasting Lipids 
by subgroup[2] 
• Summary of 
Change from 
Baseline in 
Fasting Lipids 
by subgroup[2] 
• Statistical 
Analysis of 
bone 
biomarkers by 
subgroup 
• Summary of 
Bone 
biomarkers by 
subgroup 
• Statistical analysis 
of Change from 
baseline in renal 
biomarkers by 
subgroup[3,4] 
• Summary of 
Change from 
baseline in renal 
biomarkers by 
subgroup[3,4] 
• Adverse Events Leading 
to Permanent 
Discontinuation of Study 
Treatment or Withdrawal 
from Study by subgroup 
• Post Baseline Adverse 
Events by System Organ 
Class, Maximum Toxicity 
and Subgroups 
Baseline plasma 
HIV-1 RNA (≤ vs. 
>100,000, 
>250,000, 
>400,000, 
>500,000 c/mL) 
Y 
 
 
 
 
 
Baseline plasma 
HIV-1 RNA (≤ vs. 
>100,000 c/mL) 
 
Y  
Y 
Y 
Y 
Y 
Baseline CD4+ cell 
count (≤ vs. >200 
cells/mm3) 
Y  
Y  
Y 
Y 
Y 
Y 
Age (<35, 35-<50, 
≥50) 
Y  
Y  
Y 
 
Y 
Y 
Gender (Female vs. 
Male) 
Y  
Y  
Y 
Y 
Y 
Y 
Race (White, 
African 
American/African 
Heritage, Asian, 
Other)  
Y 
Y 
Y 
Y 
Y 
Y 
CDC category 
(Stage 0-3) 
Y 
Y 
 
 
 
 


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Endpoint 
 
 
 
 
 
Covariates and 
subgroups 
• 
Proportion of subjects with 
plasma HIV-1 RNA <50 c/mL 
at week X - Snapshot algorithm 
by subgroup 
• 
Study Outcomes using the 
Snapshot algorithm by 
subgroup 
• 
Proportion of Subjects with 
Plasma HIV-1 RNA <40 c/mL - 
Snapshot Analysis 
• 
Statistical analysis of 
Change from 
baseline in CD4+ cell 
counts by subgroup 
• 
Summary of Change 
from baseline in 
CD4+ cell counts by 
subgroup 
 
• Statistical 
analysis of 
Change from 
Baseline in 
Fasting Lipids 
by subgroup[2] 
• Summary of 
Change from 
Baseline in 
Fasting Lipids 
by subgroup[2] 
• Statistical 
Analysis of 
bone 
biomarkers by 
subgroup 
• Summary of 
Bone 
biomarkers by 
subgroup 
• Statistical analysis 
of Change from 
baseline in renal 
biomarkers by 
subgroup[3,4] 
• Summary of 
Change from 
baseline in renal 
biomarkers by 
subgroup[3,4] 
• Adverse Events Leading 
to Permanent 
Discontinuation of Study 
Treatment or Withdrawal 
from Study by subgroup 
• Post Baseline Adverse 
Events by System Organ 
Class, Maximum Toxicity 
and Subgroups 
HIV subtype 
(categories will be 
defined from Q2 
Screening lab 
reports) 
Y 
Y 
 
 
 
 
Baseline HCV 
serostatus (positive 
vs negative) 
Y 
Y 
 
 
 
Y 
Country 
Y 
Y 
 
 
 
 
BMI (<vs. ≥ 25 
kg/m2) 
 
 
 
Y 
 
 
Smoking status 
(Never vs. Former 
vs. Current 
Smoker) 
 
 
 
Y 
 
 
Current Vitamin D 
use (Yes vs. No) 
 
 
 
Y 
 
 
Presence of 
diabetes mellitus 
(DM) 
 
 
 
 
Y 
 
Presence of 
hypertension 
 
 
 
 
Y 
 
Age (<50, vs ≥50) 
Y 
Y  
Y 
Y 
Y 
Y 


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Endpoint 
 
 
 
 
 
Covariates and 
subgroups 
• 
Proportion of subjects with 
plasma HIV-1 RNA <50 c/mL 
at week X - Snapshot algorithm 
by subgroup 
• 
Study Outcomes using the 
Snapshot algorithm by 
subgroup 
• 
Proportion of Subjects with 
Plasma HIV-1 RNA <40 c/mL - 
Snapshot Analysis 
• 
Statistical analysis of 
Change from 
baseline in CD4+ cell 
counts by subgroup 
• 
Summary of Change 
from baseline in 
CD4+ cell counts by 
subgroup 
 
• Statistical 
analysis of 
Change from 
Baseline in 
Fasting Lipids 
by subgroup[2] 
• Summary of 
Change from 
Baseline in 
Fasting Lipids 
by subgroup[2] 
• Statistical 
Analysis of 
bone 
biomarkers by 
subgroup 
• Summary of 
Bone 
biomarkers by 
subgroup 
• Statistical analysis 
of Change from 
baseline in renal 
biomarkers by 
subgroup[3,4] 
• Summary of 
Change from 
baseline in renal 
biomarkers by 
subgroup[3,4] 
• Adverse Events Leading 
to Permanent 
Discontinuation of Study 
Treatment or Withdrawal 
from Study by subgroup 
• Post Baseline Adverse 
Events by System Organ 
Class, Maximum Toxicity 
and Subgroups 
Race (White vs. 
Non-White) 
Y 
Y  
Y 
Y 
Y 
Y 
Ethnicity (Hispanic 
or Latino vs. Not 
Hispanic or Latino 
Y[1] 
 
 
 
 
 
[1] Only for Proportion of subjects with plasma HIV-1 RNA <50 c/mL at week X - Snapshot algorithm by subgroup 
[2] Only Age (<50, vs ≥50) subgroup after week 48 will be analysed. 
[3] Only baseline plasma HIV-1 RNA (≤ vs. >100,000 c/mL), baseline CD4+ cell count (≤ vs. >200 cells/mm3), Age (<50, vs ≥50) and presence of hypertension subgroups after week 48 will be analysed. 
[4] Only Serum Cystatin C, eGFR (based on CKD-EPI-creatinine and CKD-EPI-cystatin C), Urine Beta-2 Microglobulin/Urine Creatinine ratio and Urine Retinol Binding Protein/Urine Creatinine ratio after 
week 48 will be analysed. 
 


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10.12. 
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses 
10.12.1. 
Statistical Analysis Assumptions 
Analysis 
Multiple imputation 
• Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data. 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals (i.e. checking the normality assumption) to 
gain confidence that the model assumptions are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
• Diagnostic plots (trace and autocorrelation plots) will be checked to verify that the number of 
burn-in iterations and MCMC steps between imputed datasets are sufficient. If the trace plots 
show apparent trend or the autocorrelation plots show significant positive or negative 
autocorrelation, number of iterations will be increased until the diagnostic plots are acceptable. 
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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10.13. 
Appendix 13: Time to Event Details 
10.13.1. 
TRDF Detailed Steps 
The steps below are for the derivation of TRDF at specific timepoints when the upper 
bound of the analysis window is used as a cut-off i.e. for the table only.  
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) 
 
 
1.1 CVW event date is after the upper 
bound of the analysis visit window 
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 
CNSR=0 EVNTDESC=CVW. 
AVAL= Study Day of SVW 
immediately preceding CVW. 
 
2. Subjects with study withdrawal due to 
treatment related adverse events during the 
randomized period  
(defined as subjects that have reason for 
withdrawal =AE on disposition page and 
that the subject has at least one AE 
considered drug related (AEREL=Y) and 
was withdrawn from study (AEWD=Y))  
 
 
 
 


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2.1 Study withdrawal is after the 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 
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) 
 
 
3.1 Protocol defined stopping criteria were 
met after the 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 
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) 
 
 
4.1 Study withdrawal is after the upper bound 
of the analysis visit window 
CNSR=1 
EVNTDESC=Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 


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4.2 Study withdrawal is on or before the 
upper bound of the analysis visit window 
CNSR=0 
EVNTDESC=Study Withdrawal Due 
to Lack of Efficacy 
AVAL= Earliest of (Day of Study 
Discontinuation [from Disposition 
page]), date of Withdrawal Visit [from 
Study Visit domain], Study day of 
permanent treatment discontinuation 
[from Exposure domain]) 
5: If none of the above conditions met 
 
 
5.1 Subjects with study withdrawal for 
other reasons on or before the upper 
bound of the analysis visit window 
during the 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]) 
5.2 Subjects with study withdrawal for 
other reasons after the upper bound of 
the analysis visit window during the 
randomized period.  
(Based on disposition page) 
CNSR=1 
EVNTDESC=Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 
5.3 Subject completed the randomized 
period of the study. 
(Based on disposition page, and Open 
Label completion flag) 
CNSR=1 
EVNTDESC= Censored as completed 
the Randomized Period. 
AVAL= Date of completion of 
randomized study period 
5.4 Subject is ongoing in the study 
during the randomized period and have 
not yet completed the randomized 
period. 
CNSR=1 
EVNTDESC= Censored due to data 
cutoff. 
AVAL=Upper bound of analysis visit 
window. 


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10.13.2. 
TRDF Detailed Steps for the Kaplan-Meier plot 
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. 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) 
CNSR=0 EVNTDESC=CVW. 
AVAL=Study Day of SVW 
immediately preceding CVW. 
2. Subjects with study withdrawal due 
to treatment related adverse events 
during the randomized period  
(defined as subjects that have reason 
for withdrawal =AE on disposition 
page and that the subject has at least 
one AE considered drug related 
(AEREL=Y) and was withdrawn 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]). 


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4: Subjects with study withdrawal due 
to lack of efficacy during the 
randomized period. 
(Based on disposition page) 
CNSR=0 EVNTDESC=Study Withdrawal 
Due to Lack of Efficacy 
AVAL= Earliest of (Day of 
Study Discontinuation [from 
Disposition page]), date of 
Withdrawal Visit [from Study 
Visit domain], Study day of 
permanent treatment 
discontinuation [from Exposure 
domain]) 
5: If none of the above conditions met 
 
 
5.1 Subjects with study 
withdrawal for other reasons on 
or before the upper bound of the 
analysis visit window during the 
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]) 
5.3 Subject completed the 
randomized period of the study. 
(Based on disposition page, and 
Open label completion flag) 
CNSR=1 EVNTDESC= Censored as 
completed the Randomized 
Period. 
AVAL= Date of completion of 
randomized study period 
5.4 Subject is ongoing in the 
study during the randomized 
period and have not yet 
completed the randomized period 
CNSR=1 EVNTDESC= Ongoing in the 
Study. 
AVAL=Last visit date 
Notes: 
Randomized Period = Double-blind Randomized Phase (Day 1 to Week 96) + Open-Label Randomized Phase (Week 
96 to Week 148); ‘completed the randomized period’ is defined as having nominal week148 date or having overall 
study as ‘Completed’ or continuation phase treatment start date is not missing or enrolled into continuation phase. 
If the study day of randomized study period completion date or the last visit date is greater than day 1078, it will be 
censored to day 1078. 
Efficacy visit windows should be used throughout for the upper bound of the analysis visit window 
Subjects are considered to have completed the randomized period if they completed the Open-label Randomised 
Phase including the Week 148 visit 
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  
EVNTDESC, AVAL & CNSR variables created for the following timepoints:  
Week 24, 48, 96, 144 – for the table analysis 
Overall – for the Kaplan-Meier plot  
10.13.3. 
ERDF Detailed Steps 
Similar algorithm will be applied for ERDF analyses and Kaplan-Meier figure, where 
condition 2 and 3 in Section10.13.1 and Section 10.13.2 will not be considered.  


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10.13.4. 
Time to Viral Suppression 
• Time of event will be the first on-treatment viral load value <50 copies/mL   
• Subjects who withdraw for any reason without being suppressed during on 
treatment will be censored at earliest of (day of study discontinuation, day of 
withdrawal visit, day of treatment discontinuation). 
• Subjects who have not been withdrawn and have not had viral suppression at time 
of the analysis will be censored at last viral load date from HIV-1RNA lab data.  
• Subjects who have completed the Double Blind and Open Label phases and have 
not had viral suppression will be censored at date of completion. 
 
 
 


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10.14. 
Appendix 14: Q2 Creatinine Assay Accuracy Issue 
10.14.1. 
Q2 Creatinine Assay Accuracy Issue 
There was an issue with the Q2 instrument at the Valencia site (in California) measuring 
serum creatinine concentrations between 1-Oct-2106 and 13-Jan-2017 resulting in some 
serum creatinine values being unreliable. The unreliable serum creatinine samples will be 
excluded from the summaries. The erroneous samples will be flagged in the listings. The 
samples can be identified in SDTM.LB by searching for the following comment: 
“SERUM CREATININE WAS PRODUCED DURING AN INTERMITTENT 
INSTRUMENT MALFUNCTION FROM 01OCT16 TO 13JAN17 AT Q2 
SOLUTIONS, VALENCIA. THE SERUM CREATININE RESULT REPORTED IS 
POTENTIALLY ERONEOUS”. 
 
 
 


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10.15. 
Appendix 15: Abbreviations & Trade Marks 
 
Abbreviations 
Abbreviation 
Description 
3TC 
Lamivudine, EPIVIR 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
A&R 
Analysis and Reporting  
ART 
Antiretroviral therapy 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
COM 
Comparator arm 
CSR 
Clinical Study Report 
CVW 
Confirmed Virologic Withdrawal 
D3 
DTG + 3TC arm 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
FDC 
Fixed-dose combination 
FTC 
Emtricitabine 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
LOCF 
Last Observation Carries Forward 
PP 
Per Protocol 
QC 
Quality Control 
PPD 
Pharmaceutical Product Development 
RAP 
Reporting & Analysis Plan 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
TD 
Target Detected 
TDF 
Tenofovir disoproxil fumarate 
TFL 
Tables, Figures & Listings  
TND 
Target Not Detected  
GSK 
GlaxoSmithKline 
 


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Trademarks 
Trademarks of ViiV Healthcare 
 
Trademarks  
not owned by ViiV Healthcare 
Epivir 
 
Monogram Inc 
Tivicay  
 
PhenoSense 
 
 
SAS 
 
 
Truvada 


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10.16. 
Appendix 16: End of Study (Final) Analysis 
This appendix will provide the details of planned analyses and data displays for the End of 
Study (EOS; final) reporting. These analyses may be included in regulatory submissions, 
study reports and publications. 
10.16.1. General considerations for data analyses 
This section is written specifically for the EOS analysis. Since the primary analyses have 
been completed, the present section is written to cover only analyses included in the final 
reporting. Only those definitions and derivations that have changed since the previous 
interim and primary analyses will be included in this section, i.e., for the derivation of 
analysis windowing, how to deal with missing dates, definition of concomitant 
medications, etc. refer to the previous corresponding RAP sections. The current section 
summarizes only the key endpoints of interest for the final analysis and explains any 
deviations from the previous analysis. 
The details of the final EOS reporting and analysis are described below: 
1) The analysis for which the data have not been changed since the last interim 
analysis (Week 144 analysis) will not be reported to avoid redundancy.  
 
2) No subgroup analysis, hypotheses testing, or statistical analyses will be 
performed. 
3) As per the Time and Events Schedule health outcomes will not be reported for 
EOS. 
 
4) All required disclosure outputs following the FDAAA and EudraCT 
guidelines will be produced.  
 
5) For the purpose of creation of Mexico Final Safety Report and submission to 
Ministry of Health, some listings at Mexico sites will be reported separately. Such 
listings are identified in the Programming notes in Section 10.16.7. These listings 
will include data from both Randomized and Continuation Phase. 
 
10.16.1.1. Study Phases 
In the previous analysis (Week 144 analysis), data were summarized for the Double 
Blinded and Open Label Phases of the study. However, when data from the Continuation 
Phase were available, Continuation Phase was also included. For the EOS reporting, data 
to be analysed/ reported are from Continuation Phase unless specified otherwise, and this 
will be noted in the title of the output. Listings will contain all the data with a new 
column added to specify the phase of the study for each record. Continuation Phase is 
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Phase 
Start 
End  
Continuation Phase Week 148  (start date of 
exposure where category of 
treatment is ‘CONTINUATION 
PHASE’. 
Study 
completion/discontinuation 
date 
Note: A participant enters the Continuation Phase if they have at least one exposure to the 
Investigational Product after analysis visit Week 148.  
Due to issues with approval for the local post-study access program in GEMINI-II during 
the pandemic, total 10 Peru DTG + TDF/FTC participants continued treatment for up to 1 
year post week 148. These subjects’ post week 148 visits will be in Continuation Phase. 
Their data will be included in the listings, but not in the summary tables.  
10.16.1.2. Analysis Population for the Continuation Phase 
In addition to the populations defined in Section 4 of the RAP amendment 2, the 
following populations were defined for the End of Study Analysis: 
Population  
Definition/ Criteria.  
Analysis Evaluated  
Safety Continuation  
Comprises all participants in the 
Safety Population who receive at 
least one dose of Investigational 
Product after entering the 
Continuation Phase.  
• 
Safety  
CVW Continuation 
Comprise of all subjects in the 
ITT-E population who have met 
the derived CVW criteria during 
the Continuation Phase. 
• 
Efficacy 
• 
Study Population 
Intent-to-Treat Exposed (ITT-
E) Continuation  
Comprises all participants in the 
ITT-E Population who enter the 
Continuation Phase.  
• 
Efficacy  
• 
Study Population 
Viral Genotypic 
Continuation  
Comprises all participants in the 
ITT-E  Population with available 
on-treatment genotypic resistance 
data during the Continuation 
Phase 
• 
Genotypic  
Viral 
Phenotypic Continuation  
Comprises all participants in the 
ITT-E-  Population with available 
on-treatment phenotypic 
resistance data during the 
Continuation phase 
• 
Phenotypic  
10.16.2. Study Population  
The study population summaries and data listings will be based on the ITT-E or ITT-E 
Continuation Population, unless otherwise specified. Demographic and baseline 


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characteristics will be reported only for the subjects who entered the Continuation Phase. 
Participant accountability summary will be produced for the Continuation Population. 
Overview of the key planned study population endpoints: 
• Study Populations 
• Summary of Number of Subjects Enrolled by Country and Site ID for the 
Continuation Population. 
• Participant Accountability 
• Concomitant and Antiretroviral Medications. 
• Protocol deviation.  
Full details of the data displays are given in Section 10.16.7. 
10.16.3. Efficacy Analysis  
The efficacy summaries and data listings will be based on the ITT-E Continuation 
Population.  
Overview of the key planned efficacy endpoints: 
• Proportion of Participants with Plasma HIV-1 RNA < 50 c/ mL observed data 
• Proportion of Participants with Confirmed Virologic Withdrawal – observed 
data  
• Change from baseline CD4+ cell count over time  
• Incidence of disease progression and HIV-associated conditions 
Full details of data displays are given in Section 10.16.7. 
10.16.4. Safety Analysis 
All safety displays will be based on the Safety Population or the Safety Continuation 
Population.  
The core adverse event displays for the final report have been identified based on the 
IDSL library required tables. For the purposes of summarising the AE data (including 
COVID-19), unless stated otherwise, the summaries will include only those AEs that 
occurred during the Continuation Phase. Common AEs are those with 2% (without 
rounding) incidence for any treatment.  
Summaries of AEs required for the FDAAA and EudraCT will be generated in this 
report.  
Summaries of Maximum Post-Baseline Grade 3 or 4 Emergent Clinical Toxicities and 
Hepatobiliary Abnormality criteria will be reported only for the events that occurred 
during the Continuation Phase.  
A new figure of cumulative exposure to investigational product will be added for the 
Continuation Phase.  
Overview of the key planned safety endpoints: 


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• Extent of Exposure 
• Adverse Events  
• Maximum Post-Baseline Emergent Clinical Chemistry/ Haematology Toxicities 
• Hepatobiliary Laboratory Abnormality Criteria 
• Liver Events Assessment 
• Columbia Suicidality Severity Rating Scale (C-SSRS) 
Full details of data displays are given in Section 10.16.7. 
10.16.5. Virology analysis  
The virology summaries will be based on the Viral Genotypic and Viral Phenotypic 
Continuation Populations, unless otherwise specified.  Data listings will be presented for 
the ITT-E Continuation Population, unless otherwise specified. 
Prespecified lists of integrase substitutions have been modified since the previous interim 
analysis, hence an updated list of known INSTI mutations has been added in Table 8 and 
IAS-USA major resistance associated mutations (RAMs) to other classes (i.e., NRTI, 
NNRTI, PI) are listed in Table 9.  
Table 8  
Known INSTI mutations associated with the development of 
resistance to RAL, BIC, EVG 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: 
• 
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 INSTI-experienced participants (i.e. ING112574) and may be modified in case 
of additional substantive data availability.  
• 
INSTI mutations in bold have the maximum score of 60 and are for any INSTI drug in 
the Stanford database v9.1 (https://hivdb.stanford.edu/dr-summary/mut-scores/INSTI/, 
last updated on 2022-06-02); the rest have a maximum score <60.  
• 
The INSTI mutations listed are historically identified via the Stanford HIV Resistance 
database, and also include mutations identified during in vitro passage of DTG, or as seen 
in a previous DTG study in INI-experienced participants (ING112574).  
 


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Table 9  
Major resistance mutations to other classes (i.e., NRTI, NNRTI, PI) as 
defined by the International Antiviral Society-USA (IAS-USA) 
Class 
Mutations 
NRTIs 
M41L, K65R/E/N, D67N, 69 insert, K70E/R, L74V, Y115F, M184V/I, 
L210W, T215Y/F, K219Q/E; [A62V, V75I, F77L, F116Y, Q151M] 
NNRTIs 
L100I, K101E/P, K103N/S, V106A/M, V108I, E138A/G/K/Q/R, 
V179L, Y181C/I/V, Y188C/L/H, G190S/A, H221Y, P225H, F227C, 
M230I/L 
PIs 
D30N, V32I, M46I/L, I47A/V, G48V, I50V/L, I54V/M/L, Q58E, T74P, 
L76V, V82A/T/F/L/S, N83D, I84V, N88S, L90M 
NOTES: 
• 
Updated to “2019 Resistance Mutations Update Volume 27 Issue 3, July/August 2019 
• 
The most up to date IAS-USA guidelines available at the time of DBF will be used in the 
analysis. 
• 
Q151M Complex: Q151M usually occurs in combination with two or more of the 
following four accessory NRTI mutations A62V, V75I, F77L, and F116Y However if 
any one of these mutations occur alone, they shall be considered as major mutation for 
the NRTI class.  
 
Overview of the key planned virology endpoints: 
• Genotypic and Phenotypic Accountability  
• INSTI mutations  
• Major NRTI, NNRTI, PI mutations   
• Fold Change 
• Fold Change Ratio 
Full details of data displays are given in Section 10.16.7. 
10.16.6. COVID - 19 analysis 
This study was started in 2016 and continued during the COVID -19 pandemic. The 
information regarding the number of participants affected by COVID-19 and its 
symptoms will be reported according to GSK core standards. The visits impacted due to 
the pandemic outbreak will be reported. Protocol deviations or adverse events related to 
COVID-19 if any, will also be reported according to GSK core standards.  
If the subjects have competed /withdrawn the study before the pandemic started in the 
respective countries according the COVID-19 dataset (with start date of pandemic in each 
of the countries), they will be considered as ‘Not Related’ to COVID-19. 
 
 
 
 
 


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10.16.7. List of Data Displays for End of Study (EOS) Final Report 
• Outputs that were not reported in previous reporting effort are identified in 
Programming Notes as ‘New output’. 
 
Study Population 
Type 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Table  
1.101 
ITT-E Continuation 
Same shell as 
week 144, 
table 1.1 
Summary of Number of 
Subjects Enrolled by 
Country and Site ID 
  
Table 
1.102 
All Subjects Screened  SA1 
Summary of Study 
Populations 
CS CORE; 
Present all populations 
as defined in Sections 
4 and 10.16.1.2 
Table 
1.103 
   ITT-E 
ES1 
Summary of Subject 
Status and Subject 
Disposition by 
Relationship to COVID-
19 Pandemic - Overall 
FDAAA, EudraCT 
For overall, 
Summarise by: i) 
Overall ii) Related to 
COVID-19, ii) Not 
Related to COVID-19 
Table 
1.104 
ITT-E Continuation 
ES1 
Summary of Subject 
Status and Subject 
Disposition by 
Relationship to COVID-
19 Pandemic - 
Continuation Phase 
New Output; 
FDAAA, EudraCT 
For Continuation 
Phase 
Summarise by: i) 
Overall ii) Related to 
COVID-19, ii) Not 
related to COVID-19 
Table  
1.105 
ITT-E Continuation 
DM1 
Summary of 
Demographic 
Characteristics  
  
Table 
1.106 
ITT-E Continuation 
DV1a 
Summary of Important 
Protocol Deviations by 
Relationship to COVID-
19 Pandemic - 
Continuation Phase 
CS CORE 
Table 
1.107 
ITT-E 
Continuation 
CM1 
Summary of 
Concomitant Medication 
by ATC Level 1 and 
Ingredient – Continuation 
Phase 
  
Listing - ICH 
101 
ITT-E 
Continuation 
ES2 
Listing of Study 
Conclusions Reasons for 
Study Withdrawal – 
Continuation Phase 
CS CORE 
Listing - ICH 
102 
ITT-E 
Continuation 
DV2 
Listing of Important 
Protocol Deviations – 
Continuation Phase 
CS CORE 


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Listing - Other 
103 
ITT-E Continuation 
Same shell as 
week144, 
listing 32 
Listing of Visit Dates  
Include all visits 
Listing - Other 
104 
All Participants 
Screened 
Same shell as 
week144, 
listing 33 
Listing of Study 
Populations 
  
Listing - Other 
105 
ITT-E 
Continuation 
CM2 
Listing of Concomitant 
Medications – 
Continuation Phase 
  
Listing - Other 
106 
ITT-E Continuation 
CM6 
Listing of Relationship 
Between ATC Level 1, 
Ingredient and Verbatim 
Text – Continuation 
Phase 
  
Listing - Other 
107 
ITT-E Continuation 
CM2 
Listing of Concomitant 
ART Medications – 
Continuation phase 
  
Listing - Other 
108 
ITT-E Continuation 
CM6 
Listing of Relationship 
Between ATC Level 4, 
Ingredient and Verbatim 
Text – Continuation 
Phase 
  
 
 
 


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Efficacy 
Type 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming 
Notes 
Table 
2.101 
ITT-E Continuation Same shell as 
week 48, 
table 2.15 
Summary of Proportion of 
Subjects with Plasma HIV-1 RNA 
<50 c/mL by Visit -Observed Data  
Include all visits 
Table 
2.102 
ITT-E Continuation Same shell as 
week 48, 
table 2.16 
Summary of Change from 
Baseline in Plasma HIV-1 RNA 
(log10 c/mL) by Visit  
Include all visits 
Table 
2.103 
CVW Continuation 
Same shell as 
week 144, 
table 2.18 
Proportion of Subjects Meeting 
Confirmed Virologic Withdrawal 
Criteria by Visit by Type of Criteria  
Proportion 
instead of 
'Cumulative 
Proportion' 
comparing to 
previous REs. 
Include all visits 
Table 
2.104 
CVW Continuation 
Same shell as 
week 144, 
table 2.19 
Distribution of Quantitative Plasma 
HIV-1 RNA Results at Suspected 
and Confirmed Virologic 
Withdrawal 
Data only for the 
subjects that 
meet CVW.  We 
want to know 
how the CVW 
subjects’ viral 
loads changed 
from the SVW to 
CVW visit.. 
Include all visits 
Table 
2.105 
ITT-E Continuation Same shell as 
week 144, 
table 2.22 
Summary of Change from 
Baseline in CD4+ Cell Count 
(cells/mm3) by Visit  
Include all visits 
Table 
2.106 
ITT-E Continuation Same shell as 
week 144, 
table 2.25 
Summary of Post-Baseline HIV-1 
Associated Conditions Including 
Recurrences - Continuation Phase 
  
Table 
2.107 
ITT-E Continuation Same shell as 
week 144, 
table 2.26 
Summary of Post-Baseline HIV-1 
Associated Conditions Excluding 
Recurrences – Continuation 
Phase 
  
Table 
2.108 
ITT-E Continuation Same shell as 
week 144, 
table 2.27 
Summary of Post-Baseline HIV-1 
Disease Progressions - 
Continuation Phase 
  
Figure 
2.101 
ITT-E Continuation Same shell as 
week 144, 
figure 2.3 
Individual Plasma HIV-1 RNA and 
CD4+ Profiles by Visit for Subjects 
with at least One Suspected 
Virologic Withdrawal Visit  
Include all visits 
Listing - ICH 
201 
ITT-E Continuation Same shell as 
week 144, 
listing 12 
Listing of Quantitative and 
Qualitative Plasma HIV-1 RNA 
Data  
Include all visits 


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Listing - 
Other 
202 
ITT-E Continuation Same shell as 
week 144, 
listing 50 
Listing of Plasma HIV-1 RNA Data 
for Subjects with Confirmed 
Virologic Withdrawal  
Include all visits 
Listing - 
Other 
203 
ITT-E Continuation Same shell as 
week 144, 
listing 51 
Listing of CD4+ Cell Count Data  
Include all visits 
Listing - 
Other 
204 
ITT-E Continuation Same shell as 
week 144, 
listing 52 
Listing of HIV-1 Associated 
Conditions - Continuation Phase 
  
 
 
 
 


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Safety 
Type 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
Table 
3.101 
Safety 
Continuation 
EX1 
Summary of Extent of Exposure to 
Investigational Product for Subjects 
who Entered Continuation Phase 
Including all phases  
Table 
3.102 
Safety 
Continuation  
AE3 
Summary of Common (>=2%) 
Adverse Events by Preferred Term 
and Overall Frequency - Continuation 
Phase 
Common adverse 
events are those with 
>=2% (without 
rounding) incidence for 
any treatment. 
Table 
3.103 
Safety 
Continuation 
AE3 
Summary of Common (>=2%) Grade 
2-5 Adverse Events by Preferred 
Term and Overall Frequency - 
Continuation Phase 
  
Table 
3.104 
Safety 
Continuation 
AE5A 
Summary of All Drug-related Adverse 
Events by System Organ Class, 
Preferred Term and Maximum 
Toxicity - Continuation Phase 
  
Table 
3.105 
Safety 
Continuation  
AE3 
Summary of Common (>=1%) Drug-
related Grade 2-5 Adverse Events by 
Overall Frequency - Continuation 
Phase 
  
Table 
3.106 
Safety 
Continuation 
AE3 
Summary of Serious Adverse Events 
by System Organ Class and 
Preferred Term - Continuation Phase 
  
Table 
3.107 
Safety 
Continuation 
AE15 
Summary of Common (>=2%) Non-
serious Adverse Events by System 
Organ Class and Preferred Term 
(Number of Subjects and 
Occurrences) – Continuation Phase 
FDAAA, EudraCT 
Common adverse 
events are those with 
>=2% (without 
rounding) incidence for 
any treatment. 
Table  
3.108 
Safety 
Continuation 
AE16 
Summary of Serious Adverse Events 
by System Organ Class and 
Preferred Term (Number of Subjects 
and Occurrences) – Continuation 
Phase 
 FDAAA, EudraCT 
Table 
3.109 
Safety 
Continuation 
PAN1A 
Summary of COVID-19 Assessments 
for Subjects with Suspected, 
Probable or Confirmed COVID-19 
Case Diagnosis – Continuation 
Phase 
New output.  Please 
refer to Sailing EOS 
T8.26 
Table 
3.110 
Safety 
Continuation 
PAN3A 
Summary of COVID-19 Symptoms for 
Subjects with Suspected, Probable or 
Confirmed COVID-19 Case 
Diagnosis – Continuation Phase 
New output. Please 
refer to Sailing EOS 
T8.27 
Table 
3.111 
Safety 
Continuation 
Same shell as 
week 144, 
table 3.55 
Summary of Maximum Post-Baseline 
Emergent Clinical Chemistry 
Toxicities - Continuation Phase 
  


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Table 
3.112 
Safety 
Continuation 
Same shell as 
week 144, 
table 3.56 
Summary of Maximum Post-Baseline 
Emergent Hematology Toxicities - 
Continuation Phase 
  
Table 
3.113 
Safety 
Continuation 
Same shell as 
week 144, 
table 3.57 
Summary of Subjects Meeting 
Hepatobiliary Laboratory Abnormality 
Criteria - Post-Baseline Emergent - 
Continuation Phase 
  
Table 
3.114 
Safety 
Continuation 
Same shell as 
week 144, 
table 3.58 
Summary of True Positive Suicidal 
Indication/ Behaviour Alerts based on 
eCSSRS by Visit – Continuation 
Phase 
  
Table 
3.115 
Safety 
Continuation 
Same shell as 
week 144, 
table 3.60 
Summary of Subjects with Post-
Baseline C-SSRS Suicidal Ideation or 
Behaviour – Continuation Phase 
  
Table  
3.116 
Safety 
Continuation 
Same shell as 
week 144, 
table 3.2 
Summary of All Adverse Events by 
System Organ Class and Preferred 
Term – Continuation Phase 
  
Table  
3.117 
Safety 
Continuation 
Same shell as 
week 144, 
table 3.3 
Summary of All Adverse Events by 
Maximum Grade – Continuation 
Phase 
  
Figure 
3.101 
Safety 
Continuation 
Same shell as 
week 144, 
figure 3.3 
Scatter Plot of Maximum Post-
Baseline ALT vs. Maximum Post-
Baseline Total Bilirubin - Continuation 
Phase 
  
Figure 
3.102 
Safety  
Continuation 
gsk1349572/in
g111762/final_
01/figure 8.27 
Plot of  Cumulative Exposure to 
Investigational Product  
Include all visits 
Listing - 
ICH 
301 
Safety  
Continuation 
HIV_IP5/ EX3 
Listing of Investigational Product 
Exposure Data  
  
Listing - 
ICH 
302 
Safety 
Continuation 
AE8 
Listing of All Adverse Events 
Listing all AEs for the 
subjects in Safety 
Continuation & Include 
‘study phase’ 
Listing – 
ICH 
303 
Safety 
Continuation 
AE8 
Listing of Fatal Serious Adverse 
Events – Continuation Phase 
  
Listing - 
ICH 
304 
Safety 
Continuation 
AE8 
Listing of Non-Fatal Serious Adverse 
Events – Continuation Phase 
  
Listing - 
ICH 
305 
Safety 
Continuation 
AE8 
Listing of Adverse Events Leading to 
Withdrawal/Permanent 
Discontinuation of Investigational 
Product – Continuation Phase 
  
Listing - 
Other 
306 
Safety 
AE8 
Listing of Non-Serious AEs of 
Subjects at Mexico Sites 
  
Listing - 
Other 
307 
Safety 
AE8 
Listing of SAEs of Subjects at Mexico 
Sites 
  
Listing - 
Other 
309 
Safety 
Continuation  
Same shell as 
week 144, 
listing 63 
Listing of Post Baseline Maximum 
ALT and Maximum Bilirubin – 
Continuation Phase 
  
Listing - 
Other 
310 
Safety 
Continuation 
LIVER5 
Listing of Liver Monitoring/Stopping 
Event Reporting – Continuation 
Phase 
  


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Listing - 
Other 
311 
Safety 
Continuation 
Same shell as 
week 144 
Listing of Subjects Meeting Post-
Baseline Emergent Hepatobiliary 
Laboratory Criteria -Continuation 
Phase 
  
Listing - 
Other 
312 
Safety 
Continuation 
PREG1a 
Listing of Subjects Who Became 
Pregnant During the Study – 
Continuation Phase 
  
Listing - 
Other 
313 
Safety 
Continuation 
LB5 
Listing of Laboratory Data for 
Subjects with Grade 3 or 4 Post-
Baseline Emergent Toxicities – 
Continuation Phase 
  
Listing -
Other 
314 
Safety 
Continuation  
PAN12 
Listing of COVID-19 Assessments 
and Symptoms Assessments for 
Subjects with COVID-19 Adverse 
Events – Continuation Phase 
New output 
 
 
 


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Virology 
Type 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming 
Notes 
Table 
4.101 
Viral Genotypic 
Continuation 
Same shell as 
week144, table 4.1 
Summary of Subject Accountability: 
Genotypes Available 
  
Table 
4.102 
Viral Phenotypic 
Continuation 
Same shell as 
week144, table 4.2 
Summary of Subject Accountability: 
Phenotypes Available 
  
Table 
4.103 
Viral Genotypic 
Continuation 
PFG1 
Summary of Major Mutations in 
NNRTI, NRTI and PI Classes and 
Pre-specified Mutations in INSTI 
Class at Baseline and time of CVW 
for Subjects Meeting CVW Criteria 
  
Table 
4.104 
Viral Genotypic 
Continuation 
Same shell as 
week144, table 4.7 
Summary of S-GSS at Time of CVW 
by Genotypic Cut-Off for DTG and 
3TC - Continuation Phase 
  
Table 
4.105 
Viral Phenotypic 
Continuation 
Same shell as 
week144, table 4.8 
Summary of Phenotype at Time of 
CVW by Phenotypic Cut-off -  
Continuation Phase 
  
Table 
4.106 
Viral Phenotypic 
Continuation 
Same shell as 
week144, table 4.9 
Number of Drugs to Which Subjects 
are Phenotypically Resistant at Time 
of CVW – Continuation Phase 
  
Table 
4.107 
Viral Phenotypic 
Continuation 
Same shell as 
week144, table 4.10 
Summary of Fold Change to DTG, 
3TC, TDF and FTC at Time of CVW - 
Continuation Phase 
  
Listing -
Other 
401 
ITT-E 
Continuation 
Same shell as 
week144, listing 79 
Listing of All Genotypic Data 
  
Listing -
Other 
402 
Viral Genotypic 
Continuation 
Same shell as 
week144, listing 80 
Listing of Treatment Emergent 
Genotypic Mutations – Continuation 
Phase 
  
Listing -
Other 
403 
Viral Genotypic 
Continuation 
Same shell as 
week144, listing 81 
Listing of Genotype by Genotypic 
Cut-Off – CVWs 
  
Listing -
Other 
404 
ITT-E 
Continuation 
Same shell as 
week144, listing 82 
Listing of All Phenotypic Data 
  
Listing -
Other 
405 
Viral Phenotypic 
Continuation 
Same shell as 
week144, listing 84 
Listing of Net Assessment Score – 
CVWs 
  
Listing -
Other 
406 
Viral Genotypic 
and/or 
Phenotypic 
Continuation 
Same shell as 
week144, listing 85 
Listing of Genotypic and Phenotypic 
Data for Subjects with Confirmed 
Virologic Withdrawal Criteria 
  
Listing -
Other 
407 
ITT-E 
Continuation 
Same shell as 
week144, listing 86 
Listing of Genotypic and Phenotypic 
Data for Subjects with On-treatment 
Virology Results at Non-CVW 
Timepoints 
  
Listing -
Other 
408 
ITT-E 
Continuation 
Same shell as 
week144, listing 87 
Listing of Subject Level Summary of 
Key Virologic Data for Subjects with 
Confirmed Virologic Withdrawal or 
On-Treatment Non-CVW Timepoints 
-  Continuation Phase 
  
 
 


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10.17. 
Appendix 17: List of Data Displays 
10.17.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Genotype and Phenotype 
4.1 to 4.n 
4.1 to 4.n 
Heath Outcomes 
5.1 to 5.n 
5.1 to 5.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
y to z 
10.17.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided.  Non IDSL specifications will be referenced as indicated and 
if required an example mock-up displays provided in a separate document. 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 
Genotype and Phenotype 
Viral_Fn 
Viral_Tn 
CVW_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’ 
10.17.3. 
Deliverables 
Delivery [1] 
Description 
Datalook  
During Study 
24  
Statistical Analysis Complete at Week 24 
48  
Statistical Analysis Complete at Week 48 
96  
Statistical Analysis Complete at Week 96 
144  
Statistical Analysis Complete at Week 144 
EOS 
Final End of Study Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort. 


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10.17.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Subject Disposition 
1.1. 
All Subjects 
Screened 
NS1 
Summary of Number of Subjects Enrolled by Country 
and Site ID 
CS CORE 
All 
1.2. 
All Subjects 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
CS CORE; add subreason, 
i.e # of IE criteria 
All 
1.3. 
ITT(E) 
ES1 
Summary of Subject Disposition for the Subject 
Conclusion Record 
 
All 
1.4. 
ITT(E) 
ES1 
Summary of Subject Disposition for the Subject 
Conclusion Record: Double Blind Phase  
 
All 
1.5. 
ITT(E) 
ES1 
Summary of Subject Disposition for the Subject 
Conclusion Record: Open Label Phase 
 
All 
1.6. 
ITT(E) 
HIV_ES1 or 
SD4 or SD1 or 
ISO4 
Summary of Reasons for Withdrawal by Visit 
 
All 
Study populations 
1.7. 
All Subjects 
Screened  
SP1 
Summary of Study Populations 
 
All 
1.8. 
ITT(E) 
shell 
Summary of misrandomized strata or treatment 
 
All 
Protocol deviations 
1.9. 
ITT(E) 
DV1 
Summary of Important Protocol Deviations 
CS CORE 
All 
1.10. 
ITT(E) 
SA2 
Summary of Protocol Deviations Leading to Exclusion 
from the Per-Protocol Population 
CS CORE 
All 
 
 


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Demography 
1.11. 
ITT(E) 
DM1 
Summary of Demographic Characteristics 
CS CORE 
All 
1.12. 
All Subjects 
Screened 
DM11 
Summary of Age Ranges 
 
All 
1.13. 
ITT(E) 
DM5 
Summary of Race and Racial Combinations 
CS CORE 
All 
1.14. 
ITT(E) 
DM6 
Summary of Race and Racial Combinations Details 
CS CORE 
All 
1.15. 
ITT(E) 
shell 
Summary of Hepatitis Status at Entry 
 
All 
1.16. 
ITT(E) 
CDC1 
Summary of CDC Classification of HIV Infection at Baseline 
 
All 
1.17. 
ITT(E) 
RF1 
Summary of HIV Risk Factors 
 
All 
1.18. 
ITT(E) 
shell 
Summary of Screening Cardiovascular Risk Assessments 
 
All 
1.19. 
ITT(E) 
shell 
Distribution of Quantitative Plasma HIV-1 RNA Results at 
Screening and Baseline 
 
All 
1.20. 
ITT(E) 
shell 
Distribution of CD4+ Cell Count (cells/mm^3) Results at 
Screening and Baseline 
 
All 


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Medical Conditions, Concomitant Medications & ART 
1.21. 
ITT(E) 
MH1 
Summary of Current Medical Conditions 
CS CORE 
All 
1.22. 
ITT(E) 
MH1 
Summary of Past Medical Conditions 
CS CORE 
All 
1.23. 
ITT(E) 
MH4 
Summary of Current Cardiac, Gastrointestinal, Metabolism 
and Nutrition, Psychiatric, Renal and Urinary, and Nervous 
System Conditions 
 
All 
1.24. 
ITT(E) 
MH4 
Summary of Past Cardiac, Gastrointestinal, Metabolism and 
Nutrition, Psychiatric, Renal and Urinary, and Nervous 
System Conditions 
 
All 
1.25. 
ITT(E) 
CM1 
Summary of Concomitant Medication by Ingredient ATC 
Level 1 
 
All 
1.26. 
ITT(E) 
CM8 
Summary of Concomitant Medication by Ingredient 
Combinations 
 
All 
1.27. 
ITT(E) 
CM1b 
Summary of Concomitant Medication by Combination Term 
ATC Level 1 
 
All 
1.28. 
ITT(E) 
shell 
Summary of Lipid Modifying Agent Use at Baseline 
 
All 
1.29. 
ITT(E) 
shell 
Summary of Lipid Modifying Agent Use Starting Post-
Baseline 
 
All 
1.30. 
ITT(E) 
shell 
Summary of History of Depression and Anxiety at Baseline 
 
All 
1.31. 
ITT(E) 
shell 
Number of Subjects Attending Nominal and Actual Analysis 
Visits 
 
Week 48, 96, 144 
 
 


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10.17.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Primary Efficacy Analyses 
2.1.  
ITT(E) 
Shell  
gsk2619619/ing117
172/week48/drivers
/t_ef_analprop.sas 
Summary of Analysis for Proportion of Subjects with Plasma 
HIV-1 RNA <50 c/mL at Week X – Snapshot Analysis 
 
All 
2.2.  
Per-Protocol  
Shell  
Summary of Analysis for Proportion of Subjects with Plasma 
HIV-1 RNA <50 c/mL at Week X – Snapshot Analysis 
 
All 
2.3.  
ITT 
Shell  
Summary of Analysis for Proportion of Subjects with Plasma 
HIV-1 RNA <50 c/mL at Week X – Snapshot Analysis 
 
All 
2.4.  
ITT(E) 
Shell  
gsk2619619/ing117
172/week48/drivers
/t_sn_studout.sas 
Summary of Study Outcomes (<50 c/mL) at Week X – 
Snapshot Analysis 
 
All 
2.5.  
Per-Protocol  
Shell 
Summary of Study Outcomes (<50 c/mL) at Week X – 
Snapshot Analysis 
 
All 
2.6.  
ITT 
shell 
Summary of Study Outcomes (<50 c/mL) at Week X – 
Snapshot Analysis 
 
All 
2.7.  
ITT(E) 
Shell  
gsk2619619/ing117
172/week48/drivers
/t_snap_sum_prop
_p.sas 
Treatment by Strata Tests of Homogeneity for Proportion of 
Subjects with Plasma HIV-1 RNA <50 c/mL at Week X - 
Snapshot Analysis 
 
All 
 
 


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2.8.  
ITT(E) 
Shell 
gsk2619619/ing117
172/week48/drivers
/t_ef_km_trdf.sas 
Summary of Kaplan-Meier Estimates of Proportion of 
Subjects Without Confirmed Virologic Withdrawal at Week X 
- Treatment Related Discontinuation = Failure Overall and 
by Baseline HIV-1 RNA and CD4+ Cell Count Subgroups 
 
All 
2.9.  
ITT(E) 
Shell 
gsk2619619/ing 
117172/week48/dri
vers/t_ef_km_erdf.s
as 
Summary of Kaplan-Meier Estimates of Proportion of 
Subjects Without Confirmed Virologic Withdrawal at Week X 
- Efficacy Related Discontinuation = Failure Overall and by 
Baseline HIV-1 RNA and CD4+ Cell Count Subgroups 
 
All 
2.10. 
ITT(E) 
shell 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at 
Week 48 using Snapshot - bias Sensitivity Analysis  
 
Wk48 
Secondary Efficacy Analyses 
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL –  Snapshot 
2.11. 
ITT(E) 
shell 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL by 
Visit - Snapshot Analysis 
 
All 
2.12. 
ITT(E) 
shell 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at 
Week X by Subgroup – Snapshot Analysis – ITT-E 
See subgroups in Section 10.11 
plus categories for Baseline 
plasma HIV-1 RNA (c/mL) - <= 
100K, > 100K, >250K, >400K and 
>500K (add the last 3 more 
categories as in Table 8.3 
mid208959/postcsr_2018_01) 
All 
2.13. 
ITT(E) 
shell 
Summary of Study Outcomes (<50 c/mL) at Week X by 
Subgroup - Snapshot Analysis  
 
All 
 
 


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Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL –  Observed 
2.16.  
ITT(E) 
shell 
Summary of Change from Baseline in Plasma HIV-1 RNA 
(log10 c/mL) by Visit 
 
All 
Kaplan - Meier 
2.17. 
ITT(E) 
shell 
or Table 6.5 
mid208959/present
_2018_03  
Statistical Analysis of Kaplan-Meier Estimates of Time to 
Viral Suppression Overall and by Baseline HIV-1 RNA and 
CD4+ Cell Count Subgroups 
Add categories: 
Baseline HIV-1 RNA (c/mL) <= 
100,000 vs. > 100,000 for WK 96 
onwards  
All 
Confirmed Virologic Withdrawal (CVW) 
2.18. 
ITT(E) 
Shell 
 
Cumulative Proportion of Subjects Meeting Confirmed 
Virologic Withdrawal Criteria by Visit by Type of Criteria 
 
All 
2.19. 
ITT(E) 
Shell 
 
Distribution of Quantitative Plasma HIV-1 RNA Results at 
Suspected and Confirmed Virologic Withdrawal 
Data only for the subjects that 
meet CVW.  We want to know 
how the CVW patients viral loads 
changed from the SVW to CVW 
visit. 
All 
CD4+ Cell Counts  
2.20. 
ITT(E) 
shell 
Statistical Analysis of Change from Baseline in CD4+ Cell 
Count (cells/mm3) at Week X - (Multiple imputed Dataset - 
MAR) 
 
Week 24, 48  
2.21. 
ITT(E) 
shell 
Statistical Analysis of Change from Baseline in CD4+ Cell 
Count (cells/mm3) - MMRM 
use similar mock shell such as 
fasting lipids, just change to reflect 
CD4 endpoint 
All 
 
 


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2.22. 
ITT(E) 
Shell  
gsk2619619/ing117
172/week48/drivers
/ef_t_cd4_chg.sas 
Summary of Change from Baseline in CD4+ Cell Count 
(cells/mm3) by Visit 
 
All 
2.23. 
ITT(E) 
shell 
Summary of Change from Baseline in CD4+ Cell Count 
(cells/mm3) at Week X by Subgroup 
See subgroups in Section 10.11 
All 
2.24. 
ITT(E) 
shell 
Statistical Analysis of Change from Baseline in CD4+ Cell 
Count by subgroup (cells/mm3) at Week X– Observed case  
See subgroups in Section 10.11 
All 
Post-baseline HIV-1 Disease Progression 
2.25. 
ITT(E) 
shell 
Summary of Post-Baseline HIV-1 Associated Conditions 
Including Recurrences 
 
All 
2.26. 
ITT(E) 
shell 
Summary of Post-Baseline HIV-1 Associated Conditions 
Excluding Recurrences 
 
All 
2.27. 
ITT(E) 
shell 
Summary of Post-Baseline HIV-1 Disease Progressions 
 
All 
Additional Subgroup Analysis 
2.28. 
PP 
shell (Table 2.12) 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at 
Week X by Subgroup - Snapshot Analysis - PP 
 
Week 48, 96, 
144 
2.29. 
ITT(E) 
shell (Table 2.14) 
Summary of Study Outcomes (<50 c/mL) at Week X by 
Baseline Plasma HIV-1 RNA and CD4+ Cell Count - 
Snapshot Analysis 
Only one category of most severe 
subjects 
Week 48, 96,  
Proportion of Subjects with Plasma HIV-1 RNA <40 copies/mL –  Snapshot 
2.33. 
ITT(E) 
shell (Table 2.11) 
Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL by 
Visit - Snapshot Analysis 
 
Week 48, 96, 
144 
 
 


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2.34. 
ITT(E) 
Table 2.34 
mid208959/ 
primary_02 
Summary of CD4+ Cell Count (cells/mm3) by Visit 
 
Week 48 (ad 
hoc), 96, 144 
2.41. 
ITT(E) 
Table 9.1 
mid208959/ 
postcsr_2018_02 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at 
Week x by Baseline Plasma HIV-1 RNA and CD4+ Cell 
Count - Snapshot Analysis – ITTE  
Only one category of most severe 
subjects  
Week 96 
2.42. 
PP 
Table 9.2 
mid208959/ 
postcsr_2018_02 
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at 
Week x by Baseline Plasma HIV-1 RNA and CD4+ Cell 
Count - Snapshot Analysis - PP 
Only one category of most severe 
subjects 
Week 96 
2.43. 
ITT(E) 
mid208959/ 
present_2018_03 
Summary of Analysis for Proportion of Subjects with Plasma 
HIV-1 RNA <40 c/mL at Week X - Snapshot Analysis - ITT-
E 
 
Week 96, 144 
2.44. 
ITT(E) 
mid208959/ 
present_2018_03 
Summary of Study Outcomes (<40 c/mL) at Week X - 
Snapshot Analysis - ITT-E 
 
Week 96, 144 
2.45. 
ITT(E) 
mid208959/ 
present_2018_03 
Proportion of Subjects with Plasma HIV-1 RNA <40 c/mL at 
Week X by Subgroup - Snapshot Analysis - ITT-E 
 
Week 96, 144 


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10.17.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Efficacy 
2.1.  
ITT(E) 
shell 
Proportion (95% CI) of Subjects with HIV-1 RNA <50 c/mL by 
Visit – Snapshot Analysis 
Line plot 
All 
2.2.  
ITT(E) 
shell 
Unadjusted Treatment Difference in Proportion (95% CI) of 
Subjects with HIV-1 RNA <50 c/mL at Week X by Subgroup – 
Snapshot Analysis 
 
All 
2.3 
ITT(E) 
shell 
Individual Plasma HIV-1 RNA and CD4+ Profiles by Visit for 
Subjects with at least One Suspected Virologic Withdrawal Visit 
 
All 
2.4 
ITT(E) 
shell 
Kaplan-Meier Plot of Time to Failure - Treatment related 
discontinuation = Failure (TRDF) 
 
All 
2.5 
ITT(E) 
shell 
Kaplan-Meier Plot of Time to Failure - Efficacy related 
discontinuation = Failure (ERDF) 
 
All 
2.6 
ITT(E) 
shell 
Table 6.2 
mid208959/pre
sent_2018_03 
Kaplan-Meier Plot of Time to Viral Suppression Overall and by 
Baseline HIV-1 RNA and CD4+ Cell Count Subgroups  
add categories: 
Baseline HIV-1 RNA (c/mL) <= 
100,000 vs. > 100,000  
 
All 
2.7 
ITT(E) 
shell 
Line Plot of Adjusted Mean (95% CI) Change From Baseline in 
CD4+ Cell Count (cells/mm^3) Over Time – Repeated Measure 
Mixed Model 
 
All 


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10.17.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Exposure 
3.1.  
Safety 
EX1 
Summary of Extent of Exposure to Investigational Product 
Including Continuation Phase 
CS Core 
All, title 
update for 
Week 148 
Adverse Events 
3.2.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
CS Core 
All 
3.3.  
Safety 
AE5A 
Summary of All Adverse Events by Maximum Grade 
CS Core 
All 
3.4.  
Safety 
AE1  
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
CS Core 
All 
3.5.  
Safety 
AE5A 
Summary of Drug-Related Adverse Events by Maximum Grade 
CS Core 
All 
3.6.  
Safety 
AE3 
Summary of Common (>=2%) Adverse Events by Overall 
Frequency 
CS Core 
All 
3.7.  
Safety 
AE3 
Summary of Common (>=2%) Grade 2-5 Adverse Events by 
Overall Frequency 
CS Core 
All 
3.8.  
Safety 
AE15 
Summary of Common (>=2%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
CS Core 
All 
3.9.  
Safety 
AE3 
Summary of Common (>=1%) Drug-Related Grade 2-5 Adverse 
Events by Overall Frequency 
CS Core 
All 
3.10. 
Safety 
Dori 
Summary of Liver Monitoring/Stopping Event Reporting 
 
All 


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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.11. 
Safety 
AE5B 
Summary of Adverse Events by System Organ Class, Maximum 
Toxicity and Subgroups 
See subgroups in Section 
10.11.  
Add row for each subgroup, 
and use corresponding 
number of subjects as 
denominator 
Up to Week 
96 
3.13. 
Safety 
AE5A 
Summary of Post-treatment AE by SOC and Maximum Toxicity 
All 
Serious and Other Significant AEs 
3.14. 
Safety 
AE1 
Summary of Fatal Adverse Events 
CS Core 
All 
3.15. 
Safety 
AE1 
Summary of Drug-Related Fatal Adverse Events 
CS Core 
All 
3.16. 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ Class 
 
All 
3.17. 
Safety 
AE3 
Summary of Serious Drug-Related Adverse Events by Overall 
Frequency  
Plain Language Summary 
(PLS) requirements 
All 
3.18. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
 
All 
3.19. 
Safety 
AE1 or AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
 
All 
3.20. 
Safety 
AE1 or AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
subgroup 
See subgroups in Section 
10.11 
Up to Week 
96 
 
 


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Special Interest AEs 
3.21. 
Safety 
Shell 
Summary of Characteristics of Rash Adverse Events of Special 
Interest 
All 
3.22. 
Safety 
Shell 
Summary of Onset and Duration of the First Occurrence of Rash 
Adverse Events of Special Interest 
All 
3.23. 
Safety 
Shell 
Summary of Total Duration of Rash Adverse Events of Special Interest 
Up to Week 96 
3.24. 
Safety 
Shell 
Summary of Characteristics of Hypersensitivity Adverse Events of 
Special Interest 
All 
3.25. 
Safety 
Shell 
Summary of Onset and Duration of the First Occurrence of 
Hypersensitivity Adverse Events of Special Interest  
All 
3.26. 
Safety 
Shell 
Summary of Total Duration of Hypersensitivity Adverse Events of 
Special Interest 
 
Up to Week 96 
3.27. 
Safety 
Shell 
Summary of Characteristics of Insomnia Adverse Events of Special 
Interest 
All 
3.28. 
Safety 
Shell 
Summary of Onset and Duration of the First Occurrence of Insomnia 
Adverse Events of Special Interest  
All 
3.29. 
Safety 
Shell 
Summary of Total Duration of Insomnia Adverse Events of Special 
Interest 
 
Up to Week 96 
3.30. 
Safety 
Shell 
Summary of Characteristics of Nightmare / Abnormal Dreams Adverse 
Events of Special Interest 
All 
3.31. 
Safety 
Shell 
Summary of Onset and Duration of the First Occurrence of Nightmare / 
Abnormal Dreams Adverse Events of Special Interest  
All 
3.32. 
Safety 
Shell 
Summary of Total Duration of Nightmare / Abnormal Dreams Adverse 
Events of Special Interest 
 
Up to Week 96 


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Laboratory Values Over Time 
3.33. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline by Visit 
 
All 
3.34. 
Safety 
shell 
Statistical analysis of Change from Baseline in Fasting Lipids at Week 
X (Multiple imputed Dataset - MAR) 
 
Week 24, 48 
3.35. 
Safety 
shell 
Table 3.351 Statistical analysis of Change from Baseline in Fasting 
Lipids at Week X - MMRM-Lipid LOCF 
Table 3.352 Statistical analysis of Change from Baseline in Fasting 
Lipids at Week X – Loge Transformed Data – MMRM - Lipid LOCF 
 
All, add table 
3.352 for WK 
148 
3.36. 
Safety 
LB1 
Summary of Lipids Percentage Changes from Baseline by Visit 
 
 Up to Week 96 
3.37. 
Safety 
LB1 
Summary of Hematology Changes From Baseline by Visit 
 
All 
3.38. 
Safety 
 
Summary of Urine Concentrations Changes from Baseline by Visit 
 
All 
3.39. 
Safety 
shell 
Summary of Changes in TC/HDL ratio Category to Maximum Post-
Baseline Category  
 
Up to Week 96 
3.40. 
Safety 
shell 
Statistical analysis of Maximum post-Baseline emergent Grade 2 or 
greater laboratory abnormalities in fasting LDL cholesterol by Week X 
 
All 
3.41. 
Safety 
shell 
Summary of Changes in NCEP Lipid Baseline Category to Maximum 
Post-Baseline Category  
Exclude HDL 
Up to Week 96 
3.42. 
Safety 
shell 
Summary of Changes in NCEP Lipid Baseline Category to Minimum 
Post-Baseline Category  
For HDL only 
Up to Week 96 


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Biomarkers 
3.43. 
Safety 
shell 
Summary of Change from Baseline in Bone Biomarkers 
 
All 
3.44. 
Safety 
shell 
Summary of Percentage Change from Baseline in Bone Biomarkers 
 
 Up to Week 96 
3.45. 
Safety 
shell 
Summary of Change from Baseline in Bone Biomarkers by Subgroup 
See subgroups in 
Section 10.11 
Up to Week 96 
3.46. 
Safety 
shell 
Table 3.461 Summary of Change from Baseline in Renal Biomarkers 
Table 3.462 Summary of Change from Baseline in Renal Biomarkers - 
Loge Transformed Data 
Table 3.462 - report  
only up to Week 96 
All 
3.47. 
Safety 
shell 
Summary of Percentage Change from Baseline in renal biomarkers 
 
 Up to Week 96 
3.48. 
Safety 
shell 
Table 3.481 Summary of Change from Baseline in Renal Biomarkers 
by Subgroup 
Table 3.482 Summary of Change from Baseline in Renal Biomarkers 
by Subgroup - Loge Transformed Data 
Only Serum Cystatin 
C, eGFR (based on 
CKD-EPI-creatinine 
and CKD-EPI-cystatin 
C), Urine Beta-2 
Microglobulin/Urine 
Creatinine ratio and 
Urine Retinol Binding 
Protein/Urine 
Creatinine ratio by 
baseline plasma HIV-1 
RNA, baseline CD4+ 
cell count, Age (<50, 
vs ≥50) and presence 
of hypertension 
subgroups after week 
48 will be analysed.  
Up to Week 96 
3.49. 
Safety 
shell 
Statistical Analysis of Change from Baseline in Bone Biomarkers at 
Week X- (Multiple imputed Dataset - MAR) 
 
Week 24, 48  
3.50. 
Safety 
shell 
Statistical Analysis of Change from Baseline in Bone Biomarkers at 
Week X by Subgroup – Observed Case 
See subgroups in 
Section 10.11 
Up to Week 96 


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3.51. 
Safety 
shell 
Table 3.511 Statistical Analysis of Change from Baseline in Bone 
Biomarkers – MMRM 
Table 3.512 Statistical Analysis of Change from Baseline in Bone 
Biomarkers – Loge Transformed Data - MMRM 
 
All 
3.52. 
Safety 
shell 
Table 3.521 Statistical Analysis of Change from Baseline in Renal 
Biomarkers at Week x - (Multiple imputed Dataset - MAR) 
Table 3.522 Statistical Analysis of Change from Baseline in Renal 
Biomarkers at Week x - Loge Transformed Data - (Multiple Imputed 
Dataset - MAR)   
 
Week 24, 48  
3.53. 
Safety 
shell 
Table 3.531 Statistical Analysis of Change from Baseline in Renal 
Biomarkers at Week x by Subgroup - Observed Case 
Table 3.532 Statistical Analysis of Change from Baseline in Renal 
Biomarkers at Week x by Subgroup - Observed Case - Loge 
Transformed Data   
Only Serum Cystatin C, 
eGFR (based on CKD-
EPI-creatinine and CKD-
EPI-cystatin C), Urine 
Beta-2 
Microglobulin/Urine 
Creatinine ratio and 
Urine Retinol Binding 
Protein/Urine Creatinine 
ratio by baseline plasma 
HIV-1 RNA, baseline 
CD4+ cell count, Age 
(<50, vs ≥50) and 
presence of hypertension 
subgroups after week 48 
will be analysed. 
Up to Week 96 
3.54. 
Safety 
shell 
Table 3.541 Statistical Analysis of Change from Baseline in Renal 
Biomarkers – MMRM 
Table 3.542 Statistical Analysis of Change from Baseline in Renal 
Biomarkers - Loge Transformed Data - MMRM 
For table 3.542, include 
all renal biomarkers. so 
parameters that in 
T3.541 also should be 
added 
All 


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Treatment Emergent Laboratory Toxicities 
3.55. 
Safety 
shell 
Summary of Maximum Post-Baseline Emergent Chemistry Toxicities  
 
All 
3.56. 
Safety 
shell 
Summary of Maximum Post-Baseline Emergent Hematology Toxicities  
Where criteria is 
complex, i.e. 
AST>=2xULN and 
BLT >=2xULN use 
the whole condition 
All 
Other 
3.57. 
Safety 
Dori 
Summary of Subjects Meeting Hepatobiliary Abnormality Criteria Post-
Baseline Emergent Abnormalities  
Footnote: Note: For 
ALT >=3xULN -
<5xULN, >=5xULN -
<10xULN, 
>=10xULN -
<20xULN, 
>=20xULN, 
subjects were 
summarized based 
on post-baseline 
maximum emergent 
ALT. 
All 
3.58. 
Safety 
shell 
Summary of True Positive Suicidal Indication/ Behaviour Alerts based 
on eCSSRS by Visit 
 
All 
3.59. 
Safety 
shell 
Summary of Subjects with C-SSRS Suicidal Ideation or Behaviour at 
Baseline 
 
All 
3.60. 
Safety 
shell 
Summary of Subjects with Post-Baseline C-SSRS Suicidal Ideation or 
Behaviour  
Shell differs from 
Dori 
All 
3.61. 
Safety 
shell 
Summary of Characteristics of Anxiety Adverse Events of Special 
Interest 
 
All 
3.62. 
Safety 
shell 
Summary of Characteristics of Depression Adverse Events of Special 
Interest 
 
All 
3.63. 
Safety 
shell 
Summary of Characteristics of Suicidality and Self Injury Adverse 
Events of Special Interest 
 
All 


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3.64. 
Safety 
shell 
Summary of Onset and Duration of the First Occurrence of Anxiety 
Adverse Events of Special Interest  
 
All 
3.65. 
Safety 
shell 
Summary of Onset and Duration of the First Occurrence of Depression 
Adverse Events of Special Interest  
 
All 
3.66. 
Safety 
shell 
Summary of Onset and Duration of the First Occurrence of Suicidality 
and Self Injury Adverse Events of Special Interest  
 
All 
3.67. 
Safety 
shell 
Summary of Total Duration of Anxiety Adverse Events of Special 
Interest  
 
Up to Week 96 
3.68. 
Safety 
shell 
Summary of Total Duration of Depression Adverse Events of Special 
Interest 
 
Up to Week 96 
3.69. 
Safety 
shell 
Summary of Total Duration of Suicidality and Self Injury Adverse 
Events of Special Interest 
 
Up to Week 96 
3.70. 
Safety 
shell 
Summary of Post Baseline Depression, Anxiety and Suicidal and Self-
Injury Adverse Events by AE of Special Interest, Maximum DAIDS 
Toxicity Grade, and Prior History of Depression and Anxiety 
 
All 
3.71. 
Safety 
Dori 
Summary of AST, ALT and Total Bilirubin Maximum Post-Baseline 
Emergent Toxicity By Baseline Hepatitis C Status 
 
All 
3.72. 
Safety 
shell 
Summary of Change from Baseline in Fasting Lipids by subgroup – 
Lipid LOCF 
Only Age (<50, vs 
≥50) subgroup after 
week 48 will be 
analysed. 
Up to Week 96 
3.73. 
Safety 
shell 
Statistical analysis of Change from Baseline in Fasting Lipids at Week 
X by subgroup – Lipid LOCF 
Only Age (<50, vs 
≥50) subgroup after 
week 48 will be 
analysed. 
Up to Week 96 
3.74. 
Safety 
Shell 
Summary of Change from Baseline in Inflammation Biomarkers by Visit   
Week 96,144 
3.75. 
Safety 
Shell 
Summary of Change from Baseline in telomere length at by Visit  
 
EOS 
3.76. 
Safety 
AE1 
Summary of Drug-Related Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study  
 
All 
3.77. 
Safety 
shell 
Summary of Changes in NCEP Lipid Baseline Category to Week X  
 
All  
3.78. 
Safety 
AE3 
Summary of Drug-Related Grade 2-5 Adverse Events 
 
All 


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3.79. 
Safety 
AE5A 
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Treatment or Withdrawal from Study by Maximum Grade 
 
All 
3.80. 
Safety 
shell 
Summary of Changes in Total Cholesterol/ HDL Ratio Baseline 
Category to Week x 
 
All 
3.81. 
Safety 
Table 3.57 
Summary of Subjects Meeting Hepatobiliary Abnormality Criteria - All 
Post-Baseline Abnormalities 
Same as Table 3.57 
with the emergent 
criteria removed 
Week 48, 96 
3.89. 
Safety  
Table 3.55 
Summary of Maximum Post-Baseline Emergent Chemistry Toxicities - 
with GFR Toxicity Grading Re-Derived 
Same as Table 3.55 
Week 24 
3.90. 
Safety 
Table 2.1 
mid208959/ 
present_2018_01 
Summary of Absolute Values of Fasting Lipids by Visit 
 
Week 48 (ad 
hoc), 96, 144 
3.91. 
Safety 
T3.33 
Summary of Weight (kg) by Visit   
 
Week 96 
3.92. 
Safety 
T3.33 
Summary of Change from Baseline in Weight (kg) by Visit 
 
Week 96, 144 
3.93. 
Safety 
T3.33 
Summary of BMI (kg/m2) by Visit   
 
Week 96 
3.94. 
Safety 
T3.33 
Summary of Change from Baseline in BMI (kg/m2) by Visit 
 
Week 96, 144 
3.95. 
Safety 
AE3 
Summary of Common (>=2%) Drug-Related Adverse Events by 
Overall Frequency 
 
Week 96, 144 
3.96. 
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse Events by Overall 
Frequency 
Plain Language 
Summary (PLS) 
requirements 
Week 144 
3.97. 
Safety 
EX1 
Summary of Extent of Exposure to Investigational Product During 
Double Blind and Open Label Phase 
 
Week 144 
3.100. 
Safety 
mid208959/postcsr
_2019_02/drivers/t_
relrisk_g1.sas 
Summary of Adverse Event Categories and Relative Risk 
 
Week 144 


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10.17.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable  
Adverse Events  
3.1.  
Safety 
AE10 
Plot of Common Adverse Events and Relative Risk 
CS CORE 
All 
Laboratory Values Over Time 
3.2.  
Safety 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT 
CS CORE 
Up to Week 96 
3.3.  
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
CS CORE 
All 
3.4.  
Safety 
shell 
Bar Chart of Triglycerides, LDL Cholesterol and Total 
Cholesterol NCEP Categories at Week X vs. Baseline. 
 
All 
3.5.  
Safety 
shell 
Bar Chart of Triglycerides, LDL Cholesterol and Total 
Cholesterol  NCEP Categories at Baseline vs. Maximum 
Post-Baseline 
Exclude HDL 
Up to Week 96 
3.6.  
Safety 
shell 
Figure 3.61 Line Plot of Adjusted Mean (95% CI) Change 
From Baseline in Renal Biomarkers over Time — MMRM  
Figure 3.62 Line Plot of Ratio of Geometric Means (95% 
CI) in Renal Biomarkers over Time - LogeTransformed 
Data - MMRM 
Two figures as 3.61 and 3.62 
All 
3.7.  
Safety 
shell 
Line Plot of Adjusted Mean (95% CI) of Change from 
Basline in Bone Biomarkers over Time — MMRM  
 
All 
3.8.  
Safety 
shell 
Bar Chart of HDL Cholesterol NCEP Categories at 
Baseline vs. Minimum Post-Baseline 
For HDL only 
Up to Week 96 
3.9.  
Safety 
shell 
Bar Chart of Total Cholesterol/ HDL Ratio Category at 
Week X vs. Baseline   
 
All 
 
 


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3.10. 
Safety 
shell 
Bar Chart of Total Cholesterol/ HDL Ratio Category at 
Baseline vs. Maximum Post Baseline   
 
Up to Week 96 
3.11. 
Safety 
shell 
Bar Chart of HDL Cholesterol NCEP Categories at Week 
x vs. Baseline 
 
All 
3.12. 
Safety 
AE10 
Plot of Common (>=2%) Grade 2-5 Adverse Events and 
Relative Risk 
 
Week 96, 144 
3.13. 
Safety 
AE10 
Plot of Common (>=2%) Drug-Related Adverse Events 
and Relative Risk  
use cut-off of >=2% 
Week 96, 144 
3.14. 
Safety 
Shell  
Plot of Adverse Events Categories and Relative Risk 
 
Week 96, 144 
 


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10.17.9. 
Virology tables 
Virology: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.1.  
Viral 
Genotypic 
shell 
Summary of Subject Accountability: Genotypes Available at or prior 
to Week X  
 
All 
4.2.  
Viral 
Phenotypic 
shell 
Summary of Subject Accountability: Phenotypes Available at or 
prior to Week X 
 
All 
4.3.  
Viral 
Genotypic 
shell 
Summary of INSTI Mutations for Subjects Meeting CVW Criteria at 
or prior to Week X 
 
All 
4.4.  
Viral 
Genotypic 
shell 
Summary of Major Mutations of NRTI, NNRTI and PI Classes for 
Subjects Meeting CVW Criteria at or prior to Week X 
 
All 
4.5.  
Viral 
Genotypic 
shell 
Summary of Treatment Emergent INSTI Mutations at Time of CVW 
at or prior to Week X 
 
All 
4.6.  
Viral 
Genotypic 
shell 
Summary of Changes in Major Mutations of NRTI, NNRTI and PI 
Classes from Baseline at Time of CVW for Subjects with CVW at or 
prior to Week X 
 
All 
4.7.  
Viral 
Genotypic 
shell 
Summary of S-GSS at Time of CVW by Genotypic Cut-Off for DTG, 
3TC, TDF and FTC at or prior to week X 
 
All 
4.8.  
Viral 
Phenotypic  
shell 
Summary of Phenotype at Time of CVW by Phenotypic Cut-off at or 
prior to Week X 
 
All 
4.9.  
Viral 
Phenotypic  
shell 
Number of Drugs to Which Subjects are Phenotypically Resistant at 
Time of CVW at or prior to Week X 
 
All 
4.10. 
Viral 
Phenotypic  
shell 
Summary of Fold Change to DTG, 3TC, TDF and FTC at Time of 
CVW at or prior to Week X  
 
All 


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10.17.10. Health Outcomes Tables 
Health Outcomes: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable [Priority] 
EQ-5D-5L 
5.1.  
ITT(E) 
shell 
Summary of EQ-5D Category Scores by Visit – LOCF  
 
All 
5.2.  
ITT(E) 
shell 
Summary of EQ-5D Utility and Thermometer Scores by visit - 
LOCF 
 
All 
5.3.  
ITT(E) 
shell 
Summary of Change from Baseline in EQ-5D Utility and 
Thermometer Scores - LOCF 
 
All 
5.4.  
ITT(E) 
shell 
Statistical Analysis of Change from Baseline in EQ-5D Utility 
Scores – MMRM - LOCF 
 
All 
5.5.  
ITT(E) 
shell 
Statistical analysis of Change from Baseline in EQ-5D 
Thermometer Scores – MMRM - LOCF 
 
All 
10.17.11. Health Outcomes Figures 
Health Outcomes: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
EQ-5D-5L 
5.1.  
ITT(E) 
shell 
Line Plot of Adjusted Mean (95% CI) Change from Baseline in 
EQ-5D-5L Utility Score Over Time – MMRM - LOCF 
 
All 
5.2.  
ITT(E) 
shell 
Line Plot of Adjusted Mean (95% CI) Change From Baseline in 
EQ-5D Thermometer Score Over Time – MMRM - LOCF 
 
All 


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10.17.12. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Study Population 
1.  
ITT 
Futility listing 1 
Listing of Randomized and Actual Strata and Treatment Assignment 
use screening value for actual strata 
All 
2.  
 ITT 
Shell 
 
Listing of Subjects Randomized But Not Treated 
CS CORE  
(related to ‘Listing for exclusion from 
any population) 
All 
3.  
All Subjects 
Screened 
ES7 
Listing of Reasons for Screen Failure 
CS CORE; add subreason, i.e # of 
IE criteria 
All 
4.  
ITT(E) 
BL1 
Listing of Subjects for whom the Treatment Blind was Broken 
 
 
5.  
ITT(E) 
ES2 
Listing of Reasons for Study Withdrawal  
CS CORE 
All 
6.  
ITT(E) 
DV2 
Listing of Important Protocol Deviations  
CS CORE 
All 
7.  
ITT(E) 
Shell 
 
Listing of Protocol Deviations Leading to Exclusion from the Per-
Protocol Population 
CS CORE  
 
All 
8.  
ITT(E) 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
CS CORE 
All 
9.  
ITT(E) 
DM2 
Listing of Demographic Characteristics 
CS CORE 
All 
10.  
ITT(E) 
shell 
Listing of subgroups 
 
All 
11.  
ITT(E) 
DM9 
Listing of Race 
CS CORE 
All 
 
 


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Efficacy 
12.  
ITT(E) 
Shell 
 
Listing of Quantitative and Qualitative Plasma HIV-1 RNA Data 
Include the interpretation of whether 
the virus is detected or not 
(‘Detected’ or ‘Not Detected’) by the 
assay 
All 
13.  
ITT(E) 
Shell 
Listing of Study Outcome (<50 c/mL) at Week X – Snapshot Analysis 
 
All 
Safety 
14.  
Safety 
HIV_IP5/ EX3 
Listing of Investigational Product Exposure Data 
CS CORE 
All 
15.  
Safety 
AE8 
Listing of All Adverse Events 
CS CORE 
All 
16.  
Safety 
AE8 
Listing of Drug-Related Adverse Events 
 
All 
17.  
Safety 
AE8 
Listing of Fatal Adverse Events 
CS CORE 
All 
18.  
Safety 
AE8 
Listing of Drug-Related Fatal Adverse Events 
 
All 
19.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
CS CORE 
All 
20.  
Safety 
AE8 
Listing of Adverse Events Leading to Withdrawal/Permanent 
Discontinuation of Investigational Product 
CS CORE 
All 
21.  
Safety 
PSRAE1 
Listing of Possible Suicidality-Related Adverse Event Data: Event and 
Description (Section 1-Section 2) 
 
All 
22.  
Safety 
PSRAE3 
Listing of Possible Suicidality-Related Adverse Event Data: Possible 
Cause(s) (Section 3) 
 
All 
23.  
Safety 
PSRAE4 
Listing of Possible Suicidality-Related Adverse Event Data (Section 4) 
 
All 
24.  
Safety 
PSRAE5 
Listing of Possible Suicidality-Related Adverse Event Data (Section 5-
Section 8) 
 
All 
25.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events  
CS CORE 
All 
26.  
Safety 
AE2 
Listing of Relationship of Adverse Event System Organ Classes, 
Preferred Terms, and Verbatim Text 
CS CORE 
All 
27.  
Safety 
LB5 
Listing of Clinical Chemistry Laboratory Data for Subjects with 
Laboratory Abnormalities of Potential Clinical Concern 
CS CORE  
All 
28.  
Safety 
LB5 
Listing of Hematology Laboratory Data for Subjects with Laboratory 
Abnormalities of Potential Clinical Concern 
CS CORE 
All 
29.  
Safety 
UR2a 
Listing of Urinalysis Data for Subjects with Abnormalities of Potential 
Clinical Concern 
CS CORE, use all data; if data is 
form both dipstick and 
concentration, display separately 
All 


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10.17.13. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable  
Study Population 
30.  
All Subjects 
Screened 
Shell 
 
Listing of Subject Recruitment by Country and Site Number 
 
All 
31.  
All Subjects 
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
 
All 
32.  
ITT(E) 
Shell 
Listing of Visit Dates 
 
All 
33.  
All Subjects 
Screened 
Shell 
 
Listing of Study Populations 
 
All 
34.  
Safety 
Shell  
Listing of DTG Pharmacokinetic Concentration Data at Liver 
Event 
Please this listing under ‘Safety, 
Listing – Other’ section. 
from week 48 
35.  
ITT(E) 
Shell 
Listing of Hepatitis Test Results 
 
All 
36.  
ITT(E) 
CDC3 
Listing of CDC Classification of HIV Infection at Baseline 
 
All 
37.  
ITT(E) 
RF2 
Listing of HIV Risk Factors 
 
All 
38.  
ITT(E) 
Shell 
Listing of Screening Cardiovascular Risk Assessment Data 
 
All 
39.  
ITT(E) 
MH2 
Listing of Current and Past Medical Conditions at Baseline 
 
All 
40.  
ITT(E) 
MH2 
Listing of Current and Past Medical Conditions at Baseline – 
subjects at sites in Mexico only 
 
EOS 
41.  
ITT(E) 
Shell 
Listing of History of Cardiac Therapeutic Procedures 
 
All 
42.  
ITT(E) 
Shell 
Listing of Investigational Product Accountability 
 
All 
43.  
ITT(E) 
CM2 
Listing of Concomitant Medications 
CS CORE 
All 
44.  
ITT(E) 
CM2 
Listing of Concomitant Medications – subjects at sites in Mexico 
 
EOS 
45.  
ITT(E) 
CM6 
Listing of Relationship Between ATC Level 1, Ingredient and 
Verbatim Text 
 
All 
46.  
ITT(E) 
CM2 
Listing of Prior ART Medications 
 
All 
47.  
ITT(E) 
CM2 
Listing of Concomitant ART Medications 
 
All 
 
 


CONFIDENTIAL 
 
 
205543 
 
141 
 
48.  
ITT(E) 
CM2 
Listing of Concomitant ART Medications– subjects at sites in 
Mexico only 
 
EOS 
49.  
ITT(E) 
CM6 
Listing of Relationship Between ATC Level 4, Ingredient and 
Verbatim Text 
 
All 
Efficacy 
50.  
ITT(E) 
shell 
Listing of Plasma HIV-1 RNA data for subjects with Confirmed 
Virologic Withdrawal  
 
All 
51.  
ITT(E) 
shell 
Listing of CD4+ Cell Count Data 
 
All 
52.  
ITT(E) 
HIV4 
Listing of Stage 3 HIV-1 Associated Conditions 
List only stage 3 associated 
conditions 
All 
53.  
ITT(E) 
shell 
Listing of subjects Efficacy related discontinuation = Failure 
(ERDF)  
 
All 
54.  
ITT(E) 
shell 
Listing of subjects Treatment related discontinuation = Failure 
(TRDF) 
 
All 
55.  
ITT(E) 
shell 
Listing of Subjects who Reached Week 48 prior to and after the 
Week 24 unblinding – Bias Sensitivity Analysis 
 
48 
Safety 
56.  
Safety 
HIV_IP5 
Listing of Investigational Product Exposure Data – subjects at 
sites in Mexico 
CS CORE 
EOS 
57.  
Safety 
AE8 
Listing of Non-Serious AEs for subjects at sites in Mexico 
 
EOS 
58.  
Safety 
AE8 
Listing of SAEs for subjects at sites in Mexico 
 
EOS 
59.  
Safety 
AE8 
Listing of SAEs for subjects at sites in Mexico 
 
EOS 
60.  
Safety 
shell 
Listing of Cardiovascular Events 
 
All 
61.  
Safety 
CP_EG5 / 
CP_EG4 
Or dori 
Listing of All ECG Findings for Subjects with an Abnormal Finding 
 
All 
62.  
Safety 
VS4 
Listing of Vital Signs  
Please include all visits available. 
All 
63.  
Safety 
shell 
Listing of Post Baseline Maximum ALT and Maximum Bilirubin  
 
All 
64.  
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
 
All 
65.  
Safety 
LIVER6 
Listing of Liver Event Information for RUCAM Score 
 
All 
66.  
Safety 
LIVER7 
Listing of Liver Biopsy Details 
 
All 
67.  
Safety 
LIVER8 
Listing of Liver Imaging Details 
 
All 
68.  
Safety 
MH2 
Listing of Past and Current Liver Disease Medical Conditions 
 
All 


CONFIDENTIAL 
 
 
205543 
 
142 
 
69.  
Safety 
shell 
Listing of Laboratory Data from Liver Event Follow-Up 
 
All 
70.  
Safety 
Dori 
Subjects Meeting Hepatobiliary Abnormality Criteria - Post-
Baseline Emergent Abnormalities  
 
This is about “emergent” – the 
subjects do not have such 
conditions at baseline.   If missing 
baseline (i.e. some or all ALT, BILT 
etc were missing), we assume they 
are normal.  Any conditions met 
post-baseline will be included in the 
table. 
All 
71.  
Safety 
shell  
Listing of C-SSRS Suicidal Ideation and Behaviour Positive Alerts 
(4-9) 
 
All 
72.  
Safety 
shell  
Listing of C-SSRS Suicidal Ideation and Behaviour Data  
Similar shell for listing 71 
All 
73.  
Safety 
shell 
Listing of C-SSRS False Positive Alerts with Corresponding 
Reasons 
 
All 
74.  
Safety 
shell 
Listing of all C-SSRS True Positives, with Corresponding Reasons 
for not being considered an AE or SAE 
 
All 
75.  
Safety 
PREG1a 
Listing of Subjects Who Became Pregnant During the Study 
 
All 
76.  
Safety 
shell 
Patient profiles for subjects meeting protocol defined liver stopping 
criteria 
 
All 
77.  
Safety 
shell 
Patient profiles for subjects meeting confirmed virologic 
withdrawal criteria 
 
All 
78.  
Safety 
Dori 
Listing of Liver Event Results and Time of Event Relative to 
Treatment 
 
All 
Virology 
79.  
ITT(E) 
shell 
Listing of All Genotypic Data 
 
All 
80.  
Viral 
Genotypic 
shell 
Listing of Treatment Emergent Genotypic Mutations 
 
All 
81.  
Viral 
Genotypic 
shell 
Listing of Genotype by Genotypic Cut-Off - CVWs 
 
All 
82.  
ITT(E) 
shell 
Listing of All Phenotypic Data 
 
All 
84.  
Viral 
Phenotypic  
shell 
Listing of Net Assessment Score - CVWs 
 
 
All 


CONFIDENTIAL 
 
 
205543 
 
143 
 
85.  
ITT(E) 
shell 
Listing of Genotypic and Phenotypic Data for Subjects with 
Confirmed Virologic Withdrawal Criteria 
 
All 
86.  
ITT(E) 
shell 
Listing of Genotypic and Phenotypic Data for Subjects with on-
treatment Virology Results at non-CVW timepoints 
 
All 
87.  
ITT(E) 
shell 
Listing Subject Level Summary of Key Virologic Data for Subjects 
with Confirmed Virologic Withdrawal or On-Treatment Non-CVW 
Timepoints 
 
All 
Health Outcomes  
88.  
ITT(E) 
shell 
Listing of EQ-5D Category, Utility and Thermometer Scores 
 
All 


CONFIDENTIAL 
 
 
205543 
 
144 
 
Other  
90.  
Safety  
shell 
Listing of Renal Biomarker Data 
 
All 
91.  
Safety  
shell 
Listing of Bone Biomarker Data 
 
All 
92.  
Safety  
shell 
Listing of Inflammation Biomarkers data 
 
Week 96,144 
93.  
Safety  
shell 
Listing of Telomere Length Data 
 
EOS 
94.  
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
Keep in ICH listing in HARP 
All 
95.  
Safety 
AE8 
Listing of Drug-related Non Fatal Serious Adverse Events  
Keep in ICH listing in HARP 
All 
96.  
Safety  
Listing 70 
Subjects Meeting Hepatobiliary Abnormality Criteria - All Post-
Baseline Abnormalities 
Same as Listing 70 with the 
emergent criteria removed 
Week 48, 96 
97.  
Safety 
LB5 
Listing of Clinical Chemistry Laboratory Data for Subjects with 
Laboratory Abnormalities of Potential Clinical Concern - with GFR 
Toxicity Grading Re-Derived 
Keep in ICH listing in HARP 
CS CORE 
 
Week 24 
98.  
Safety 
CVATIA1 
Patient Profiles for Subjects with Cardiovascular Events 
Provided if detailed cardiovascular 
event information is available. 
Week 144 
 


 
CONFIDENTIAL 
 
 
205543 
 
145 
 
10.18. 
Appendix 18: Example Mock Shells for Data Displays 
Mock shells are included in a separate document. 
There are no new mock shells added for EOS, therefore, no update is needed for the previous mock shell document.  

Prot_000.pdf: 
2015N263962_02
CONFIDENTIAL
ViiV Healthcare and the GlaxoSmithKline group of companies
205543
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase III, randomised, double-blind, multicentre, parallel 
group, non-inferiority study evaluating the efficacy, safety, and 
tolerability of dolutegravir plus lamivudine compared to 
dolutegravir plus tenofovir/emtricitabine in HIV-1-infected 
treatment-naïve adults
Compound Number:
GSK1349572+GR109714 (GSK3515864)
Development Phase:
III
Effective Date:
14-JUN-2018
Protocol Amendment Number:  02
Author (s):
 
Copyright 2018 ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
PPD


2015N263962_02
CONFIDENTIAL
ViiV Healthcare and the GlaxoSmithKline group of companies
205543
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N263962_00
2016-APR-25
Original
2015N263962_01
2017-NOV-29
Amendment No. 1
The double barrier method of contraception (male condom combined with a vaginal 
spermicide) was added in this study as a permitted method for preventing pregnancy in 
females of reproductive potential.
Exclusion criterion #15 (limitations on investigational drug use) was broadened to 
include additional countries as needed.  Inclusion of Portugal was required by the 
Portuguese National Ethics Committee for Clinical Research.
Assessment of weight at Weeks 96 and 144 was added to monitor the incidence of 
significant weight gain with dolutegravir use.
Assessment of inflammation biomarkers (IL-6, hs-CRP) at Day 1, and Weeks 48, 96 and 
144, was added as a new exploratory endpoint. 
Assessment of telomere length at Day 1, and Weeks 96 and 144, was added as a new 
exploratory endpoint. 
For clarification purposes, the ‘peripheral blood mononuclear cell (PBMC)’ sample in 
Section 7.1 (Time and Events table) and Section 7.6.1 (HIV-1 Exploratory Analyses) was 
renamed as a ‘whole blood’ sample. 
The Day 1 ‘PBMC’ sample (now named ‘whole blood’ sample) originally designated for 
virology use was additionally designated for telomere length measurement, where 
possible.  Additional whole blood samples were added for measurement of telomere 
length at Week 96 and Week 144.
A description of commercial image dolutegravir tablets was added to Section 6.1 
(Investigational Product and Other Study Treatment) to allow use of commercial material 
as well as clinical trial material during the study.
The physical description for open-label lamivudine in Section 6.1 was corrected. 
Standard procedures for forwarding pregnancy information to the Antiretroviral 
Pregnancy Register were added.
For clarification purposes, the AE severity gradings in Appendix 7, Section 12.7.6 
(Evaluating AEs and SAEs) were updated to be consistent with Appendix 6, Section 12.6. 
(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.
2015N263962_02
2018-JUN-14
Amendment No. 2
Changes were made to the protocol to manage and mitigate risks following identification 


2015N263962_02
CONFIDENTIAL
ViiV Healthcare and the GlaxoSmithKline group of companies
205543
3
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 update the 
references to the DTG IB to reflect the most current versions. 

The Risk Assessment table (Section 4.6.1) was updated to include language regarding 
risk and mitigation of neural tube defects.

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.

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.

The modified list of highly effective methods for avoiding pregnancy in FRP (Section
12.9.1) was updated to exclude the double barrier method of contraception, which 
does not meet updated GSK/ViiV criteria for a highly effective method.


PPD
PPD
PPD


2015N263962_02
CONFIDENTIAL
205543
5
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Site Address
Primary 
Medical 
Monitor 
 
 MD
ViiV Healthcare
5 Moore Drive
Research 
Triangle Park, 
NC  27709 
(USA)
Secondary 
Medical 
Monitor
 
MD
ViiV Healthcare
980 Great West 
Road, Brentford, 
Middlesex, TW8 
9GS, UK
SAE 
contact  
information 
Medical 
Monitor as 
above
This study is sponsored by ViiV Healthcare.  PPD Inc. and GlaxoSmithKline are 
supporting ViiV Healthcare in the conduct of this study. 
Global Sponsor Legal Registered Address (excluding US): 
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
US IND Sponsor Legal Registered Address:
ViiV Healthcare Company
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity.  In these instances, the appropriate company to be identified 
as sponsor must be agreed with the global ViiV Healthcare clinical team and signed 
off by the VP, Global Medical Strategy.   
Regulatory Agency Identifying Number(s): US IND 75,382; EudraCT 2016-000459-28
PPD
PPD
PPD
PPD
PPD
PPD


2015N263962_02
CONFIDENTIAL
205543
6
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205543
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


2015N263962_02
CONFIDENTIAL
205543
7
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205543......................................................11
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................17
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................20
4.3.
Type and Number of Subjects.....................................................................21
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................22
4.6.1.
Risk Assessment .........................................................................23
4.6.2.
Benefit Assessment.....................................................................27
4.6.3.
Overall Benefit:Risk Conclusion...................................................27
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............27
5.1.
Inclusion Criteria.........................................................................................28
5.2.
Exclusion Criteria........................................................................................29
5.3.
Screening Failures......................................................................................31
5.4.
Withdrawal/Stopping Criteria.......................................................................32
5.4.1.
Virologic Criteria for Subject Management and Viral 
Resistance Testing ......................................................................33
5.4.1.1.
Virologic Withdrawal Criteria.......................................33
5.4.1.2.
Managing Subjects Meeting Suspected 
Virologic Withdrawal Criteria.......................................34
5.4.1.3.
Managing Subjects Meeting Confirmed 
Virologic Withdrawal Criteria.......................................35
5.4.1.4.
Managing subjects with HIV-1 RNA 50 c/mL 
at Weeks 24, 48, 96 and 144......................................35
5.4.2.
Liver Chemistry Stopping Criteria ................................................36
5.4.2.1.
Study Treatment Restart ............................................37
5.5.
Subject and Study Completion....................................................................38
6.
STUDY TREATMENT ............................................................................................38
6.1.
Investigational Product and Other Study Treatment....................................38
6.2.
Treatment Assignment................................................................................41
6.3.
Blinding.......................................................................................................42
6.3.1.
Emergency Unblinding.................................................................42
6.3.2.
Scheduled Unblinding..................................................................43
6.4.
Packaging and Labeling..............................................................................43
6.5.
Preparation/Handling/Storage/Accountability..............................................43
6.6.
Compliance with Study Treatment Administration.......................................43
6.7.
Treatment of Study Treatment Overdose....................................................44


2015N263962_02
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205543
8
6.8.
Treatment after the End of the Study ..........................................................44
6.9.
Concomitant Medications and Non-Drug Therapies....................................44
6.9.1.
Permitted Medications and Non-Drug Therapies..........................45
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................45
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
7.1.
Time and Events Table...............................................................................47
7.2.
Screening and Critical Baseline Assessments ............................................51
7.2.1.
Screening Assessments ..............................................................51
7.2.2.
Baseline Assessments.................................................................52
7.3.
Efficacy.......................................................................................................52
7.4.
Safety .........................................................................................................53
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........53
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................53
7.4.1.2.
Method of Detecting AEs and SAEs ...........................54
7.4.1.3.
Follow-up of AEs and SAEs........................................54
7.4.1.4.
Cardiovascular and Death Events ..............................54
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................54
7.4.1.6.
Regulatory Reporting Requirements for SAEs............55
7.4.2.
Pregnancy ...................................................................................55
7.4.3.
Physical Exams ...........................................................................56
7.4.4.
Electrocardiogram (ECG).............................................................56
7.4.5.
Clinical Safety Laboratory Assessments ......................................56
7.4.6.
Suicidal Risk Monitoring...............................................................58
7.5.
Biomarkers .................................................................................................59
7.6.
HIV-1 Polymerase Viral Genotyping and Phenotyping ................................60
7.6.1.
HIV-1 Exploratory Analyses .........................................................60
7.7.
Value Evidence and Outcomes...................................................................60
7.7.1.
Value Evidence and Outcomes Endpoints ...................................61
8.
DATA MANAGEMENT ...........................................................................................61
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................61
9.1.
Hypotheses.................................................................................................61
9.2.
Sample Size Considerations.......................................................................62
9.2.1.
Sample Size Assumptions ...........................................................62
9.2.1.1.
Rationale for non-inferiority margin.............................62
9.2.1.2.
Response rate assumptions .......................................62
9.2.2.
Sample Size Sensitivity................................................................62
9.2.3.
Sample Size Re-estimation or Adjustment...................................63
9.3.
Data Analysis Considerations .....................................................................63
9.3.1.
Analysis Populations....................................................................63
9.3.1.1.
Intent-to-Treat Exposed (ITT-E) Population ................63
9.3.1.2.
Per Protocol (PP) Population......................................63
9.3.1.3.
Safety Population .......................................................63
9.3.2.
Analysis Data Sets.......................................................................64
9.3.3.
Treatment Comparisons ..............................................................64
9.3.3.1.
Primary Comparison of Interest ..................................64
9.3.3.2.
Other Comparisons of Interest....................................64
9.3.3.3.
Secondary comparisons .............................................64


2015N263962_02
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205543
9
9.3.4.
Interim Analyses ..........................................................................65
9.4.
Key Elements of Analysis Plan ...................................................................65
9.4.1.
Efficacy Analyses.........................................................................65
9.4.2.
Safety Analyses...........................................................................67
9.4.3.
Viral Genotyping/Phenotyping Analyses ......................................67
9.4.4.
Other Analyses ............................................................................67
10. STUDY GOVERNANCE CONSIDERATIONS........................................................68
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............68
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................68
10.3.
Quality Control (Study Monitoring) ..............................................................68
10.4.
Quality Assurance.......................................................................................69
10.5.
Study and Site Closure ...............................................................................69
10.6.
Records Retention......................................................................................70
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................70
10.8.
Independent Data Monitoring Committee....................................................71
11. REFERENCES.......................................................................................................72
12. APPENDICES........................................................................................................76
12.1.
Appendix 1: Abbreviations and Trademarks................................................76
12.2.
Appendix 2: Child-Pugh Classification ........................................................79
12.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................80
12.4.
Appendix 4: Liver Safety – Study Treatment Restart Guidelines.................83
12.5.
Appendix 5: CDC Classification for HIV-1 Infection (2014)..........................87
12.6.
Appendix 6:  Division of AIDS table for Grading Severity of Adult 
and Pediatric Adverse Events.....................................................................89
12.7.
Appendix 7: Definition of and Procedures for Recording, Evaluating, 
Follow-up and Reporting of Adverse Events .............................................114
12.7.1.
Definition of Adverse Events......................................................114
12.7.2.
Definition of Serious Adverse Events.........................................115
12.7.3.
Definition of Cardiovascular Events ...........................................116
12.7.4.
Sentinel Events..........................................................................117
12.7.5.
Recording of AEs and SAEs ......................................................117
12.7.6.
Evaluating AEs and SAEs..........................................................118
12.7.7.
Reporting of SAEs and other events to ViiV 
Healthcare/GSK/PPD.................................................................119
12.8.
Appendix 8: Toxicity Management ............................................................121
12.8.1.
Specific Toxicities/Adverse Event Management.........................122
12.8.1.1.
Liver Chemistry Stopping and Follow-up 
Criteria......................................................................122
12.8.1.2.
Restarting Study Drug ..............................................122
12.8.1.3.
Decline in Renal Function.........................................123
12.8.1.4.
Proteinuria................................................................123
12.8.1.5.
Allergic reaction........................................................124
12.8.1.6.
Rash.........................................................................124
12.8.1.7.
Hypertriglyceridemia/Hypercholesterolemia..............125
12.8.1.8.
Creatine Phosphokinase (CPK) Elevation ................125


2015N263962_02
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10
12.9.
Appendix 9: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.....................126
12.9.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ............126
12.9.2.
Collection of Pregnancy Information ..........................................126
12.10. Appendix 10 – Country-specific Requirements .........................................128
12.11. Appendix 11: Protocol Changes................................................................129
12.11.1. Protocol Amendment 01 ............................................................129
12.11.2. Protocol changes for Amendment 02 (14-JUN-2018) from   
Amendment 01 (29-NOV-2017) .................................................145


2015N263962_02
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205543
11
1.
PROTOCOL SYNOPSIS FOR STUDY 205543
Rationale
Study 205543 is being conducted to compare a simplified two-drug regimen of 
dolutegravir (DTG) plus lamivudine (3TC) with a standard three-drug first-line regimen 
in human immunodeficiency virus type 1 (HIV-1) infected, antiretroviral therapy (ART)-
naïve adult subjects.  The study is designed to demonstrate the non-inferior antiviral 
activity of DTG plus 3TC once daily compared to DTG plus tenofovir disoproxil 
fumarate/emtricitabine (TDF/FTC) fixed dose combination (FDC) once daily at 48 
weeks.  This study will also characterise the long-term antiviral activity, tolerability and 
safety of DTG plus 3TC through Week 148.  
An identical sister study, 204861, will be conducted in parallel with Study 205543 in 
some countries.  The clinical development programme of DTG plus 3TC aims to develop 
a FDC tablet of these products. 
Objectives/Endpoints
Objectives
Endpoints
Primary
To demonstrate non-inferior antiviral activity 
of DTG + 3TC versus DTG + TDF/FTC at 48 
weeks in HIV-1-infected, ART-naïve subjects
Proportion of subjects with plasma HIV-1 
RNA <50 copies/mL (c/mL) at Week 48 
using the FDA Snapshot algorithm [Missing, 
Switch or Discontinuation = Failure, 
(MSD=F)] for the Intent-to-Treat exposed 
(ITT-E) population
Secondary
To demonstrate the antiviral activity of DTG 
+ 3TC versus DTG + TDF/FTC at 24, 96 and 
144 weeks
Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Weeks 24, 96 and 144 
using the FDA Snapshot algorithm (MSD=F) 
for the ITT-E population
To evaluate the antiviral activity, 
immunological effects, and incidence of 
disease progression (HIV-associated 
conditions, AIDS and death) of DTG + 3TC 
compared to DTG + TDF/FTC over time
Time to viral suppression (HIV-1 RNA <50 
c/mL);
Absolute values and changes from Baseline 
in CD4+ cell counts at Weeks 24, 48, 96 and 
144;
Incidence of disease progression (HIV-
associated conditions, AIDS and death).
To assess viral resistance in subjects 
meeting confirmed virologic withdrawal 
(CVW) criteria
Incidence of treatment-emergent genotypic 
and phenotypic resistance to DTG and 3TC 
or TDF/FTC in subjects meeting CVW 
criteria
To evaluate the safety and tolerability of 
DTG + 3TC compared to DTG + TDF/FTC 
over time
Incidence and severity of adverse events 
(AEs) and laboratory abnormalities;
Proportion of subjects who discontinue 
treatment due to AEs over 24, 48, 96 and 
144 weeks


2015N263962_02
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205543
12
Objectives
Endpoints
To evaluate renal biomarkers (in urine and 
blood) and bone biomarkers (in blood) in 
subjects treated with DTG + 3TC compared 
to DTG + TDF/FTC
Change from Baseline in renal and bone 
biomarkers at Weeks 24, 48, 96 and 144
To evaluate the effects of DTG + 3TC on 
fasting lipids compared to DTG + TDF/FTC 
over time
Change from Baseline in fasting lipids at 
Weeks 24, 48, 96, and 144;
The incidence of Grade 2 or greater 
laboratory abnormalities in fasting LDL 
cholesterol by Weeks 24, 48, 96, and 144;
To evaluate the effect of patient 
demographics and baseline characteristics 
(e.g. demographic factors, HIV-1 subtype, 
baseline CD4+ cell count) on response to 
DTG + 3TC compared to DTG + TDF/FTC 
over time
Proportion of subjects by patient 
subgroup(s) (e.g., by age, gender, Baseline 
CD4+ cell count) with plasma HIV-1 RNA 
<50 c/mL at Weeks 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 and 144 by patient 
subgroups
To assess change in health-related quality-
of-life for subjects treated with DTG plus 3TC 
compared to DTG + TDF/FTC
Change from Baseline in health related 
quality of life using EQ-5D-5L at Weeks 4, 
24, 48, 96, and 144 (or Withdrawal from the 
study)
Overall Design
This study is a Phase III, randomised, double-blind, active-controlled, multicentre, 
parallel-group, non-inferiority study.  The study will enrol approximately 700 HIV-1 
infected, ART-naïve subjects with a Screening HIV-1 RNA of 1000 to 500,000 
copies/mL (c/mL).  Subjects will be randomised 1:1 to receive a two-drug regimen of 
DTG plus 3TC once daily (approximately 350 subjects) or DTG plus the FDC tablet of 
TDF/FTC once daily (approximately 350 subjects) until Week 148.  Subjects will be 
stratified by screening HIV-1 RNA (100,000 c/mL or >100,000 c/mL) and Screening 
CD4+ cell count (or >200 cells/mm3).  
The study initially will enrol approximately 100 subjects with a Screening HIV-1 RNA of 
1000 to 100,000 c/mL.  Accumulated data from other clinical trials investigating the 
DTG plus 3TC dual regimen will undergo independent review.  If the independent review 
is supportive of evaluating the dual regimen’s efficacy in subjects with a Screening viral 
load of up to 500,000 c/mL, recruitment will be opened to subjects with a Screening 
HIV-1 RNA of 1000 to ≤500,000 c/mL.  If the review does not support enrolment of 
such subjects, the Screening viral load will remain capped at 100,000 c/mL. This
independent review of accumulated data on the DTG plus 3TC dual regimen was 
supportive, enabling an increase in the Screening viral load cap to ≤500,000 c/mL for 
subjects screened on/after 5 November 2016.


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Treatment Arms and Duration
The study will comprise a 28-day Screening Phase (which may be extended to 35 days to 
allow receipt of all Screening assessment results), a Double-blind Randomised Phase 
(Day 1 to Week 96), and an Open-label Randomised Phase (Week 96 to Week 148).  If 
required by local regulations, subjects randomised to receive DTG plus 3TC once daily 
who successfully complete 148 weeks of treatment will continue to have access to DTG 
plus 3TC once daily (Continuation Phase) until (i) DTG and 3TC are both locally 
approved for use as part of a dual regimen, and the single entities of DTG and 3TC are 
available to patients (e.g. through public health services), or (ii) the DTG/3TC FDC 
tablet, if required by local regulations, is available, or (iii) the subject no longer derives 
clinical benefit, or (iv) the subject meets a protocol-defined reason for discontinuation, or 
(v) development of the DTG plus 3TC dual regimen is terminated.  Subjects randomised 
to the DTG plus TDF/FTC FDC arm will receive DTG plus TDF/FTC FDC through their 
Week 148 visit only, after which subjects will complete the study and will need to have 
alternate arrangements in place to access antiretroviral medication.  No dose reductions, 
modifications in dosage, or changes in the frequency of dosing will be allowed in this 
study.
At Weeks 28, 52, 100, and 148, a confirmatory viral load measurement will be performed 
for subjects presenting with HIV-1 RNA 50 c/mL at the Week 24, 48, 96 and 144 visits, 
respectively.  The primary and secondary efficacy endpoints correspond to viral load 
measurements collected within a 6 week window around the visits of interest (including 
data from the visits at Weeks 28, 52, 100, and 148), as per the FDA’s Snapshot 
algorithm.  For this reason, the primary and secondary analyses are denoted as occurring 
at Weeks 24, 48, 96 and 144 with the understanding that respective data from the Week 
28, 52, 100 and 148 visits may be included.
An Independent Data Monitoring Committee (IDMC) will be instituted to ensure external 
objective medical and/or statistical review of efficacy and safety in order to protect the 
ethical interests and well-being of subjects and to protect the scientific validity of this 
study and sister study 204861.
Type and Number of Subjects
The study will be conducted in approximately 700 HIV-1 infected, ART-naïve adults 
with a Screening HIV RNA of 1000 to ≤500,000 c/mL.  Approximately 950 subjects will
be screened such that approximately 700 subjects are enrolled into the study.
Analysis
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 responders at Week 48 will be a Cochran-Mantel-Haenszel test 
stratified by Baseline plasma HIV-1 RNA (vs. >100,000 c/mL) and Baseline CD4+ cell 
count (vs. >200 cells/mm3).  
Assuming a true 87% response rate in the DTG plus 3TC arm and an 89% response rate 
in the DTG plus TDF/FTC FDC arm at Week 48, a non-inferiority margin of -10%, and a 


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2.5% one-sided significance level, this study requires 347 subjects per treatment arm.  
This would provide 90% power to show non-inferiority for the proportion of subjects 
with plasma HIV-1 RNA <50 c/mL at 48 weeks. If we observed an 89% response rate 
for the DTG plus TDF/FTC FDC arm, non-inferiority would be declared if the observed 
treatment difference was better than -4.8 percentage points.
2.
INTRODUCTION
2.1.
Study Rationale
Current HIV treatment guidelines recommend first-line antiretroviral (ARV) regimens 
consisting of two nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) 
as a “backbone” combined with a third agent from the non-nucleoside reverse 
transcriptase inhibitor (NNRTI), protease inhibitor (ritonavir-boosted) (PI/RTV), or 
integrase strand transfer inhibitor (INSTI) classes [BHIVA, 2015; DHHS, 2016; EACS, 
2015; IAS-USA, 2014].  While these regimens are highly efficacious and generally well 
tolerated, there is growing concern about long-term toxicities, and great interest from 
patients and clinicians in unique regimens that might avoid such toxicities, and to provide 
effective long-term ART with the most streamlined regimens possible.
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 immuno-deficiency 
syndrome (AIDS)-defining events such as cardiovascular disease, liver disease and 
cancer. These non-AIDS-defining events are now the leading causes of morbidity and 
mortality among treated HIV-infected persons. The aetiologies of these non-AIDS-
defining events are multi-factorial and 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. 
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].


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DTG is a potent dual cation binding INSTI, exhibiting rapid reduction in viral load, best 
in class efficacy, and a high barrier to resistance.  In addition, due to its mechanism of 
metabolism, DTG lacks many of the frequent drug interactions associated with other 
medications commonly taken by HIV-positive patients.  To date, the efficacy, 
pharmacokinetics (PK), safety and drug interaction potential of DTG has been evaluated 
in an extensive program of Phase I to IIIB clinical trials [TIVICAY™ Package Insert, 
2017; GlaxoSmithKline Document Number RM2007/00683/11, GlaxoSmithKline 
Document Number 2017N352880_00, GlaxoSmithKline Document Number
2017N352880_01].
3TC is a potent cytidine nucleoside analogue without major side effects and has a well 
proven safety profile.  Available since 1995 as a single agent (EPIVIR™) [EPIVIR
Package Insert, 2017], it is also available as part of two backbone FDC products 
(zidovudine (ZDV)/3TC, COMBIVIR™ and abacavir (ABC)/3TC, 
EPZICOM™/KIVEXA™).  3TC monotherapy is known to select for resistance due to a 
single point mutation that reduces antiviral activity.  However, it is predicted that 3TC, 
when combined with DTG with its high barrier to resistance and ability to confer a very 
rapid decline in HIV-1 RNA, may be less likely to select for resistance consistent with 
clinical studies combining DTG, 3TC and ABC [GlaxoSmithKline Document Number 
RM2007/00683/11, GlaxoSmithKline Document Number 2017N352880_00, 
GlaxoSmithKline Document Number 2017N352880_01; Walmsley, 2013].
DTG plus 3TC may provide a novel, well-tolerated two-drug first-line regimen for HIV-
infected treatment- naïve patients, limiting the risk of many common adverse reactions 
associated with other ARV drugs.  This regimen could be particularly valuable for 
patients with co-morbid conditions such as bone or cardiovascular disease, and in 
resource-limited settings due to DTG’s known efficacy advantages and both drugs’ 
tolerability and long-term safety profiles, as well as ease of use (once daily dosing, no 
food dosing effects/requirements, and limited potential for drug-drug interactions).  
Study 205543 compares a simplified two-drug regimen of DTG plus 3TC once daily with 
one of the preferred first line three-drug regimens consisting of DTG plus two NRTIs 
(TDF/FTC FDC) once daily in HIV-1-infected, ART-naïve subjects [BHIVA, 2015; 
DHHS, 2016; EACS, 2015; IAS-USA, 2014].  Initially, it will enrol subjects with a 
Screening HIV 1 RNA of 1000 to 100,000 c/mL, but recruitment may later be opened to 
subjects with a Screening HIV-1 RNA of 1000 to ≤500,000 c/mL.  The selection of 
500,000 c/mL as the Screening viral load cap is reasonable based on the response rates 
previously observed during short-term monotherapy with DTG and for 3TC.  In the DTG 
Phase IIa dose-ranging study, subjects receiving monotherapy of DTG 50 mg once daily 
had a 2.5 log10 decline in HIV-1 RNA after 10 days of treatment [Min, 2011].  In early 
studies of HIV treatments, in which subjects were given 3TC monotherapy, a 1.5 log10 
decline in HIV-1 RNA was observed over 2 weeks [Eron, 1995; Kuritzkes, 1996].  Thus, 
based on these levels of response, a 4 log10 decline in HIV-1 RNA could perhaps be 
achieved due to the combined activity of the two components. Starting with a viral load 
of 500,000 c/mL (5.7 log10 c/mL), a 4 log10 decline would result in HIV-1 RNA levels 
approximately at or less than 50 c/mL (1.7 log10 c/mL). 


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An identical sister study, 204861, will be conducted in parallel with Study 205543 in 
some countries.  The overall objective of the clinical development program of DTG plus 
3TC is to develop a FDC tablet.  
2.2.
Brief Background
A number of clinical studies have been published to date that provide supportive clinical 
data on the efficacy as well as favourable safety of two-drug first-line treatment regimens 
when they include a highly-effective ARV, such as a boosted PI or an INSTI.
One of the potential risks of a two-drug regimen, such as DTG plus 3TC, is the increase 
in virologic failure associated with the emergence of resistance.  DTG, with its higher 
barrier to resistance, may reduce treatment-emergent resistance in patients taking a two-
drug regimen.  The overall efficacy data from the pivotal Phase III studies of DTG in 
ART-naïve subjects are extensive, with no resistance mutations being identified through 
144 weeks of treatment (SINGLE, ING114467) [Walmsley, 2015; GlaxoSmithKline 
Document Number RM2007/00683/11, GlaxoSmithKline Document Number
2017N352880_00, GlaxoSmithKline Document Number 2017N352880_01].  The 
absence of treatment-emergent mutations to DTG or background agents in ART-naïve 
individuals, rapid virologic response demonstrated for DTG-based regimens, and the in 
vitro potency and well-tolerated safety profile of both DTG and 3TC all provide a strong 
rationale for the development of a DTG/3TC single tablet regimen (STR) as a treatment 
option for patients.
Three randomised clinical trials have shown comparable results of PI/RTV-based dual 
therapies among treatment-naïve patients:  

The AIDS Clinical Trials Group Study A5142 found that the virological efficacy 
of an NRTI-sparing regimen of efavirenz (EFV) plus lopinavir/ritonavir 
(LPV/RTV) was similar to that of the EFV plus two NRTIs but was more likely to 
be associated with drug resistance [Riddler, 2008].  

In the PROGRESS study, patients were randomly assigned to an NRTI-sparing 
regimen of LPV/RTV plus raltegravir (RAL) or a standard triple-therapy regimen 
consisting of LPV/RTV plus TDF/FTC FDC [Reynes, 2011].  At 48 weeks, 
83.2% of participants in the LPV/RTV plus RAL group and 84.6% of those in the 
LPV/RTV plus TDF/FTC group achieved plasma viral loads of <50 c/mL, 
although this study did not enrol patients with advanced HIV disease.  The mean 
baseline HIV-1 RNA was low (~18,000 c/mL).  

The GARDEL (Global AntiRetroviral Design Encompassing Lopinavir/r and 
Lamivudine vs LPV/r based standard therapy) study randomly assigned 426 
treatment-naïve patients with HIV to receive open-label LPV/RTV (400 mg/100 
mg) twice daily plus two NRTIs (triple therapy) or an experimental dual therapy 
regimen of LPV/RTV plus 3TC (150 mg) twice daily [Cahn, 2014].  After 48 
weeks of treatment, the virological response rates were 88.3% in the dual-therapy 
group and 83.7% in the triple-therapy group, meeting the study’s primary non-
inferiority endpoint.  All enrolled subjects who maintained viral suppression at 
Week 48 were invited to participate in an extension phase up to Week 96; non-


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inferiority was again demonstrated with response rates at Week 96 of 90.3% (dual 
therapy) and 84.4% (triple-therapy) [Cahn, 2015].
Limited data are also available from two pilot studies to evaluate the dual regimen of 
DTG plus 3TC:

An investigator-initiated 48-week pilot study, the PADDLE trial (NCT02211482), 
has been conducted in 20 HIV treatment-naïve subjects with no genotypic resistance 
to 3TC and a viral load of ≤100,000 c/mL at Screening and has provided notable early 
data on the efficacy of a once-daily DTG plus 3TC two-drug regimen.  Subjects were 
enrolled in two separate groups of 10, allowing close evaluation of response while 
employing a set of stopping rules with intensive follow-up in each cohort.  By Week 
8, all 20 subjects, including 4 subjects with a Baseline HIV-1 RNA of >100,000 
c/mL, had reached a viral load of <50 c/mL and all maintained virologic suppression 
through Week 24 [Figueroa, 2015]. At Week 48, 18/20 (90%) of subjects achieved 
the primary endpoint of plasma HIV-1 RNA <50 copies/mL using the FDA snapshot 
algorithm for the intention to treat – exposed (ITT-E) population [Cahn, 2017].

The ongoing ACTG A5353 trial is a Phase II, single-arm pilot study of once-daily 
DTG plus 3TC in treatment-naïve HIV-1-infected participants with a viral load of 
≥1000 to <500,000 c/mL.  Virologic efficacy (plasma HIV-1 RNA <50 c/mL using 
the FDA Snapshot) at Week 24 was 108/120 (90%) with no significant difference 
between the low (≤100,000 c/mL) and high (>100,000 c/mL) viral load strata: 90% 
and 89%, respectively [Taiwo, 2017].
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To demonstrate non-inferior antiviral activity 
of DTG + 3TC versus DTG + TDF/FTC at 48 
weeks in HIV-1-infected, ART-naïve subjects
Proportion of subjects with plasma HIV-1 
RNA <50 copies/mL (c/mL) at Week 48 
using the FDA Snapshot algorithm [Missing, 
Switch or Discontinuation = Failure 
(MSD=F)] for the intent-to-treat exposed 
(ITT-E) population
Secondary
To demonstrate the antiviral activity of DTG 
+ 3TC versus DTG + TDF/FTC at 24, 96 and 
144 weeks
Proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Weeks 24, 96 and 144 
using the FDA Snapshot algorithm (MSD=F) 
for the ITT-E population
To evaluate the antiviral activity, 
immunological effects, and incidence of 
disease progression (HIV-associated 
conditions, AIDS and death) of DTG + 3TC 
compared to DTG + TDF/FTC over time
Time to viral suppression (HIV-1 RNA <50 
c/mL);
Absolute values and changes from Baseline 
in CD4+ cell counts at Weeks 24, 48, 96 and 
144;
Incidence of disease progression (HIV-
associated conditions, AIDS and death).
To assess viral resistance in subjects 
Incidence of treatment-emergent genotypic 


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Objectives
Endpoints
meeting confirmed virologic withdrawal 
(CVW) criteria
and phenotypic resistance to DTG and 3TC 
or TDF/FTC in subjects meeting CVW 
criteria
To evaluate the safety and tolerability of 
DTG + 3TC compared to DTG + TDF/FTC 
over time
Incidence and severity of adverse events 
(AEs) and laboratory abnormalities;
Proportion of subjects who discontinue 
treatment due to AEs over 24, 48, 96 and 
144 weeks
To evaluate renal biomarkers (in urine and 
blood) and bone biomarkers (in blood) in 
subjects treated with DTG + 3TC compared 
to DTG + TDF/FTC
Change from Baseline in renal and bone 
biomarkers at Weeks 24, 48, 96 and 144
To evaluate the effects of DTG + 3TC on 
fasting lipids compared to DTG + TDF/FTC 
over time
Change from Baseline in fasting lipids at 
Weeks 24, 48, 96, and 144;
The incidence of Grade 2 or greater 
laboratory abnormalities in fasting LDL 
cholesterol by Weeks 24, 48, 96, and 144;
To evaluate the effect of patient 
demographics and baseline characteristics 
(e.g. demographic factors, HIV-1 subtype, 
baseline CD4+ cell count) on response to 
DTG + 3TC compared to DTG + TDF/FTC 
over time
Proportion of subjects by patient 
subgroup(s) (e.g., by age, gender, Baseline 
CD4+ cell count) with plasma HIV-1 RNA 
<50 c/mL at Weeks 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 and 144 by patient 
subgroups
To assess change in health-related quality-
of-life for subjects treated with DTG plus 3TC 
compared to DTG + TDF/FTC
Change from Baseline in health related 
quality of life using EQ-5D-5L at Weeks 4, 
24, 48, 96, and 144 (or Withdrawal from the 
study)
Exploratory

To evaluate inflammation biomarkers in 
subjects treated with DTG+ 3TC compared 
to DTG + TDF/FTC
Change from Baseline in inflammation 
biomarkers at Weeks 48, 96 and 144
To evaluate telomere length in subjects 
treated with DTG + 3TC compared to DTG + 
TDF/FTC
Change from Baseline in telomere length at 
Weeks 96 and 144
4.
STUDY DESIGN
4.1.
Overall Design
This study is a Phase III, randomised, double-blind, active-controlled, multicentre, 
parallel-group, non-inferiority study.  The study will be conducted in approximately 700 
HIV-1 infected, ART-naïve subjects with a Screening HIV-1 RNA of 1000 to ≤500,000 


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copies/mL (c/mL).  Subjects will be randomised 1:1 to receive a two-drug regimen of 
DTG plus 3TC once daily (approximately 350 subjects) or DTG plus the FDC tablet of 
TDF/FTC once daily (approximately 350 subjects).  Subjects will be stratified by 
screening HIV-1 RNA (100,000 c/mL or >100,000 c/mL) and Screening CD4+ cell 
count (or >200 cells/mm3).  
The study initially will enrol approximately 100 subjects with a Screening HIV-1 RNA of 
1000 to 100,000 c/mL.  Accumulated data from other clinical trials investigating the 
DTG plus 3TC dual regimen will undergo independent review.  If the independent review 
is supportive of evaluating the dual regimen’s efficacy in subjects with a Screening viral 
load of up to 500,000 c/mL, recruitment will be opened to subjects with a Screening 
HIV-1 RNA of 1000 to ≤500,000 c/mL. If the review does not support enrolment of such 
subjects, the Screening viral load will remain capped at 100,000 c/mL.  This
independent review of accumulated data on the DTG plus 3TC dual regimen was 
supportive, enabling an increase in the Screening viral load cap to ≤500,000 c/mL for 
subjects screened on/after 5 November 2016.
The study will comprise:

a 28-day Screening Phase (which may be extended to 35 days to allow receipt of 
all Screening assessment results), 

a Double-blind Randomised Phase (Day 1 to Week 96), 

an Open-label Randomised Phase (Week 96 to Week 148), and 

a Continuation Phase (Figure 1).  
All subjects who successfully complete 96 weeks of randomised, blinded treatment will 
continue to receive their randomised treatment (DTG plus 3TC or DTG plus TDF/FTC 
FDC) in an open-label manner as part of the study through Week 148.  Data from these 
subjects will provide long-term, comparative, descriptive information on durability of 
response, safety, and tolerability.
Subjects randomised to receive DTG plus 3TC who successfully complete 148 weeks of 
treatment may continue to have access to DTG plus 3TC in a Continuation Phase.
At Weeks 28, 52, 100, and 148, a confirmatory viral load measurement will be performed 
for subjects presenting with HIV-1 RNA 50 c/mL at the Week 24, 48, 96 and 144 visits, 
respectively.  The primary and secondary efficacy endpoints correspond to viral load 
measurements collected within a 6 week window around the visits of interest (including 
data from the visits at Weeks 28, 52, 100, and 148), as per the FDA’s Snapshot 
algorithm.  For this reason, the primary and secondary analyses are denoted as occurring 
at Weeks 24, 48, 96 and 144 with the understanding that respective data from the Week 
28, 52, 100 and 148 visits may be included.
Assuming a true response rate of 87% for the DTG plus 3TC arm and an 89% response
rate for the DTG plus TDF/FTC arm at Week 48, the study requires 347 subjects per arm 
to have 90% power with a 10% non-inferiority margin and a 2.5% one-sided alpha level.


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Figure 1
205543 Study Schematic
4.2.
Treatment Arms and Duration
The study will be conducted in approximately 700 HIV-1 infected, ART-naïve 
individuals.  Eligible subjects will be randomised 1:1 to receive DTG plus 3TC once 
daily or DTG plus TDF/FTC FDC once daily. 
No dose reductions, modifications in dosage, or changes in the frequency of dosing will 
be allowed in this study, except those allowed and defined in the protocol.
The study will include a 28-day Screening Phase (which may be extended to 35 days to 
allow receipt of all Screening assessment results), a Double-blind Randomised Phase 
(Day 1 to Week 96), an Open-label Randomised Phase (Week 96 to Week 148), and a 
Continuation Phase (post-Week 148).  
If required by local regulations, subjects randomised to receive DTG plus 3TC once daily 
who successfully complete 148 weeks of treatment will continue to have access to DTG 
plus 3TC once daily in a Continuation Phase until

DTG and 3TC are both locally approved for use as part of a dual regimen, and the 
single entities of DTG and 3TC are available to patients (e.g. through public 
health services), or

the DTG/3TC 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.  
Subjects randomised to the DTG plus TDF/FTC FDC arm will receive DTG + TDF/FTC 
FDC through their Week 148 visit only, after which subjects will complete the study and 
will need to have alternate arrangements in place to access antiretroviral medication.
Subjects with ongoing AEs or laboratory abnormalities considered to be AEs will attend 
a Follow-up visit approximately four weeks after their last dose of study treatment.  


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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.
An IDMC will be instituted to ensure external objective medical and/or statistical review 
of efficacy and safety in order to protect the ethical interests and well-being of subjects 
and to protect the scientific validity of this study and sister study 204861.  An ad-hoc 
review of data by the IDMC will be triggered whenever the number of CVWs exceeds 
thresholds pre-specified in the IDMC charter.  Further, an interim futility analysis will be 
performed for the IDMC to evaluate the efficacy and safety of DTG plus 3TC when 
approximately 50% of subjects have completed their visit at Week 24; the sponsor will 
remain blinded to this analysis.  Full details of the methods, timing, decision criteria and 
operating characteristics will be pre-specified in the IDMC Charter.
All communications received from the IDMC regarding the status of the study will be 
shared with investigators in a timely manner.
4.3.
Type and Number of Subjects
Assuming a 26% screen failure rate, approximately 950 HIV-1-infected adult subjects 
will be screened to achieve approximately 700 randomised subjects to include 
approximately 350 subjects per treatment group.  
The study initially will enrol approximately 100 subjects with a Screening HIV-1 RNA of 
1000 to 100,000 c/mL.  Accumulated data from other clinical trials investigating the 
DTG plus 3TC dual regimen will undergo independent review.  If the independent review 
is supportive of evaluating the dual regimen’s efficacy in subjects with a Screening viral 
load of up to 500,000 c/mL, recruitment will be opened to subjects with a Screening 
HIV-1 RNA of 1000 to ≤500,000 c/mL.  If the review does not support enrolment of 
such subjects, the Screening viral load will remain capped at 100,000 c/mL.  This
independent review of accumulated data on the DTG plus 3TC dual regimen was 
supportive, enabling an increase in the Screening viral load cap to ≤500,000 c/mL for 
subjects screened on/after 5 November 2016.
A goal of this study is to target populations who are underrepresented in clinical studies, 
including approximately 15% women and approximately 15% subjects aged 50 years or 
older.
4.4.
Design Justification
The use of randomised, active-controlled, double-blind, multicentre, parallel group, fully-
powered non-inferiority studies as pivotal proof of safety and efficacy is a well 
established experimental design for establishing the non-inferiority of an investigational 
agent or regimen compared to an active comparator and is generally accepted at 
regulatory authorities as rigorous proof of antiviral activity [CDER, 2015].  The primary 
endpoint, proportion of subjects at Week 48 with plasma HIV-1 RNA below the assay 
limit of detection (e.g. <50 c/mL), is also a very well-established surrogate endpoint for 
prognosis of HIV-1 infection and disease progression [CDER, 2015].  


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A number of clinical studies to date have provided supportive clinical data on the efficacy 
as well as favourable safety of two-drug first-line treatment regimens that include a 
boosted PI or an INSTI (see Section 2.2).
The comparator regimen, DTG plus TDF/FTC, has been established as one of the 
preferred first-line treatment regimens for treatment-naïve HIV infected subjects and is 
recognised as such, as evidenced by its wide acceptance in treatment guidelines [BHIVA, 
2015; DHHS, 2016; EACS, 2015; IAS-USA, 2014].  
Considering these points above, the proposed study design should allow a thorough 
assessment of the DTG plus 3TC regimen. 
4.5.
Dose Justification
The efficacy, PK, safety, and drug interaction potential of DTG, 3TC, TDF and FTC as 
individual agents and of TDF/FTC FDC have been evaluated in extensive clinical 
development programmes.  DTG, 3TC and TDF/FTC FDC are approved and marketed as 
TIVICAY 50 mg once daily, EPIVIR 300 mg once daily, and Truvada 300 mg/200 mg 
once daily, respectively, the doses used in the current study.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with DTG 
and 3TC can be found in the most recent version of the DTG Investigator’s Brochure (IB)
and any IB supplements [GlaxoSmithKline Document Number RM2007/00683/11, 
GlaxoSmithKline Document Number 2017N352880_00, GlaxoSmithKline Document 
Number 2017N352880_01] and DTG and 3TC product labels.  The following section 
outlines the risk assessment and mitigation strategy primarily for DTG in this protocol.  
For 3TC and TDF/FTC, the approved country product labels should be referenced.  The 
comparator regimen, DTG plus TDF/FTC, has been established as a preferred first line 
treatment regimen for treatment-naïve HIV infected subjects and is recognised as such, as 
evidenced by it wide acceptance in treatment guidelines [BHIVA, 2015; DHHS, 2016; 
EACS, 2015; IAS-USA, 2014].  
.


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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
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG, 3TC, TDF/ FTC]
Refer to DTG IB and country product labels for additional information
DTG: Hypersensitivity 
reaction (HSR) and rash
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 (Section 5.2).
Specific/detailed toxicity management guidance is provided for HSR 
(Section 12.8.1.5) and rash (Section 12.8.1.6).
The subject informed consent form includes information on this risk 
and the actions subjects should take in the event of 1) an HSR or 
associated signs and symptoms, or 2) developing any type of rash 
or skin abnormality.  For Grade 3/4 rash, except where the aetiology 
is clear and not associated with study drug or where there is a 
definitive diagnosis clearly attributable to a concomitant medication 
(and not to study drug) or to a concomitant infection, subjects must 
permanently discontinue study drug and be withdrawn from the 
study.
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
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.
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 
Subjects meeting either of the following criteria during the screening 
period are excluded from participating (Section 5.2).

Alanine aminotransferase (ALT) 5 times the upper limit of 
normal (ULN) or ALT 3x ULN and bilirubin 1.5x ULN (with 
>35% direct bilirubin);

Subjects positive for Hepatitis B surface antigen (HBsAg); 
subjects negative for HBsAg and negative for Hepatitis B 
surface antibody (anti-HBs or HBsAb) but positive for Hepatitis 
B core antibody (anti-HBc) and positive for HBV DNA;

Subjects with an anticipated need for any HCV therapy during 
the first 48 weeks of the study and for HCV therapy based on 
interferon or any drugs that have a potential for adverse 


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG, 3TC, TDF/ FTC]
Refer to DTG IB and country product labels for additional information
HBV variants associated with resistance to 3TC has been reported in HIV-1-
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.
drug:drug interactions with study treatment throughout the 
entire study period.
Specific/detailed liver stopping criteria and toxicity management 
guidance is provided for suspected DILI or other clinically significant 
liver chemistry elevations (Appendix 3, Section 12.3).  
DTG: Psychiatric disorders
Psychiatric disorders including suicidal ideation and behaviours are common 
in HIV-infected patients. The psychiatric profile for DTG (including suicidality, 
depression, bipolar and hypomania, anxiety and abnormal dreams) was 
similar to RAL- or favourable compared with EFV-based regimens. 
The reporting rate for insomnia was statistically higher for blinded DTG plus 
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 (Section 5.2).
Because of the elevated risk in the HIV- infected population, 
treatment emergent assessment of suicidality will be monitored 
during this study.  Investigators are advised to consider mental 
health consultation or referral for subjects who experience signs of 
suicidal ideation or behaviour (Section 7.4.6).
The subject informed consent form includes information on this risk 
of depression and suicidal ideation and behaviours.


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG, 3TC, TDF/ FTC]
Refer to DTG IB and country product labels for additional information
DTG and 3TC: Increased 
rates of virologic failure/ 
observed resistance
Lower responses in subjects with higher baseline viral loads have been 
observed in previous treatment-naïve studies, including studies with 2-drug 
arms such as the MODERN study [Stellbrink, 2014].
DTG, with its higher barrier to resistance, may reduce treatment-emergent 
resistance in patients taking a two-drug regimen.  Week 96 and Week 144 
analyses for the Phase III/IIIb clinical studies demonstrate robust maintenance 
of viral suppression with no finding of HIV-1 resistance in treatment-naïve 
subjects.
3TC: M184V is a common single mutation that leads to full resistance to 3TC.
Subjects with evidence of primary viral resistance based on the 
presence of any major resistance-associated mutation (including 
M184V) are excluded from this study (Section 5.2). 
The study initially will enrol subjects with a Screening HIV 1 RNA of 
1000 to 100,000 c/mL.  Following an independent review of clinical 
data on the DTG plus 3TC treatment regimen, the Screening viral 
load cap may be increased to 500,000 c/mL.  The viral load cap will 
maximise the opportunity for subjects randomised to the DTG plus 
3TC arm to rapidly achieve an undetectable viral load (HIV-1 RNA 
<50 c/mL), which may help minimise the potential for emergent drug 
resistance that could result in functional DTG monotherapy (i.e. if the 
M184V mutation arises, conferring 3TC resistance).  
Subjects will have HIV-1 RNA measured at each study visit. An 
IDMC will be instituted to ensure external objective medical and/or 
statistical review of efficacy and safety (Section 10.8).  An ad-hoc 
review of data by the IDMC will be triggered whenever the number 
of CVWs exceeds thresholds pre-specified in the IDMC charter 
(Section 9.3.4).
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 2 (OCT2), resulting in 
potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide or pilsicainide is 
prohibited in the study (Section 6.9.2).
DTG, 3TC, and TDF/FTC: 
Renal function
Mild elevations of creatinine have been observed with DTG which are related 
to a likely benign effect on creatinine secretion with blockade of OCT2.  DTG 
has been shown to have no significant effect on glomerular filtration rate 
(GFR) or effective renal plasma flow.
3TC, TDF and FTC are eliminated by renal excretion and exposures increase 
in patients with renal dysfunction.  Renal failure, renal impairment, elevated 
creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi 
syndrome) have been reported with the use of TDF in clinical practice.
Due to requirements for dose reduction of 3TC or dose interval 
adjustments of TDF/FTC in patients with renal dysfunction, subjects 
with a creatinine clearance (CrCL) <50 mL/min/1.73 m2 are 
excluded (Section 5.2).
CrCl 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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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG, 3TC, TDF/ FTC]
Refer to DTG IB and country product labels for additional information
Specific/detailed toxicity management guidance is provided for 
subjects who develop a decline in renal function/proximal renal 
tubule dysfunction (PRTD) (Section 12.8.1.3) or proteinuria (Section 
12.8.1.4). 
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 
12.8.1.8).
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 9, Section 12.9.1) 
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
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) 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
DTG is 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.  DTG in combination with other ARVs has demonstrated durable 
virologic and immunologic response.  In addition, the high barrier to resistance observed 
with DTG should help protect against the development of resistance to both components 
of the DTG plus 3TC regimen.  
Two-drug regimens have been tested in a number of clinical trials (see Section 2.2).  
Results from these trials pave the way for the exploration of other dual-therapy strategies, 
such as DTG plus 3TC, a regimen of two well-characterised antiretrovirals that may 
provide a novel, well-tolerated two-drug regimen for HIV-infected patients, limiting the 
risk of many common adverse reactions associated with other ARV drugs.  Dual therapy 
also has the potential benefit of decreasing the likelihood of drug-drug interactions and 
preserving future treatment options by limiting drug exposure.
Study participants may also benefit from the medical tests and screening procedures 
performed as part of the study.
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risks to subjects participating in this 
study, the potential risks identified in association with the DTG plus 3TC are justified by
the anticipated benefits that may be afforded to HIV-1 infected treatment-naïve adults 
starting this two-drug first-line regimen.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the ViiV Healthcare investigational product or other 
study treatment that may impact subject eligibility is provided in the DTG IB and the 
respective product labels. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardise the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects are allowed to re-screen for this study one time, except where exclusionary 
HIV-1 resistance was present; re-screening will require a new subject number.
With the exception of a disqualifying viral genotype, a single repeat test (re-test) per 
analyte or assessment is allowed during the screening period to determine eligibility.  
Laboratory results provided from the central laboratory services will be used to assess 
eligibility.
The following are study specific eligibility criteria unless stated otherwise. In addition to 
these criteria, Investigators must exercise clinical discretion regarding selection of 


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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 oral 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. HIV-1 infected adults 18 years of age (or older, if required by local regulations), at 
the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Screening plasma HIV-1 RNA of 1000 c/mL to 100,000 c/mL.  If an independent 
review of accumulated data from other clinical trials investigating the DTG plus 3TC 
dual regimen is supportive of the DTG plus 3TC treatment regimen, enrolment will 
be opened to subjects with Screening plasma HIV-1 RNA of 1000 c/mL to 500,000 
c/mL;
3. Antiretroviral-naïve (defined as 10 days of prior therapy with any antiretroviral 
agent following a diagnosis of HIV-1 infection).  Subjects who received HIV post-
exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP) in the past are 
allowed as long as the last PEP/PrEP dose was >1 year from HIV diagnosis or there is 
documented HIV seronegativity between the last prophylactic dose and the date of 
HIV diagnosis. 
SEX
4. 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 Screening and negative 
urine test at Baseline), not lactating, and at least one of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation


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Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea and ≥45 
years of age [in questionable cases a blood sample with simultaneous follicle 
stimulating hormone (FSH) and oestradiol levels consistent with menopause is 
confirmatory (refer to laboratory reference ranges for confirmatory levels)].  
Females on hormone replacement therapy (HRT) and whose menopausal status 
is in doubt will be required to use one of the highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, they 
must discontinue HRT to allow confirmation of post-menopausal status prior to 
study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 9, Section 12.9.1) from 30 days prior to 
the first dose of study medication and for at least 2 weeks after the last dose of study 
medication.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
All subjects participating in the study should also be counselled on safer sexual practices, 
including the use and benefit/risk of effective barrier methods (e.g. male condom), and on 
the risk of HIV transmission to an uninfected partner.
INFORMED CONSENT
5. Subject or the subject’s legal representative 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.
OTHER 
6. Subjects enrolled in France: A subject will be eligible for inclusion in this study 
only if either affiliated to or a beneficiary of a social security category.
5.2.
Exclusion Criteria
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;


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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 and historical or current CD4 cell counts less than 200 cells/mm3.
3. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh 
classification (Appendix 2, Section 12.2);
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 HBV infection based on the results of testing at Screening for HBV 
surface antigen (HBsAg), HBV core antibody (anti-HBc), HBV surface antibody 
(anti-HBs or HBsAb), 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.
6. Anticipated need for any HCV therapy during the first 48 weeks of the study and for 
HCV therapy based on interferon or 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 14 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; other localised malignancies require agreement between the 
investigator and the Study Medical Monitor for inclusion of the subject.
10. Subjects who in the investigator’s judgment, poses a significant suicidality risk.  
Recent history of suicidal behaviour and/or suicidal ideation may be considered as 
evidence of serious suicide 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
i.
radiation therapy,
ii. cytotoxic chemotherapeutic agents,
iii. any systemic immune suppressant;
13. Treatment with any agent, except recognised ART as allowed above (inclusion 
criterion 3.),  with documented activity against HIV-1 in vitro within 28 days of first 
dose of study treatment;
14. 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 study treatment.
15. Subjects enrolled in France (and other countries as required by local regulations 
or ethics committees/IRBs): the subject has participated in any study using an 
investigational drug during the previous 60 days or 5 half-lives, or twice the duration 
of the biological effect of the experimental drug or vaccine, whichever is longer, prior 
to screening for the study or the subject will participate simultaneously in another 
clinical study.
LABORATORY VALUES OR CLINICAL ASSESSMENTS AT SCREENING
16. Any evidence of pre-existing viral resistance based on the presence of any major 
resistance-associated mutation [IAS-USA, 2014] in the Screening result or, if known, 
in any historical resistance test result.  NOTE: retests of disqualifying Screening 
genotypes are not allowed.
17. Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during 
the Screening period to verify a result.
18. Any acute laboratory abnormality at Screening, which, in the opinion of the 
Investigator, would preclude the subject’s participation in the study of an 
investigational compound.
19. Alanine aminotransferase (ALT) 5 times the upper limit of normal (ULN) or ALT 
3xULN and bilirubin 1.5xULN (with >35% direct bilirubin).
20. Creatinine clearance of <50 mL/min/1.73 m2 via the Chronic Kidney Disease-
Epidemiology Collaboration (CKD-EPI) method.
5.3.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomised. 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 Serious Adverse Events (see Section 7.4.1.6).


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Subjects are allowed to re-screen for this study one time, except where exclusionary 
HIV-1 resistance was present; re-screening will require a new subject number.
5.4.
Withdrawal/Stopping Criteria
Subjects permanently discontinuing study treatments prior to Week 148 are considered to 
be withdrawn from the study treatments and also from the study.
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural 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.  Withdrawn subjects will not be replaced.  
Subjects are not obligated to state the reason for withdrawal.  However, the reasons for 
withdrawal, or failure to provide a reason, must be documented by the Investigator on the 
Completion/Withdrawal section of the electronic case report form (eCRF).  Every effort 
should be made by the Investigator to follow up subjects who withdraw from the study. 
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:

CVW criteria as specified in Section 5.4.1.3 are met;

Subject requires substitution or dose modification of DTG, 3TC, TDF or FTC; 

Liver toxicity where stopping criteria specified in Section 5.4.2 and Appendix 3, 
Section 12.3 are met and no compelling alternate cause is identified;

Renal toxicity criteria as specified in Appendix 8, Section 12.8.1.3 are met and no 
compelling alternate cause is identified;

Grade 4 clinical AE considered causally related to study drug (Appendix 8, 
Section 12.8.1); 

Allergic reaction or rash criteria as specified in Appendix 8 (Section 12.8.1.5 and 
Section 12.8.1.6, respectively) are met and no compelling alternate cause is 
identified;


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
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 (Section 7.1) for the Withdrawal visit – and if 
necessary the Follow Up visit – are to be performed.  
A Follow-up visit may occur approximately 4 weeks after the last dose of study treatment 
and is only required in subjects with ongoing clinical or laboratory AEs at the time of 
Withdrawal.  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.
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, 3 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 in Section 5.4.1.1
wherein the virologic withdrawal criteria revolve around the HIV-1 RNA cut-off of 
200 c/mL.
5.4.1.1.
Virologic Withdrawal Criteria
Suspected Virologic Withdrawal criteria

A single HIV-1 RNA value as defined by Virologic Non-response or Virologic 
Rebound (see below)


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Confirmed Virologic Withdrawal criteria

A second and consecutive HIV-1 RNA value meeting Virologic Non-response or 
Rebound 
Virologic withdrawal criteria must be confirmed for each criterion by a repeat and 
consecutive plasma HIV-1 RNA measurement between two and four weeks after the 
subject met a SVW criterion unless a delay is necessary to meet the requirements of 
confirmatory HIV-1 RNA testing as described in Section 5.4.1.2.  For the purposes of 
clinical management in this study, virologic withdrawal criteria are defined as any of the 
following:
Virologic Non-response

A decrease in plasma HIV-1 RNA of less than 1 log10 c/mL by Week 12, with 
subsequent confirmation, unless plasma HIV-1 RNA is <200 c/mL.

Confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24.
Virologic Rebound

Confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL after prior 
confirmed suppression to <200 c/mL.
Subjects who meet any CVW criterion must be discontinued from the study.
Cases of subjects meeting CVW criteria will trigger virologic resistance testing.  
Investigators should use their discretion as to the most appropriate clinical management 
of their subjects if more stringent local guidelines apply.
5.4.1.2.
Managing Subjects Meeting Suspected Virologic Withdrawal Criteria
Only plasma HIV-1 RNA values determined by the central laboratory will be used to 
assess virologic withdrawal criteria.  Upon notification that a subject’s HIV-1 RNA 
plasma level qualifies him/her as meeting an SVW criterion, the Investigator should 
query the subject regarding intercurrent illness, recent immunisation, or interruption of 
therapy as inadequate adherence is a common cause of elevated HIV-1 RNA 
measurements.
All cases that meet an SVW 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 a 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.


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
Confirmatory testing should be scheduled at least 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 Medical Monitor to discuss individual subjects, whenever 
necessary.
5.4.1.3.
Managing Subjects Meeting Confirmed Virologic Withdrawal Criteria
Once a subject has been confirmed as meeting a virologic withdrawal criterion, a ‘plasma 
for storage’ sample from the time of meeting SVW criteria and the Day 1 sample 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.  
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 withdrawn 
from the study, except in cases where subject samples have HIV-1 RNA <500 c/mL as 
noted below.  A subject who meets a CVW criterion must be discontinued from the 
study.  
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, additional plasma samples will be analysed in an attempt to obtain 
genotype/phenotype data on as many samples 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 samples collected 
from these subjects.
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 (Section 7.1).  These data will be recorded, as they comprise an essential 
evaluation that needs to be done before discharging any subject from the study.
5.4.1.4.
Managing subjects with HIV-1 RNA 50 c/mL at Weeks 24, 48, 96 and 
144
At Weeks 24, 48, 96 and 144 (key study endpoint visits) repeat HIV-1 RNA testing is 
required for any HIV-1 RNA 50 c/mL and must be performed at the Week 28, Week 52, 
Week 100 and Week 148 study visits respectively, so long as the guidelines provided 
above for scheduling confirmatory HIV-1 RNA assessment to avoid false-positive results 
have been followed.  


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NOTE: Subjects whose HIV-1 RNA is <50 c/mL at Weeks 24, 48 and 96 will not attend 
the Week 28, Week 52 and Week 100 study visits, respectively.
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 aetiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf


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Liver Chemistry Stopping and Increased Monitoring Algorithm
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 
Appendix 3, Section 12.3.
5.4.2.1.
Study Treatment Restart
If a subject meets liver chemistry stopping criteria do not restart the subject with study 
treatment unless:


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
ViiV Healthcare Safety and Labelling Committee (VSLC) approval is granted,

Ethics and/or Institutional Review Board (IRB) approval is obtained, if required, 
and

Separate consent for treatment restart is signed by the subject.
Refer to Appendix 4, Section 12.4 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 arm, completed the Open-label 
Randomised Phase including the Week 148 visit, and did not enter the 
Continuation Phase;

Randomly assigned to DTG plus 3TC, completed the Open-label Randomised 
Phase including the Week 148 visit, entered and completed the Continuation 
Phase (defined as remaining on study until DTG and 3TC are both locally 
approved for use as part of a dual regimen and the single entities of DTG and 3TC 
are available to patients (e.g. through public health services) or the DTG/3TC 
FDC tablet, if required by local regulations, is available or development of the 
DTG plus 3TC dual regimen is terminated). 
Subjects with ongoing AEs or laboratory abnormalities considered to be AEs will attend 
a Follow-up visit approximately four weeks after their last dose of study treatment.  The 
Follow-up visit is not required for successful completion of the study.
The end of the study is defined as the last subject’s last visit.
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.


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Study Treatment 
(Double-blind Randomised Phase, Day 1 to Week 96)
Product name:
Dolutegravir, DTG
Lamivudine, 3TC
Tenofovir disoproxil 
fumarate/emtricitabine 
fixed-dose combination, 
TDF/FTC FDC
Formulation 
description:
Commercial supply
or 
Clinical trial material, which 
is the same formulation as 
the commercial material 
with the exception of the 
film coat colour
Over-encapsulated 
commercial supply 
tablet to visually match 
over-encapsulated 
TDF/FTC FDC tablet
Over-encapsulated 
commercial supply tablet 
to visually match over-
encapsulated 3TC tablet
Dosage form:
Tablet
Capsule
Capsule
Unit dose 
strength(s)/Dosage 
level(s):
50 mg
300 mg
300 mg TDF/200 mg FTC
Route of 
Administration:
Oral
Oral
Oral
Dosing instructions:
Take one tablet once daily 
with or without food
Take one capsule once 
daily with or without 
food
Take one capsule once 
daily with or without food
Physical 
description:
Commercial supply: 
Yellow, round, film-coated, 
biconvex tablets debossed 
with “SV 572” on one side 
and “50” on the other side.  
The tablets are packaged 
into HDPE bottles with 
induction seals and child-
resistant closures, each 
containing 30 tablets.
Clinical trial supply: White, 
round, biconvex, film-
coated tablets debossed 
on one side with “SV 572” 
and on the other side with 
“50”.  The tablets are 
packaged into high density 
polyethylene (HDPE) 
bottles with induction seals 
and child-resistant 
closures. Each 45 ml bottle 
contains 30 tablets and a 
desiccant.
Swedish Orange, size 
AA elongated double-
blind hydroxypropyl 
methylcellulose 
(HPMC) capsules.  The 
capsules are packaged 
into HDPE bottles with 
induction seals and 
child- resistant 
closures.   Each 150 
mL bottle contains 
30 capsules and a 
desiccant.
Swedish Orange, size AA 
elongated double-blind 
HPMC capsules.  The 
capsules are packaged 
into HDPE bottles with 
induction seals and child-
resistant closures.   Each 
150 mL bottle contains 
30 capsules and a 
desiccant.


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Study Treatment 
(Open-label Randomised Phase, Week 96 to Week 148)
Product name:
Dolutegravir, DTG
Lamivudine, 3TC
Tenofovir disoproxil
fumarate/emtricitabine 
fixed-dose combination, 
TDF/FTC FDC
Formulation 
description:
Commercial supply
or
Clinical trial material, 
which is the same 
formulation as the 
commercial material with 
the exception of the film 
coat colour
Commercial supply
Commercial supply
Dosage form:
Tablet
Tablet
Tablet
Unit dose 
strength(s)/Dosage 
level(s):
50 mg
300 mg
300 mg TDF/200 mg FTC
Route of 
Administration:
Oral
Oral
Oral
Dosing 
instructions:
Take one tablet once 
daily with or without food
Take one tablet once 
daily with or without food
Take one tablet once daily 
with or without food
Physical 
description:
Commercial supply: 
Yellow, round, film-
coated, biconvex tablets 
debossed with “SV 572” 
on one side and “50” on 
the other side.  The 
tablets are packaged into 
HDPE bottles with 
induction seals and child-
resistant closures, each 
containing 30 tablets.
Clinical trial supply:
White, round, biconvex, 
film-coated tablets 
debossed on one side 
with “SV 572” and on the 
other side with “50”.  The 
tablets are packaged into 
HDPE bottles with 
induction seals and child-
resistant closures. Each 
45 ml bottle contains 
30 tablets and a 
desiccant.
Gray, diamond-shaped, 
film-coated tablets 
engraved with “GX EJ7” 
on one side and plain on 
the reverse side.  The 
tablets are packed into
HDPE bottles with child-
resistant closures each 
containing 30 tablets. 
Blue, capsule-shaped, 
film-coated tablet, 
debossed on one side with 
“GILEAD” and on the other 
side with “701”.  The 
tablets are packed in over-
labelled HDPE bottles with 
polypropylene child-
resistant closures each 
containing 30 tablets and 
a desiccant.


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Study Treatment 
(Continuation Phase)
Product name:
Dolutegravir, DTG
Lamivudine, 3TC
Formulation 
description:
Commercial supply
or 
Clinical trial material, which is the 
same formulation as the commercial 
material with the exception of the 
film coat colour
Commercial supply
Dosage form:
Tablet
Tablet
Unit dose 
strength(s)/Dosage 
level(s):
50 mg
300 mg
Route of 
Administration:
Oral
Oral
Dosing instructions:
Take one tablet once daily with or 
without food
Take one tablet once daily with or without 
food
Physical description:
Commercial supply: 
Yellow, round, film-coated, biconvex 
tablets debossed with “SV 572” on 
one side and “50” on the other side.  
The tablets are packaged into 
HDPE bottles with induction seals 
and child-resistant closures, each 
containing 30 tablets.
Clinical trial supply:
White, round, biconvex, film-coated 
tablets debossed on one side with 
“SV 572” and on the other side with 
“50”.  The tablets are packaged into 
HDPE bottles with induction seals 
and child-resistant closures. Each 
45 ml bottle contains 30 tablets and 
a desiccant.
Gray, diamond-shaped, film-coated 
tablets engraved with “GX EJ7” on one 
side and plain on the reverse side.  The 
tablets are packed into HDPE bottles with 
child-resistant closures each containing 
30 tablets. 
6.2.
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 randomisation schedule.  The central randomisation schedule will 
be generated by PPD using a validated SAS developed program.   
Randomisation 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 plus 3TC or DTG 
plus TDF/FTC FDC in accordance with the computer-generated randomisation schedule.   
Each subject will be assigned a unique identifier (designating the subject’s randomisation 


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code) and a unique treatment number, which matches the randomised treatment 
assignment. 
Subjects will maintain the assigned treatment group throughout both the Double-blind 
Randomised Phase (Day 1 to Week 96) and the Open-label Randomised Phase (Week 96 
to Week 148).
Subjects who are randomly assigned into the study and subsequently withdrawn may not 
be rescreened.  Once a randomisation number has been assigned it must not be re-
assigned.
6.3.
Blinding
Participants and investigators will remain blinded during the Double-blind Randomised 
Phase.  The sponsor will be unblinded at Week 24 in order to provide results from the 24-
week interim analysis to regulatory authorities but no external dissemination of results 
will occur until at least all the patients are through the primary time point, i.e. Week 48.
Subjects will receive open-label DTG plus double-blinded 3TC or open-label DTG plus 
double-blinded TDF/FTC FDC therapy during the Double-blind Randomised Phase (i.e. 
through their Week 96 study visit).  Study treatment during the Open-label Randomised 
Phase after Week 96 up to Week 148 will be unblinded.
6.3.1.
Emergency Unblinding

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate ViiV Healthcare/GSK/PPD study personnel to discuss 
options before unblinding the subject’s treatment assignment. 

If ViiV Healthcare/GSK/PPD personnel are not contacted before the unblinding, the 
investigator must notify ViiV Healthcare/GSK/PPD as soon as possible after 
unblinding, but without revealing the treatment assignment of the unblinded subject, 
unless that information is important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the case report 
form (CRF). 
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician.  The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 


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report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or ViiV Healthcare/GSK policy.
6.3.2.
Scheduled Unblinding
Investigators will unblind all subjects to study treatment as they complete the Week 96 
visit (see Section 7.1) prior to subjects entering the Open-label Randomised Phase (Week 
96 to Week 148).
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorised 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 authorised site staff.  

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

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 investigator, where this is required by local laws, or is available 
upon request from ViiV Healthcare /GSK.
6.6.
Compliance with Study Treatment Administration
Study treatment accountability will be evaluated using pill counts of unused study 
treatments (DTG plus 3TC or DTG plus TDF/FTC FDC).  This assessment will be 
conducted each time the subject receives a new (refill) supply of study treatments through 
the Withdrawal visit or study completion.  These data will be recorded in the subject’s 
CRF but will not be summarised for analysis purposes.


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6.7.
Treatment of Study Treatment Overdose
For this double-blind study, any tablet intake exceeding the randomised daily number of 
tablets for study treatment will be considered an overdose (see [TIVICAY Product 
Information, 2017]; [EPIVIR Product Information, 2017]; [Truvada Product Information, 
2017]).  The Investigator should use clinical judgment in treating overdose, as ViiV 
Healthcare/GSK is unable to recommend specific treatment.
For the purposes of this study, an overdose is not an AE (see Section 12.7.1) unless it is 
accompanied by a clinical manifestation associated with the overdose.  If the clinical 
manifestation presents with serious criteria, the event is an SAE (see Section 12.7.2). 
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.
6.8.
Treatment after the End of the Study
Prior to completion of the Week 148 visit, randomised subjects will need to have 
alternative arrangements in place for access to antiretroviral medication.  If required by 
local regulations, subjects randomised to receive DTG plus 3TC once daily therapy and 
who have successfully completed both the 96 weeks of treatment in the Double-blind 
Randomised Phase and the Open-label Randomised Phase through Week 148 will be 
given the opportunity to continue to receive DTG plus 3TC once daily (Continuation 
Phase) until 

DTG and 3TC are both locally approved for use as part of a dual regimen, and the 
single entities of DTG and 3TC are available to patients (e.g. through public 
health services), or

the DTG/3TC FDC tablet, if required by local regulations, is available, or

the subject no longer derives clinical benefit, 

the subject meets a protocol-defined reason for discontinuation, or 

development of the DTG plus 3TC dual regimen is terminated.  
Subjects randomised to the DTG plus TDF/FTC FDC arm will receive DTG plus 
TDF/FTC FDC through their Week 148 visit only, after which subjects will complete the 
study and will need to have alternate arrangements in place to access antiretroviral 
medication.
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 Healthcare/GSK is 
providing specific post-study treatment.
6.9.
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 


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the most current version of the U.S. and local prescribing information for DTG, 
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.
6.9.1.
Permitted Medications and Non-Drug Therapies
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study (except prohibited medications described in 
Section 6.9.2).  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 samples for laboratory tests have been drawn 
and only when scheduled visits are ≥4 weeks apart.  This approach will minimise the risk 
of non-specific increases in the level of HIV-1 plasma RNA at the next scheduled 
assessment.
DTG plus 3TC and DTG plus TDF/FTC FDC should be administered 2 hours before OR 
6 hours after taking polyvalent cation-containing antacids.  Proton pump inhibitors and 
H2-antagonists may be used in place of antacids with no scheduling restrictions.  
Concurrent administration with multivitamins is acceptable.  Calcium or iron 
supplements can be taken with study treatment provided that all are taken together with a 
meal. Under fasted conditions, DTG should be given 2 hours prior to OR 6 hours after 
calcium or iron supplements.
Metformin concentrations may be increased by DTG.  A dose adjustment of metformin 
should be considered when starting and stopping co-administration of DTG with 
metformin, to maintain glycaemic control.
Clinical monitoring is recommended for subjects taking methadone as methadone 
maintenance therapy may need to be adjusted in some subjects.
6.9.2.
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 6.9.1 for guidance regarding non-HIV 
vaccines). 

Other experimental agents, ART drugs not otherwise specified in the protocol, 
cytotoxic chemotherapy, or radiation therapy (see Exclusion Criteria, Section 5.2). 

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited through Week 148 (a list of examples is provided in the SRM).  


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This includes topical agents with substantial systemic exposure and systemic effects.  
Use of topical imiquimod is permitted.

HCV therapy during the study is prohibited during the first 48 weeks of the Double-
blind Randomised Phase; interferon-based HCV therapy and HCV therapy based any 
drugs that have a potential for adverse drug:drug interactions with study treatment 
are prohibited throughout the entire study. 

Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided; 
however, topical, inhaled or intranasal use of glucocorticosteroids of any duration 
will be allowed.  Short treatment courses (14 days or less) of oral prednisone/ 
prednisolone/methylprednisolone are allowed.

Acetaminophen is not to be used in patients with acute viral hepatitis [James, 2009].
The following medications or their equivalents may cause decreased concentrations of 
DTG and therefore must not be administered concurrently with DTG.

Carbamazepine

Oxcarbamazepine

Phenobarbital

Phenytoin

Rifampicin or rifapentine

St. John’s wort (Hypericum perforatum)
Dofetilide and pilsicainide are prohibited as DTG may inhibit their renal tubular secretion 
resulting in increased dofetilide/pilsicainide concentrations and potential for toxicity.
NOTE: Any prohibited medications that substantially decrease DTG concentrations 
should be discontinued for a minimum of four weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose and any other prohibited medications should 
be discontinued for a minimum of two weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose.
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen, please consult the local prescribing information.
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. 


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7.1.
Time and Events Table
Procedures
Screening Visita
Double-blind Randomised Phase
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline / Day 1
Week
Every 12 
weeks after 
Week 148
4
8
12
16
24
28b
36
48
52b
60
72
84
96
100b
108
120
132
144
148
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
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
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
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symptom Directed 
Physical Exam/Medical 
Decision Makingi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGj
X


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Procedures
Screening Visita
Double-blind Randomised Phase
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline / Day 1
Week
Every 12 
weeks after 
Week 148
4
8
12
16
24
28b
36
48
52b
60
72
84
96
100b
108
120
132
144
148
Adverse events
X
X
X
X
X
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
X
X
X
X
X
EQ-5D-5Ll
X
X
X
X
X
X
X
Laboratory Assessments
Plasma for HIV 
genotyping
X
Quantitative plasma HIV-
1 RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xm
X
X
Lymphocyte subset 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for 
storage/inflammation 
biomarkersn
X
X
X
X
X
X
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
X
X
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and 
glucoseo
X
X
X
X
X
Xp
Urinalysis and spot urine 
for protein analysisq
X
X
X
X
X
X
X
Pregnancy testr,s
S
U
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
HBsAg, anti-HBc, anti-
HBs, and HBV DNAt
X
HCV antibody
X
RPR
X


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Procedures
Screening Visita
Double-blind Randomised Phase
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline / Day 1
Week
Every 12 
weeks after 
Week 148
4
8
12
16
24
28b
36
48
52b
60
72
84
96
100b
108
120
132
144
148
Renal and bone marker 
analytes (blood/urine)u
X
X
X
X
X
X
Whole blood for 
virology/telomere lengthv
Xv
Xv
Xv
Whole blood for telomere 
lengthw
X
X
Study Treatment
IVRS/IWRSx
X
X
X
X
X
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
X
X
X
X
Study treatment 
accountability (pill 
counts)
X
X
X
X
X
X
X
X
X
X
X
X
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, ECG = electrocardiograph, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus type 1, INR = international 
normalised ratio, IVRS = interactive voice recognition system, IWRS = interactive web recognition system, PT = prothrombin time, RNA = ribonucleic acid, RPR = rapid plasma reagin
a.
Randomisation may occur as soon as all Screening results are available.
b.
Subjects with plasma HIV-1 RNA levels 50 c/mL at Week 24, Week 48 and Week 96 must have HIV-1 levels re-assessed by a second measurement performed four weeks later 
at the Week 28, Week 52 visit and Week 100 visit, respectively. Subjects should have received full doses of study treatment for at least 2 weeks at the time of HIV-1 RNA re-
assessment for any HIV-1 RNA level 50 c/mL.  Subjects with plasma HIV-1 RNA levels <50 c/mL at Week 24, Week 48 and Week 96 should not attend the Week 28 visit,  Week 
52 visit and Week 100 visit, respectively.
c.
Subjects randomised to DTG plus 3TC who complete through Week 148 may 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.


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e.
Inclusion/exclusion criteria will be assessed fully at the Screening visit. Changes between the Screening visit and the Day 1 visit should be considered to ensure eligibility, 
including review of additional assessments performed at Day 1.
f.
Full medical history will be conducted prior to randomisation 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.
At screening, 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. Body mass index (BMI) will be calculated within the eCRF.  At Week 96 and Week 144, only weight will be 
measured.
h.
On Day 1, the electronic Columbia Suicidality Severity Rating Scale (eC-SSRS) is to be administered prior to randomisation. 
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 Healthcare/GSK product will be collected between obtaining informed consent and administration 
of study drug at Day 1.
l.
The questionnaire is recommended to be administered at the beginning of the visit before any other assessments are conducted.  Only conduct the questionnaire at Withdrawal if 
occurring prior to Week 144. 
m.
At Week 148, repeat HIV-1 RNA testing will only be performed for subjects with HIV-1 RNA 50 c/mL at Week 144. 
n.
Plasma samples for storage will be collected at each visit, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  Additionally, these samples will 
be used when needed such as when samples are lost or arrive at the laboratory unevaluable or as a priority need for genotypic and/or phenotypic analyses when subjects meet 
CVW criteria.  Additionally, inflammation biomarkers (Interleukin-6 [IL-6], high-sensitivity C-reactive protein [hs-CRP]) will be measured at Day 1, Week 48, Week 96 and Week 
144 using stored plasma samples.
o.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
p.
Only collect fasting lipids and glucose if the Withdrawal visit occurs at Week 24, Week 48, Week 96 or Week 144.
q.
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
r.
Pregnancy testing will be conducted (females of reproductive potential only) on serum (S) samples with the exception of Day 1, which must be a urine (U) test to confirm status 
prior to administration of study treatment.
s.
Remind females of reproductive potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements.
t.
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.
u.
Blood samples for renal and bone biomarker assessments: Renal: Cystatin C; Beta-2 Microglobulin; Retinol Binding Protein (RBP); Bone: bone specific alkaline phosphatase, 
procollagen type I N-terminal propeptide, type I collagen cross-linked C-telopeptide, osteocalcin, 25-hydroxyvitamin D. Urine sample for renal biomarker assessments: RBP and 
Beta-2-Microglobulin.  Only collect at the Withdrawal visit if it occurs at Week 24, Week 48, Week 96 or Week 144.
v.
Whole blood samples may be used for virologic analyses as described in the protocol; a sample at Day 1 and a second sample at either Week 148 or at Withdrawal (if a subject is 
withdrawn prior to Week 148 will be taken for all subjects.  Additionally, where possible, stored whole blood from Day 1 will be used for telomere length evaluation (while telomere 
length evaluation at Week 96 and Week 144 require a separate whole blood sample).
w.
Whole blood samples for telomere length evaluation will be taken at Week 96 and Week 144 (where possible, the Day 1 evaluation will be done from the stored whole blood 
‘virology/telomere length’ sample in footnote ‘v’)
x.
At Screening, a subject number will be generated.


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7.2.
Screening and Critical Baseline Assessments
Written informed consent must be obtained from each potentially eligible subject (or 
his/her legal representative) 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 study enrolment 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 GSK/PPD.
7.2.1.
Screening Assessments
Assessments to be conducted at Screening are provided in the Time and Events Table 
(Section 7.1).
Eligibility criteria must be carefully assessed 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 
screening 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.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5. 
Other information to be collected at Screening includes current medical conditions.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
All subjects must provide a plasma sample for determination of viral genotypic resistance 
at the central laboratory.  For eligibility the resistance report must show no evidence of 
primary viral resistance based on the presence of any major resistance-associated 
mutation [IAS-USA, 2014].  The study virologists will confirm the lack or presence of 
exclusionary resistance mutations, and communicate eligibility based on the resistance 
test results.
Severe hepatic impairment is exclusionary and will be assessed by Child-Pugh grading at 
Screening (see Appendix 2, Section 12.2).
CrCl is calculated at Screening, and subjects with a CrCL <50 mL/min per 1.73 m2 are 
excluded due to requirements for dose reduction of 3TC or dose interval adjustments of 
TDF/FTC in patients with renal dysfunction.
Subjects with chronic active hepatitis B are excluded.  Evidence of HBV infection is 
based on the results of testing at Screening for HBsAg, anti-HBc, anti-HBs (HBsAb), and 


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HBV DNA.  HBV DNA testing will only be performed during screening and prior to 
randomisation for subjects with positive anti-HBc and both negative HBsAg and anti-
HBs (past and/or current evidence).
All subjects will be screened for syphilis using a rapid plasma reagin (RPR) at Screening.  
Subjects with untreated syphilis infection, defined as a positive RPR without clear 
documentation of treatment, are excluded.  Subjects with a positive RPR test who have 
not been treated may be rescreened at least 14 days after completion of antibiotic 
treatment for syphilis.
Subjects who meet all entry criteria may be randomly assigned 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 (extendable to 35 days) prior to 
Baseline (Day 1) during which all clinical and laboratory assessments of eligibility must 
be performed and reviewed.  All Screening results must be available prior to 
randomisation.
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.  Subjects who are 
randomised into the trial and subsequently withdrawn from the study for any reason may 
not be rescreened.
7.2.2.
Baseline Assessments
Assessments to be conducted at Baseline (Day 1) are provided in the Time and Events 
Table (Section 7.1).
At Day 1 and prior to randomisation, any changes to the eligibility parameters must be 
assessed and any results required prior to randomisation (e.g. Day 1 urine pregnancy test 
for females of reproductive potential) must be available and reviewed.  
The electronic Columbia Suicidality Severity Rating Scale (eC-SSRS) must also be 
administered prior to randomisation.
7.3.
Efficacy
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 with a lower limit of quantitation of 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 characterise 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+ cell 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 
Classification System for HIV Infection in Adults (see Appendix 5, Section 12.5).  
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.
7.4.
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 Appendix 7, Section 12.7.
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 
Healthcare/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 
(see Section 7.4.1.3), at the time points specified in the Time and Events Table 
(Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to the Medical Monitor within 24 hours, as 
indicated in Appendix 7, Section 12.7.7.

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 


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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 the Medical Monitor.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to ViiV 
Healthcare/GSK/PPD are provided in Appendix 7, Section 12.7.
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 will be followed until resolution, until the 
condition stabilises, until the event is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.4).  Further information on follow-up procedures is 
given in Appendix 7, Section 12.7.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 7 (Section 12.7.3) and all deaths, 
whether or not they are considered SAEs, specific Cardiovascular (CV) and Death 
sections of the CRF will be required to be completed. These sections include questions 
regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
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 
(Appendix 5, Section 12.5) will be recorded on the HIV-Associated Conditions eCRF 
page if they occur.  However, these individual events or outcomes, as well as any sign, 


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symptom, diagnosis, illness, and/or clinical laboratory abnormality that can be linked to 
any of these events or outcomes are not reported to ViiV Healthcare/GSK/PPD as AEs 
and SAEs even though such event or outcome may meet the definition of an AE or SAE, 
unless the following conditions apply:

The investigator determines that the event or outcome qualifies as an SAE under part 
‘f’ of the SAE definition (see Section 12.7.2), or

The event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual subject, or

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 Healthcare or designee of SAEs related to 
study treatment 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 Healthcare/GSK has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a product under clinical 
investigation.  ViiV Healthcare/GSK will comply with country specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/ IEC and 
investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and ViiV Healthcare/GSK policy 
and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g. summary or listing of SAEs) from ViiV Healthcare/GSK 
will file it with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of dosing 
and until and ending at the final Follow-up visit.

If a pregnancy is reported then the investigator should inform ViiV 
Healthcare/GSK/PPD within 2 weeks of learning of the pregnancy and should follow 
the procedures outlined in Appendix 9, Section 12.9.2.


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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.
Electrocardiogram (ECG)
A 12-lead ECG will be performed at Screening for possible use as a reference during the 
study (i.e. in evaluation of any pertinent cardiovascular event).
7.4.5.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Section 7.1, must be 
performed by the central laboratory, Q2 Solutions, or a laboratory contracted by the 
central laboratory.   Laboratory assessments must be conducted in accordance with the 
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 Q2 Solutions and are detailed in the laboratory 
manual.  Reference ranges for all safety parameters will be provided to the site by Q2
Solutions.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g. SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 1. 


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Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute)
MCH
Lymphocytes
Haemoglobin
Monocytes
Haematocrit
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Chloride
Alkaline phosphatise
Creatine 
phosphokinase
Creatinine
Calcium
Phosphate
Creatinine clearance 4
Glucose 2
Total CO2
Total bilirubin 3
Lipase
Potassium
AST
Total protein
Sodium
ALT
Albumin
Fasting Lipid 
Panel 5

Total cholesterol

HDL cholesterol

LDL cholesterol

Triglycerides
Other 
Laboratory 
Tests

Plasma HIV-1 RNA 6

CD4+ cell counts

Hepatitis B (HBsAg, anti-HBc, anti-HBs, HBV DNA)

Hepatitis C (anti-HCV)

RPR

PT/INR 

Serum hCG pregnancy test (as needed for females of reproductive 
potential) 7

Urinalysis, urine albumin/creatinine ratio, and urine 
protein/creatinine ratio, urine phosphate

Renal biomarkers including Cystatin C (blood), Retinol Binding 
Protein (RBP, blood/urine); and Beta-2 Microglobulin (B2M, 
blood/urine) 8

Bone biomarkers including: bone-specific alkaline phosphatase, 
procollagen type I N-terminal propeptide, type I collagen cross-
linked C-telopeptide, osteocalcin, 25-hydroxyvitamin D 8

Inflammation biomarkers including IL-6 and hs-CRP 8

Telomere length 8
ALT = alanine aminotransferase,  anti-HBc = hepatitis B core antibody, anti-HBs = hepatitis B surface 
antibody, anti-HCV = hepatitis C antibody, AST = aspartate aminotransferase,  BUN = blood urea nitrogen, 
CO2 = carbon dioxide, HBsAg = hepatitis B surface antigen, HBV DNA = hepatitis B virus 
deoxyribonucleic acid, HDL = high density lipoprotein, LDL = low density lipoprotein, MCH = mean 
corpuscular haemoglobin, MCV = mean corpuscular volume, PT/INR = prothrombin time/international 
normalised ratio, RBC = red blood cells, RPR = rapid plasma reagin, WBC = white blood cells, IL-6 = 
interleukin 6, hs-CRP = high-sensitivity C-reactive protein


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NOTES :
1. Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-up Assessments after 
liver stopping or monitoring event are given in Section 5.4.2 and Appendix 3, Section 12.3.  Details of 
other stopping/withdrawal criteria and Toxicity Management are given in Section 5.4 and Appendix 8, 
Section 12.8.
2. For fasting glucose assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is 
acceptable for subjects with afternoon appointments.
3. Direct bilirubin will be reflexively performed for all total bilirubin values >1.5× ULN.
4. Glomerular filtration rate (GFR) will be estimated by the central laboratory using the CKD-EPI method 
[Levey, 2009].
5. For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is 
acceptable for subjects with afternoon appointments.
6. For subjects meeting virologic withdrawal criteria, plasma samples will be analysed in attempt to obtain 
genotype/phenotype data.
7. Pregnancy testing will be conducted on serum samples with the exception of Day 1, when a urine test is 
used to confirm status prior to administration of study treatment.
8. Since the intention is to utilise these biomarker data for research purposes, the sponsor will not be 
reporting the results of these assessments to the investigator, except for some individual renal 
biomarkers and 25-hydroxyvitamin D.  No summary analysis of biomarker data will be made until a 
study endpoint is reached.
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 aetiology
should be identified and the sponsor notified.
7.4.6.
Suicidal Risk Monitoring
Subjects with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour).  In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in patients with a pre-
existing history of depression or psychiatric illness) in some patients being treated with 
INSTIs, 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 behaviour or any other unusual changes in behaviour.  It is recommended that the 
investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behaviour.  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.


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Assessment of treatment-emergent suicidality will be monitored during this study using 
the electronic version of the Columbia Suicidality Severity Rating Scale (eC-SSRS).  The 
definitions of behavioural suicidal events used in this scale are based on those used in the 
Columbia Suicide History Form [Posner, 2007].  Questions are asked on suicidal 
behaviour, suicidal ideation, and intensity of ideation. Day 1 (Baseline) visit questions 
will be in relation to lifetime experiences and current experiences (within the past 2 
months) and all subsequent questioning in relation to the last assessment.  The eC-SSRS 
is to be administered as a patient completed questionnaire specified in the Time and 
Events Table (Section 7.1).  The eC-SSRS will be conducted electronically by telephone 
or by computer/tablet connected to the internet.
Additionally, the investigator will collect information using the Possible Suicidality-
Related AE (PSRAE) eCRF form in addition to the 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 behaviour, a suicide attempt, or a 
completed suicide.  The investigator will exercise his or her medical and scientific 
judgment in deciding whether an event is possibly suicide-related.  PSRAE forms should 
be completed and reported to ViiV Healthcare/GSK/PPD within 1 week of the 
investigator diagnosing a possible suicidality-related AE.
7.5.
Biomarkers
Blood and/or urine are being collected to perform evaluations of renal, bone and 
inflammation biomarkers, and telomere length as outlined in Section 7.1.  
Renal biomarkers include: 

Cystatin C (blood)

Retinol Binding Protein (RBP, blood/urine),

Beta-2-Microglobulin (B2M, blood/urine), 

urine albumin/creatinine ratio, 

urine protein/creatinine ratio, 

urine phosphate, and 

serum creatinine.  
Bone biomarkers (blood) include:

bone-specific alkaline phosphatase, 

procollagen type 1 N-propeptide, 

type 1 collagen cross-linked C-telopeptide, 

osteocalcin, and 

25-hydroxyvitamin D.  


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Inflammation biomarkers include:

interleukin-6 (IL-6, blood)

high-sensitivity C reactive protein (hs-CRP, blood)
Telomere length (whole blood)
Since the intention is to utilise these biomarkers for research purposes, the Sponsor will 
not be reporting the results of these assessments to the investigator except for some renal 
biomarkers and 25-hydroxyvitamin D.  No summary analysis of biomarker data will be 
made until a study endpoint is reached.
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 (Section 7.1).  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 Baseline samples and 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.  See Section 5.4.1.3 for details.
Details concerning the handling, labelling and shipping of these samples will be supplied 
separately.  Genotypic analyses for RT and PRO will be carried out at Screen by Q2
Solutions, and 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.
7.6.1.
HIV-1 Exploratory Analyses
To assess the future drug options in subjects meeting CVW criteria, drugs potentially 
impacted and remaining available for subjects with treatment emergent resistance will be 
evaluated.
Additional virologic analyses for HIV-1 may, for example, be carried out on whole blood 
samples collected at Baseline or on study per Time and Events Table (Section 7.1), 
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 at that time point (e.g. 
Withdrawal visit) have HIV-1 RNA 400 c/mL while receiving study treatment 
regardless of confirmatory HIV-1 RNA.
7.7.
Value Evidence and Outcomes
The Health outcomes assessment will be conducted according to the Time and Events 
Table (Section 7.1). The assessment is recommended to be administered at the beginning 


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of the visit prior to collection of blood for analysis and other scheduled assessments.  The 
questionnaire will be administered on paper.  
The European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L), developed by 
EuroQol group, is a standardised, 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 analogue scale (VAS) that assesses overall health [Herdman, 2011].
7.7.1.
Value Evidence and Outcomes Endpoints

Summary statistics as well as between and within group change from Baseline in 
health related quality of life using EQ-5D-5L at Weeks 4, 24, 48, 96, and 144 (or 
Withdrawal from the study).
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK-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 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
and an internal validated medication dictionary, GSKDrug.  

eCRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent at the end of the study in CD format to GSK to be retained.  Each investigator 
will receive a copy of his or her site-specific data in the same format to maintain as 
the investigator copy.  Subject initials will not be collected or transmitted to ViiV 
Healthcare/GSK according to ViiV Healthcare/GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to show that the antiviral effect of a simplified two-drug regimen 
of DTG plus 3TC once-daily is not inferior to a standard three-drug regimen of DTG plus 
TDF/FTC FDC once daily in HIV-1 infected ART-naïve adult subjects.
Non-inferiority can be concluded if the lower bound of a two-sided 95% confidence 
interval for the difference in response rates between the two treatment arms is greater 
than -10%.  If rd is the response rate on DTG plus 3TC and rf is the response rate on DTG 
plus TDF/FTC FDC, then the hypotheses can be written as follows:


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H0:  rd - rf ≤ -10%                   H1: rd - rf > -10%
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Assuming a true response rate of 87% for the DTG plus 3TC arm and an 89% response 
rate for the DTG plus TDF/FTC arm, the study requires 347 subjects per arm to have 
90% power with a 10% non-inferiority margin and a 2.5% one-sided alpha level.
9.2.1.1.
Rationale for non-inferiority margin
The use of a 10% non-inferiority margin for treatment-naïve subjects is in accordance 
with current FDA guidance [CDER, 2015]. 
9.2.1.2.
Response rate assumptions
Response rates at week 48 in previous studies with DTG plus two NRTIs range from 
85% - 90% (Table 2).  The response rate on the DTG plus TDF/FTC arm is assumed to 
be 89% at Week 48 based on the combined evidence.  Response rates at Week 48 in 
previous two-drug regimen studies range from 83% - 88% (Table 2).  However, there is 
no previous two-drug regimen study conducted with DTG.  The response rate on the 
DTG plus 3TC arm at week 48 is assumed to be 87% combining evidence from both 
previous DTG studies and studies with other two-drug regimen. 
Table 2
Response rates in previous DTG and two-drug regimen studies
n
Treatment regimen
Week 48 response rate 
(<50 c/mL)
SPRING-21
411
DTG + 2 NRTIs (ABC/3TC or TDF/FTC)
88%
SINGLE2
414
DTG + ABC/3TC
88%
FLAMINGO3
242
DTG + 2 NRTIs (ABC/3TC or TDF/FTC)
90%
ACTG A51424
250
LPV/RTV + EFV
83%
PROGRESS5
101
LPV/RTV+ RAL
83%
GARDEL6
214
LPV/RTV + 3TC
88%
1 [Raffi, 2013]
2 [Walmsley, 2013]
3 [Clotet, 2014]
4 [Riddler, 2008]; Week 96 response rates are shown.
5 [Reynes, 2011]
6 [Cahn, 2014]
9.2.2.
Sample Size Sensitivity
Figure 2 shows sensitivity of the required sample size to the true response rate for the 
DTG plus 3TC arm assuming an 89% response rate in the DTG plus TDF/FTC arm. 


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Figure 2
Sample Size Sensitivity
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 randomised subjects who receive at least one dose of 
study medication.  Subjects will be assessed according to their randomised 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 
major 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.
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 analysed according to the actual treatments received. 
Unless otherwise stated, the Safety Population will be used for safety analyses.


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9.3.2.
Analysis Data Sets
Subjects’ responses at <50 c/mL will be 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 are allowed in this protocol.
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 (as 
specified in the RAP).
Full details of this snapshot algorithm will be contained in the RAP.
A 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 will be the primary dataset for assessing safety.
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 dataset.  
The primary comparison will be made at a one-sided 2.5% level of significance. 
Treatment with DTG plus 3TC will be declared non-inferior to treatment with DTG plus 
TDF/FTC FDC if the lower end of a two-sided 95% confidence interval for the difference 
between the two groups in response rates at Week 48 lies above -10%.
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 plus 3TC is superior to treatment with DTG plus TDF/FTC FDC 
will be tested using the same level of significance as for the tests of non-inferiority.  
Superiority will be declared if the lower end of the confidence internal is above 0%.  The 
primary comparison will also be performed using the ITT population and will be 
compared for consistency with the results from the ITT-E and PP populations.
9.3.3.3.
Secondary comparisons
The following key secondary comparison will be tested:

Superiority of DTG plus 3TC compared to DTG plus TDF/FTC FDC with respect 
to change from baseline in CD4+ cell counts;


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
Superiority of DTG plus 3TC compared to DTG plus TDF/FTC FDC with respect 
to renal biomarkers, RBP and B2M.
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 Analyses
At least four analyses will be conducted to evaluate primary and secondary objectives of 
the protocol, one when all subjects have completed their visits at Week 24, at Week 48, at 
Week 96, and at Week 144.   Further data cuts and analyses may be conducted as 
necessary after Week 144 in order to support regulatory submissions and publications.  
The Week 48 analysis will be primary.  No adjustment for multiplicity caused by 
repeated evaluation of the primary endpoint will be made as the Week 24, Week 96 and 
Week 144 analyses will be secondary.  ViiV Healthcare/GSK/PPD will unblind the study 
for the purpose of the Week 24 analysis; however, subjects and investigators will remain 
blinded to treatment allocation until each subject has reached their Week 96 visit.  The 
Week 24 analysis will be used for regulatory purposes and no external presentation of the 
data will occur until at least all patients have reached the Week 48 visit (when the 
primary analysis will occur).
An IDMC will be instituted to ensure external objective medical and/or statistical review 
of efficacy and safety in order to protect the ethical interests and well-being of subjects 
and to protect the scientific validity of this study and sister study 204861.  An ad-hoc 
review of data by the IDMC will be triggered whenever the number of CVWs exceeds 
thresholds pre-specified in the IDMC charter.  Further, an interim futility analysis will be 
performed for the IDMC to evaluate the efficacy and safety of DTG plus 3TC when 
approximately 50% of subjects have completed their visit at Week 24; the sponsor will 
remain blinded to this analysis.  Full details of the methods, timing, decision criteria and 
operating characteristics will be pre-specified in the IDMC Charter.
9.4.
Key Elements of Analysis Plan
9.4.1.
Efficacy Analyses
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. All CIs will be two-sided. For the 
statistical analysis, four strata (subgroups) will be formed according to the combinations 
of levels of the following categorical variables:

Baseline plasma HIV-1 RNA (vs.>100,000c/mL); 

Baseline CD4+ cell count (vs. >200 cells/mm3).
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.


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If nk is the number of DTG plus 3TC treated subjects, mk is the number of DTG plus 
TDF/FTC 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
using the variance estimator 
given by [Sato, 1989] which is consistent in both 
sparse data and large strata.  The full equation for this variance estimate is provided in the 
RAP.  Full details will be contained in the RAP. 
The weighted least squares chi-squared statistic [Fleiss, 1981] will be used to test for one-
way homogeneity across the levels of each categorical variable, with each categorical 
variable considered separately.  Following Lui and Kelly [Lui, 2000], ½ will be added to 
each cell in any strata for which the stratum-specific rate estimates of either rd or rf are 
zero, and tests will be one-sided.  Any heterogeneity found to be statistically significant 
will be explored and if necessary results will be reported for each level of the categorical 
variable.  Investigation of heterogeneity will be confined to the primary endpoint using 
the Week 24 and Week 48 Snapshot analyses.  Tests of homogeneity will be assessed at 
the one-sided 10% level of significance.
A sensitivity analysis will be performed at Week 48 to assess whether bias was 
introduced by the unblinded analysis performed at Week 24. The Week 48 Snapshot 
results of the subjects who reached Week 48 prior to the Week 24 unblinding will be 
compared to the Week 48 results in the subjects who reached Week 48 after the Week 24 
unblinding.
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 ‘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.
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 and changes from baseline in 
CD4+ cell count will be summarised by subgroups (e.g. age, gender, race, baseline CD4+ 
cell counts).


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Details for secondary efficacy endpoints will be discussed in the RAP.
Data gathered after subjects withdraw from study treatment 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).
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 
summarised 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; and

Incidence of SAEs.
Statistical analysis of selected biomarkers and fasting lipids may be performed overall 
and by baseline demographics using appropriate methods for missing data.  Further 
details will be provided in the RAP.
Laboratory, biomarker and vital signs data will be summarised by visit and treatment 
group.  In addition, the number and percentage of subjects with graded laboratory 
toxicities (based on DAIDS categories; Appendix 6, Section 12.6) will be summarised by 
treatment group.  The proportion of subjects experiencing changes from Baseline in their 
National Cholesterol Education Program (NCEP) lipid categories will be summarised by 
treatment arm.  Further details of safety analyses will be included in the RAP.
9.4.3.
Viral Genotyping/Phenotyping Analyses
The incidence of treatment-emergent genotypic and phenotypic resistance to DTG, 3TC 
and TDF/FTC will be summarised by treatment arm for subjects meeting CVW criteria 
(Section 5.4.1). Details of the analyses to be performed will be specified in the RAP.
9.4.4.
Other Analyses
The change from Baseline in health related quality of life using EQ-5D-5L will be 
summarised as detailed in Section 7.7.


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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 Healthcare/GSK will obtain favourable opinion/approval 
from the appropriate regulatory agency to conduct the study in accordance with 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and 
applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with ViiV Healthcare/GSK policy.
The study will also be conducted in accordance with ICH 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 Healthcare/GSK/PPD will provide full details of the above procedures, either 
verbally, in writing, or both.
Signed informed consent must be obtained for each subject (or his/her legal 
representative) prior to participation in the study (and for amendments as applicable).
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and PPD procedures, PPD 
monitors will contact the site prior to the start of the study to review with the site
staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and ViiV Healthcare, GSK or PPD 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.
PPD will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.


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
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, ViiV 
Healthcare/GSK/PPD 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 PPD monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and PPD Standard Operating 
Procedures.

ViiV Healthcare/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 multicentre studies, this can occur at 
one or more or at all sites.  

If ViiV Healthcare/GSK determines such action is needed, ViiV Healthcare/GSK 
will discuss the reasons for taking such action with the investigator or the head of the 
medical institution (where applicable).  When feasible, ViiV Healthcare/GSK will 
provide advance notification to the investigator or the head of the medical institution, 
where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, ViiV 
Healthcare/GSK/PPD will promptly inform all investigators, heads of the medical 
institutions (where applicable) and/or institution(s) conducting the study. ViiV 
Healthcare/GSK/PPD 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.


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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 Healthcare/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.  

The investigator must notify ViiV Healthcare, GSK or PPD of any changes in the 
archival arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a ViiV Healthcare/GSK site or other 
mutually-agreeable location.
ViiV Healthcare/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.
ViiV Healthcare/GSK will provide the investigators with the randomisation codes for 
their sites only after completion of the full statistical analysis.
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 
Healthcare/GSK Policy.


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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 this study and sister study 
204861.  The schedule of any planned interim analysis and the analysis plan for IDMC 
review is described in the charter, which is available upon request.
All 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.
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British HIV Association (BHIVA) guidelines for the treatment of HIV-1-infected adults 
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Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir and 
ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two 
nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with 
HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL 
trial. Lancet Inf Dis. 2014;14:572-580.
Cahn P, Rolón MJ, Figueroa MI, et al. Dolutegravir-lamivudine as initial therapy in HIV-
Infected, ARV-naïve patients, 48 Week results of the PADDLE (Pilot Antiretroviral 
Design with Dolutegravir LamivudinE) study. J.Int AIDS Society 2017, 20:21678.
Cahn P. Durability of Dual Therapy (DT) with Lopinavir/Ritonavir (LPV/r) and 
Lamivudine (3TC) in Comparison to Standard Triple Drug Therapy (TT): 96-week 
Results of the GARDEL Study. EACS 2015. 15th European AIDS Conference. 21-24 
October 2015. Barcelona, Spain. Abstract 961.
CDC. Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10.
Clotet B, Feinberg J, van Lunzen J, et al; ING114915 Study Team. Once-daily 
dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 
infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. 
Lancet. 2014;383:2222-2231.
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of 
Health and Human Services. 28 January 2016.  Available at 
http://www.aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.  Accessed 6 April 
2016.
EPIVIR Product Information (lamivudine), September 2017.
Eron JJ, Benoit SL, Jemsek J, et al. Treatment with Lamivudine, Zidovudine, or both in 
HIV-Positive Patients with 200 to 500 CD4+ Cells per Cubic Millimeter. NEJM. 
1995;333:1662-1669.
European AIDS Clinical Society (EACS) Guidelines for the clinical management and 
treatment of HIV Infected Adults in Europe Version 8.0, October 2015.  Available at: 
http://www.eacsociety.org/files/2015_eacsguidelines_8_0-english_rev-20160124.pdf.  
Accessed 6 April 2015.


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Figueroa MI, Sued O, Patterson P, et al. Dolutegravir-Lamivudine as Initial Therapy in 
HIV-infected, ARV Naive Patients: First Results of the PADDLE Trial. EACS 2015. 15th
European AIDS Conference. 21-24 October 2015. Barcelona, Spain. Abstract 1066.
Fleiss JL. Statistical Methods for the Rates and Proportions. 2 ed. New York: John Wiley; 
1981.
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure, Version 11. October 2017.
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.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727-1736.
International Antiviral Society (IAS)-USA Antiretroviral Treatment of Adult HIV 
Infection: 2014 Recommendations of the International Antiviral Society-USA Panel. 
Günthard HF, Aberg JA, Eron JJ, et al. JAMA. 2014;312:410-425.
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos. 2009;37:1779-1784.
Kuritzkes DR, Quinn JB, Benoit SL, et al. Drug resistance and virologic response in 
NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus 
ZDV plus 3TC in previously untreated patients. AIDS. 1996;10:975-981.
Leeansyah E, Cameron PU, Solomon A, et al. Inhibition of telomerase activity by human 
immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential 
factor contributing to HIV-associated accelerated aging. J Infect Dis. 2013;207:1157–65.
Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular 
filtration rate.  Ann Int Med. 2009; 150:604-612.
Lui, K-J, Kelly C. A revisit on tests for homogeneity of the risk difference. Biometrics. 
2000; 56:309-315.
Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and 
pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-
infected adults. AIDS. 2011;25:1737-1745.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
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Raffi F, Rachlis A, Stellbrink HJ, et al. SPRING-2 Study Group. Once-daily dolutegravir 
versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results 
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of lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/ 
emtricitabine in antiretroviral-naive subjects: the PROGRESS study, 48-week results. 
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Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment 
of HIV-1 infection. N Engl J Med. 2008;358:2095-2106.
Sato T. On the variance estimator for the Mantel-Haenszel risk difference. Biometrics. 
1989; 45:1323-1324.
Solomon A, Tennakoon S, Leeansyah E, et al. No Difference in the Rate of Change in 
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http://journals.plos.org/plosone/article/asset?id=10.1371/journal.pone.0109718.PDF. 
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Stella-Ascariz N, Montejano R, Pintado-Berninches P, et al. Brief Report: Differential 
effects of tenofovir, abacavir, emtricitabine, and darunavir on telomerase activity in vitro. 
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Stellbrink HJ, Pulik P, Szlavik J, et al. Maraviroc (MVC) dosed once daily with 
darunavir/ritonavir (DRV/r) in a 2 drug-regimen compared to emtricitabine/tenofovir 
(TDF/FTC) with DRV/r; 48-week results from MODERN (Study A4001095). AIDS 
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Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir Plus Abacavir/Lamivudine 
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1818.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B core antibody
Anti-HBs
Hepatitis B surface antibody
ARV
Antiretroviral
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
B2M
Beta-2 Microglobulin
BMI
Body mass index
c/mL
Copies/millilitre
CDC
Centers for Disease Control and Prevention
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMH
Cochran-Mantel-Haenszel
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CrCl
Creatinine clearance
CRF
Case report form
CSR
Clinical study report
C-SSRS
Columbia Suicidality Severity Rating Scale
CV
Cardiovascular
CVW
Confirmed Virologic Withdrawal
DAIDS
Division of Acquired Immunodeficiency Syndrome
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DRV
Darunavir
DTG
Dolutegravir, TIVICAY
ECG
Electrocardiogram
eCRF
Electronic case report form
eC-SSRS
Electronic Columbia Suicidality Severity Rating Scale
EFV
Efavirenz
EQ-5D-5L
EuroQol – 5 Dimensions – 5 Levels
EU
European Union
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FRP
Females of Reproductive Potential
FSH
Follicle stimulating hormone
FTC
Emtricitabine


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GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GFR
Glomerular filtration rate
GSK
GlaxoSmithKline
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotrophin
HCV
Hepatitis C virus
HDL
High density lipoprotein
HDPE
High density polyethylene
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HPMC
Hydroxypropyl methylcellulose
HRT
Hormone replacement therapy
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
INR
International normalised ratio
INSTI
Integrase strand transfer inhibitor
IP
Investigational Product
IRB
Institutional Review Board
ITT-E
Intent-to-treat exposed
IVRS
Interactive voice recognition system 
IWRS
Interactive web recognition system
LDH
Lactate dehydrogenase
LDL 
Low density lipoprotein
LPV
Lopinavir
MCH
Mean corpuscular haemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
mg
Milligram
mg/dL
Milligram per decilitre
MSD=F
Missing, switch, or discontinuation equals failure
MSDS
Material Safety Data Sheet
NCEP
National Cholesterol Education Program
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed case
OCT2
Organic cation transporter 2
PBMC
Peripheral blood mononuclear cell
PEP
Post-exposure prophylaxis
PI
Protease inhibitor


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PK
Pharmacokinetic(s)
PP
Per-protocol
PPD
Pharmaceutical Product Development
PrEP
Pre-exposure prophylaxis
PRO
Protease
PRTD
Proximal Renal Tubule Dysfunction
PSRAE
Possible suicidality-related adverse event
RAL
Raltegravir
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RBP
Retinol Binding Protein
RNA
Ribonucleic acid
RPR
Rapid plasma reagin
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
TDF
Tenofovir disoproxil fumarate
TEN
Toxic epidermal necrolysis
TRDF
Treatment Related Discontinuation = Failure
ULN
Upper limit of normal
US
United States
VAS
Visual analogue scale
VSLC
ViiV Healthcare Safety and Labelling Committee
WBC
White blood cell
ZDV
Zidovudine, RETROVIR
ZDV/3TC
Zidovudine/lamivudine, COMBIVIR
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
COMBIVIR
Abbott RealTime
EPIVIR
GenoSure
EPZICOM/KIVEXA
Monogram Biosciences
RETROVIR
PhenoSense
TIVICAY
Q2 Solutions
ZIAGEN
Truvada


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12.2.
Appendix 2: Child-Pugh Classification
A subject is classified with mild hepatic impairment (Class A) if their overall sum of 
scores is 5-6 points, moderate hepatic impairment (Class B) if their overall sum of scores 
is 7-9 points, and severe hepatic impairment (Class C) if their overall sum of scores is 10-
15 based on the Child-Pugh system [Pugh, 1973] scoring described in the following table 
(Table 3).  For subjects requiring anticoagulation therapy, discussion with the study 
Medical Monitor will be required.
Table 3
Child-Pugh System
Finding 
Points Scored for Each Observed Finding 
1
2
3
Encephalopathy Grade1 
None
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum bilirubin, SI units (μmol/L), 
Serum bilirubin, conventional units (mg/dL) 
<34
<2
34 to 52
2 to 3
>52
>3
Serum albumin, SI units (g/L) 
Serum albumin, conventional units (mg/dL) 
>35
>3.5
28 to 35
2.8 to 3.5
<28
<2.8
Prothrombin Time (seconds prolonged) or 
INR 
<4
<1.7
4 to 6
1.7 to 2.3
>6
>2.3
1.
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cycles per second delta activity
[Pugh, 1973; Lucey, 1997]
References
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on 
the liver transplant waiting list: a report of a national conference organized by the 
American Society of Transplant Physicians and the American Association for the Study 
of Liver Diseases. Liver Transpl Surg 1997; 3:628-37.
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646-9.


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12.3.
Appendix 3: Liver Safety Required Actions and Follow up
Assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
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>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.

Complete the liver imaging and/or liver 
biopsy eCRFs if these tests are performed.

Perform liver event follow up assessments. 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below).

Do not restart subject with study treatment 
unless allowed per protocol and VSLC 
approval is granted (refer to Appendix 4).

If restart is 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.

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 


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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, stabilise or return to 
within baseline.

A specialist or hepatology consultation is 
recommended.
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 within 60 hours of last 
dose4.

Serum CPK and lactate dehydrogenase 
(LDH).

Fractionate bilirubin, if total bilirubin 
1.5xULN.

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 CRF.
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) 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


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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study 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 collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
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 resolution or stabilisation (ALT 
<5×ULN on 2 consecutive evaluations)  

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above
Reference
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.4.
Appendix 4: 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 4, Figure 3).
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 3): 

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 4).
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 4
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 3
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. 
Principal Investigator Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of drug 
restart, as required. 


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
If drug re-initiation VSLC-approved, the patient must provide informed consent with 
a clear description of possible benefits and risks of drug administration including 
recurrent, more severe liver injury or possible death.

The patient’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed once weekly for ‘restart’ cases for one month or 
for as long as clinically indicated following drug re-initiation.  If subject exhibits 
protocol-defined liver chemistry elevations, study drug should be discontinued as 
protocol specified.
VSLC and the IRB/IEC must be informed of the patient’s outcome following drug 
restart.
Restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting subject stopping criteria

2 = recurrent liver chemistry elevation meeting subject stopping criteria

3 = serious adverse event

4 = fatality
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009; 8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010; 
52:2216-2222. 
Papay JI, Clines D, Rafi R, et al.  Drug-induced liver injury following positive drug 
rechallenge.  Regul Tox Pharm. 2009; 54:84-90. 


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12.5.
Appendix 5: 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


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
Coccidioidomycosis, disseminated or extrapulmonary 

Cryptococcosis, extrapulmonary 

Cryptosporidiosis, chronic intestinal (>1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related 

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
oesophagitis (onset at age >1 month)

Histoplasmosis, disseminated or extrapulmonary 

Isosporiasis, chronic intestinal (>1 month's duration) 

Kaposi's sarcoma 

Lymphoma, Burkitt's (or equivalent term) 

Lymphoma, immunoblastic (or equivalent term) 

Lymphoma, primary, of brain 

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary 

Mycobacterium tuberculosis of any site, pulmonary, disseminated or extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis jirovecii pneumonia 

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy 

Salmonella septicaemia, recurrent 

Toxoplasmosis of brain, onset at age >1 month 

Wasting syndrome attributed to HIV.
Reference
CDC. Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10.


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12.6.
Appendix 6:  Division of AIDS table for Grading Severity of 
Adult and Pediatric Adverse Events
VERSION 2.0, November 2014
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term.
Estimating Severity Grade for Parameters Not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as grade 5.
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 + 
5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic)
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension
(e.g., malignant
hypertension) OR
Hospitalization 
indicated
Hypotension
No symptoms
Symptoms 
corrected with oral
fluid replacement
Symptoms AND IV
fluids indicated
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood
pressure
Cardiac Ischemia
or
Infarction
Report only one
NA
NA
New symptoms
with ischemia 
(stable angina) OR
New testing
consistent with 
ischemia
Unstable angina 
OR Acute
myocardial 
infarction
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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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)
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines 
for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; 
originally published online November 14, 2011; DOI: 10.1542/peds.2009-2107C. 
2 As per Bazett’s formula.


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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
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
Localized rash
Diffuse rash
OR Target
lesions
Diffuse rash AND
Vesicles or limited 
number of bullae 
Extensive or
generalized bullous
lesions OR Ulceration


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
applicable
or superficial
ulcerations of
mucous 
membrane limited
to one site
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Stevens- Johnson
syndrome OR Toxic 
epidermal necrolysis
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions 
section. 
Endocrine and Metabolic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Diabetes 
Mellitus
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
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 
Symptoms 
causing 
inability to
Life-threatening 
consequences (e.g., 
myxedema coma)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
interference with 
usual social & 
functional
activities OR 
Thyroid 
replacement
therapy indicated
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
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
Lipohypertrophy
5
Detectable by
study participant, 
caregiver, or 
physician AND
Causing no or
minimal
interference with
usual social &
functional activities
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and 
abdomen.
Gastrointestinal
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 parenteral 
nutrition)
Ascites
No symptoms
Symptoms AND
Intervention
indicated (e.g.,
diuretics, 
therapeutic 
paracentesis)
Symptoms 
recur or 
persist
despite 
intervention
Life-threatening 
consequences


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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)
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 
pseudomembran
es or ulcerations 
OR Mucosal 
bleeding with 
minor trauma
Life-threatening 
consequences (e.g., 
aspiration, choking) 
OR Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Nausea
Transient (< 24 
hours) or 
intermittent 
AND No or 
minimal 
interference 
with oral intake
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours
Persistent 
nausea resulting 
in minimal oral 
intake for > 48 
hours OR 
Rehydration 
indicated (e.g., 
IV fluids)
Life-threatening 
consequences (e.g., 
hypotensive shock)
Pancreatitis
NA
Symptoms with 
hospitalization not 
indicated
Symptoms with 
hospitalization 
indicated
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis)
Perforation
(colon or rectum)
NA
NA
Intervention 
indicated
Life-threatening 
consequences
Proctitis
Rectal 
discomfort with 
no intervention 
indicated
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities OR 
Operative 
intervention 
indicated
Life-threatening 
consequences (e.g., 
perforation)
Rectal Discharge
Visible 
discharge
Discharge requiring 
the use of pads
NA
NA
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


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


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


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Headache
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
Symptoms causing 
greater than
minimal 
interference with 
usual social & 
functional activities
Symptoms 
causing inability
to perform usual
social & 
functional
activities
Symptoms 
causing inability
to perform basic 
self-care functions
OR
Hospitalization 
indicated  OR
Headache with
significant 
impairment of
alertness or other
neurologic 
function
Neuromuscular 
Weakness 
(includes 
myopathy and 
neuropathy)
Specify type, if 
applicable
Minimal muscle 
weakness 
causing no or 
minimal 
interference 
with usual social 
& functional 
activities OR No 
symptoms with
decreased 
strength on 
examination
Muscle weakness 
causing greater than 
minimal 
interference with 
usual social & 
functional activities
Muscle weakness 
causing inability 
to perform usual 
social & 
functional 
activities
Disabling muscle 
weakness causing 
inability to 
perform basic 
self-care functions 
OR  Respiratory 
muscle weakness 
impairing 
ventilation
Neurosensory 
Alteration 
(includes 
paresthesia and 
painful 
neuropathy)
Specify type, if 
applicable
Minimal 
paresthesia 
causing no or 
minimal 
interference 
with usual social 
& functional 
activities OR No 
symptoms with 
sensory 
alteration on 
examination
Sensory alteration 
or paresthesia 
causing greater than 
minimal 
interference with 
usual social & 
functional activities
Sensory 
alteration or 
paresthesia 
causing inability 
to perform usual 
social & 
functional 
activities
Disabling sensory 
alteration or 
paresthesia 
causing inability 
to perform basic 
self-care functions
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)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Pre-existing 
Seizure
NA
Increased frequency 
from previous level 
of control without 
change in seizure 
character
Change in 
seizure character 
either in duration 
or quality (e.g., 
severity or 
focality)
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to 
control (e.g., 
refractory 
epilepsy)
Syncope
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope)
Loss of 
consciousness with 
no intervention 
indicated
Loss of 
consciousness 
AND 
Hospitalization 
or intervention 
required
NA
Pregnancy, Puerperium, and Perinatal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Fetal Death or 
Stillbirth (report
using mother’s 
participant ID)
Report only one
NA
NA
Fetal loss 
occurring at ≥ 20
weeks gestation
NA
Preterm
Delivery7 
(report using
mother’s 
participant ID)
Delivery at 34 to < 
37 weeks 
gestational age
Delivery at 28 to < 
34 weeks gestational
age
Delivery at 24 to 
< 28 weeks 
gestational age
Delivery at < 24
weeks gestational age
Spontaneous 
Abortion or 
Miscarriage8
(report using
mother’s participant 
ID)
Report only one
Chemical
pregnancy
Uncomplicated 
spontaneous 
abortion or
miscarriage
Complicated 
spontaneous 
abortion or
miscarriage
NA
7 Definition:  A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age.
8 Definition:  A clinically recognized pregnancy occurring at < 20 weeks gestational age.


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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
Moderate 
difficulty falling
asleep, staying 
asleep, or waking
up early
Severe difficulty 
falling asleep,
staying asleep,
or waking up 
early
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
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


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


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Uveitis
No symptoms
AND
Detectable on 
examination
Anterior uveitis 
with symptoms OR
Medicamylasal 
intervention
indicated
Posterior or pan-
uveitis OR
Operative 
intervention
indicated
Disabling visual loss in 
affected eye(s)
Vertigo
Vertigo causing
no or minimal 
interference
with usual
social & 
functional
activities
Vertigo causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Vertigo
causing 
inability to
perform usual
social & 
functional
activities
Disabling vertigo 
causing inability to 
perform basic self-care 
functions
Visual Changes
(assessed from
baseline)
Visual changes 
causing no or 
minimal
interference with
usual social & 
functional
activities
Visual changes 
causing greater
than minimal
interference with
usual social & 
functional
activities
Visual changes 
causing
inability to 
perform usual
social & 
functional
activities
Disabling visual loss in 
affected eye(s)
Systemic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute Allergic
Reaction
Localized
urticaria 
(wheals) with no 
medical
intervention 
indicated
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with
no intervention 
indicated
Generalized
urticaria OR
Angioedema
with 
intervention
indicated OR
Symptoms of
mild 
bronchospasm
Acute anaphylaxis OR
Life-threatening 
bronchospasm OR
Laryngeal edema
Chills
Symptoms 
causing no or
minimal 
interference with
usual social & 
functional 
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform 
usual social
& 
functional
activities
NA
Cytokine Release
Syndrome9
Mild signs and 
symptoms AND
Therapy (i.e.,
antibody infusion)
interruption not
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND
Responds
Prolonged
severe signs 
and symptoms 
OR
Recurrence of 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
indicated
promptly to
symptomatic 
treatment OR
Prophylactic 
medications 
indicated for ≤24 
hours
symptoms
following 
initial
improvement
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
Pain10 (not
associated with
study agent 
injections and not 
specified
elsewhere)
Specify location
Pain causing no
or minimal
interference with
usual social & 
functional
activities
Pain causing
greater than
minimal 
interference with 
usual social & 
functional
activities
Pain causing
inability to
perform usual
social & 
functional
activities
Disabling pain causing 
inability to perform basic 
self-care functions OR
Hospitalization indicated
Serum Sickness11 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)
Underweight12
> 5 to 19
years of age
NA
WHO BMI z-score 
< -2 to ≤ -3
WHO BMI z-
score
< -3
WHO BMI z-score < -3
with life-threatening 
consequences
2 to 5 years of
age
NA
WHO Weight-
for- height z-
score < -2 to ≤ -3
WHO
Weight-
for- height
z-score < -
3
WHO Weight-for-height 
z-score < -3 with life-
threatening consequences
< 2 years of age
NA
WHO Weight-
for- length z-
score < -2 to ≤ -3
WHO
Weight-
for- length
z-score < -
3
WHO Weight-for-length 
z-score < -3 with life-
threatening consequences
Weight Loss 
(excludes 
postpartum weight
NA
5 to < 9% loss in 
body weight
≥ 9 to < 
20% loss in 
≥ 20% loss in body weight 
from baseline OR


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
loss)
from baseline
body weight
from 
baseline
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition)
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness 
of breath.
10For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.
11Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.
12WHO reference tables may be accesed by clicking the desired age range or by accessing the following 
URLs: http://www.who.int/growthref/who2007_bmi_for_age/en / for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.
Urinary
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Urinary Tract
Obstruction
NA
Signs or symptoms 
of urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction
Signs or symptoms 
of urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction
Obstruction causing life-
threatening 
consequences
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 
Redness13
Report only one
2.5 to < 5 cm in 
diameter OR 6.25
≥ 5 to < 10 cm in 
diameter OR ≥ 25
≥ 10 cm in
diameter OR ≥ 
Potentially life-
threatening 


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
> 15 years of age
to < 25 cm2
surface area AND
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
to < 100 cm2
surface area OR 
Symptoms causing
greater than 
minimal
interference with
usual social & 
functional
activities
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
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)
≤ 15 years of age
≤ 2.5 cm in
diameter
> 2.5 cm in
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh)
≥ 50% surface 
area of the 
extremity
segment 
involved (e.g.,
upper arm or
thigh) OR
Ulceration OR
Secondary
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)
Injection Site
Induration or 
Swelling
Report only one
> 15 years 
of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age
≤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
13Injection 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
pH > ULN to ≤ 7.5
pH > 7.5
without life-
threatening
consequences
pH > 7.5 with life-
threatening 
consequences
ALT or SGPT, High
Report only one
1.25 to
< 2.5 x
ULN
2.5 to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Amylase (Pancreatic)
or
Amylase (Total),
High
Report only one
1.1  to < 1.5 x
ULN
1.5  to < 3.0 x ULN
3.0  to < 5.0 x
ULN
≥ 5.0 x ULN
AST or SGOT, High
Report only one
1.25 to
< 2.5 x
ULN
2.5  to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Bicarbonate, Low
(mEq/L; mmol/L)
16.0 to <  LLN
16.0 to <  LLN
11.0 to < 16.0
11.0 to < 16.0
8.0  to < 11.0
8.0  to < 11.0
< 8.0
< 8.0
Bilirubin
Direct
Bilirubin14, 
High
> 28 days of age
NA
> ULN
> ULN with life-
threatening
consequences (e.g., signs
and symptoms of liver 
failure)
≤ 28 days of age
ULN to ≤ 1
mg/dL
> 1 to ≤ 1.5 mg/dL
> 1.5 to ≤2
mg/dL
> 2 mg/dL
Total Bilirubin,
High
> 28 days of
age
1.1 to < 1.6 x
ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x
ULN
≥ 5.0 x ULN
≤ 28 days of age
See 
Appendix A. 
Total
Bilirubin for 
Term and
See Appendix A. 
Total Bilirubin
for Term and
Preterm Neonates
See 
Appendix
A. Total
Bilirubin
for Term
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Preterm 
Neonates
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 < 10 x ULN
10 to < 20 x 
ULN
≥ 20 x ULN
Creatinine, High
1.1 to 1.3 x 
ULN
> 1.3 to 1.8 x ULN 
OR Increase of > 0.3 
mg/dL above baseline
> 1.8  to < 3.5 
x ULN OR 
Increase of 1.5 
to < 2.0 x 
above baseline
≥ 3.5 x ULN OR Increase 
of ≥ 2.0 x above baseline
Creatinine Clearance 
15
or eGFR, Low
Report only one
NA
< 90 to 60 ml/min or 
ml/min/1.73 m2 OR 
10 to < 30% decrease 
from baseline
< 60 to 30 
ml/min or 
ml/min/1.73 
m2 OR
≥ 30 to < 50% 
decrease from 
baseline
< 30 ml/min or 
ml/min/1.73 m2
OR
≥ 50% decrease from 
baseline or dialysis needed
Glucose
(mg/dL; mmol/L)
Fasting, High
110 to 125
6.11 to < 6.95
> 125 to 250
6.95 to < 13.89
> 250 to 500
13.89 to < 
27.75
> 500
≥ 27.75
Nonfasting, High
116 to 160
6.44 to < 8.89
> 160 to 250
8.89 to < 13.89
> 250 to 500
13.89  to < 
> 500
≥ 27.75


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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
LDL, Fasting, High
≥ 18 years of age
130  to < 160
3.37  to < 4.12
160 to < 190
4.12  to < 4.90
≥ 190
≥ 4.90
NA
> 2 to < 18 years of 
age
110  to < 130
2.85  to < 3.34
130 to < 190
3.34  to < 4.90
≥ 190
≥ 4.90
NA
Triglycerides, 
Fasting, High
150 to 300
1.71 to 3.42
>300  to 500
>3.42 to 5.7
>500 to < 
1,000
>5.7 to 11.4
> 1,000
> 11.4
Magnesium16, Low
(mEq/L; mmol/L)
1.2   to < 1.4
0.60  to < 0.70
0.9  to < 1.2
0.45  to < 0.60
0.6  to < 0.9
0.30  to < 0.45
< 0.6
< 0.30
Phosphate, Low
(mg/dL; mmol/L)
> 14 years of age
2.0 to < LLN
0.81 to < LLN
1.4 to < 2.0
0.65 to < 0.81
1.0 to < 1.4
0.32 to < 0.65
< 1.0
< 0.32
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


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Potassium, High
(mEq/L; mmol/L)
5.6  to < 6.0
5.6  to < 6.0
6.0  to < 6.5
6.0  to < 6.5
6.5  to < 7.0
6.5  to < 7.0
≥ 7.0
≥ 7.0
Potassium, Low
(mEq/L; mmol/L)
3.0  to < 3.4
3.0  to < 3.4
2.5  to < 3.0
2.5  to < 3.0
2.0  to < 2.5
2.0  to < 2.5
< 2.0
< 2.0
Sodium, High
(mEq/L; mmol/L)
146  to < 150
146  to < 150
150  to < 154
150  to < 154
154  to < 160
154  to < 160
≥ 160
≥ 160
Sodium, Low
(mEq/L; mmol/L)
130  to < 135
130  to < 135
125  to < 130
125  to < 135
121  to < 125
121  to < 125
≤ 120
≤ 120
Uric Acid, High
(mg/dL; mmol/L)
7.5  to < 10.0
0.45  to < 0.59
10.0  to < 12.0
0.59  to < 0.71
12.0  to < 15.0
0.71  to < 0.89
≥ 15.0
≥ 0.89
14Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the 
total bilirubin.
15Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).
16To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.
Hematology
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Absolute CD4+
Count, Low
(cell/mm3; cells/L)
> 5 years of age
(not HIV infected)
300 to < 400
300 to < 400
200 to <  300
200 to < 300
100 to < 200
100  to < 200
< 100
< 100
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 109 to
< 0.600 x 109
350 to < 500
0.350 x 109 to
< 0.500 x 109
< 350
< 0.350 x 109
Absolute 
Neutrophil
Count (ANC),
Low
(cells/mm3;
cells/L)
> 7 days
of age
800 to 1,000
0.800 x 109 to
1.000 x 109
600 to 799
0.600 x 109 to 0.799 x
109
400 to 599
0.400 x 109 to
0.599 x
109
< 400
< 0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to
1,000 to 1,249
1.000 x 109 to 1.249 x
750 to 999
0.750 x 109 to
< 750


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
1.500 x 109
109
0.999 x
109
< 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
Hemoglobin17
, Low
(g/dL; mmol/L)18
≥ 13 years of age
(male only)
10.0 to 10.9
6.19 to 6.76
9.0 to < 10.0
5.57 to < 6.19
7.0 to < 9.0
4.34 to < 5.57
< 7.0
< 4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
57 days of age to <
13 years of age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of 
age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72
22 to 35 days of 
age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of 
age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59
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; 
100,000  to
< 124,999
50,000  to
< 100,000
25,000  to
< 50,000
< 25,000
< 25.000 x 109


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
cells/L)
100.000 x 109  to
< 124.999 x 109
50.000 x 109  to
< 100.000 x 109
25.000 x 109  
to
< 50.000 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
17Male and female sex are defined as sex at birth.
18The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion 
factor.  For grading hemoglobin results obtained by an analytic method with a conversion factor other than 
0.6206, the result must be converted to g/dL using the appropriate conversion factor for the particular 
laboratory.
Urinalysis
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Glycosuria
(random 
collection tested
by dipstick)
Trace to 1+ or
≤ 250 mg
2+ or ˃ 250 to
≤ 500 mg
> 2+ or > 500
mg
NA
Hematuria (not to be 
reported based on
dipstick findings or
on blood believed to
be of
menstrual origin)
6 to < 10 RBCs
per high power
field
≥ 10 RBCs per high
power field
Gross, with
or without
clots OR
With RBC
casts OR
Intervention
indicated
Life-
threatening 
consequences
Proteinuria
(random 
collection tested
by dipstick)
1+
2+
3+  or higher
NA


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Reference
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.0. [November 2014]. Available from:
http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GRADING_TABLE_v2_
NOV2014.pdf  (accessed 10 September 2015)


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12.7.
Appendix 7: Definition of and Procedures for Recording, 
Evaluating, Follow-up and Reporting of Adverse Events
12.7.1.
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 unfavourable 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 (haematology, 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.
12.7.2.
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., hospitalisation 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 hospitalisation or prolongation of existing hospitalisation
NOTE:

In general, hospitalisation 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 hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.

Hospitalisation 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.


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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise 
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 hospitalisation, 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.
12.7.3.
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


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
12.7.4.
Sentinel Events
Sentinel Event Definition:
A sentinel event is a 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 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 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)
12.7.5.
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 GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 


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submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.7.6.
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 Appendix 6, Section 12.6.:

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 IB and/or Product Information, for marketed 
products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 


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that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to ViiV Healthcare/GSK/PPD.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs:

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognised follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to ViiV Healthcare/GSK/PPD 
within the designated reporting time frames.
12.7.7.
Reporting of SAEs and other events to ViiV Healthcare/GSK/PPD
Reporting of SAEs and other events to ViiV Healthcare/GSK/PPD:

Primary mechanism for reporting SAEs to the Medical Monitor will be the electronic 
data collection tool.

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it (or 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 (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 


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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.
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” data 
collection tool
Cardiovascular or 
death event
Initial and 
follow-up 
reports to be 
completed when 
the 
cardiovascular 
event or death 
is reported 
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Initial and follow-up 
reports to be 
completed when 
the cardiovascular 
event or death is 
reported
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
ALT 3×ULN and
bilirubin 2×ULN 
(>35% direct)
24 hoursa
“SAE” data 
collection tool. 
“Liver Event eCRF” 
and “Liver Imaging” 
and/or “Liver 
Biopsy” eCRFs, if 
applicableb
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” documentsb
ALT≥5×ULN that 
persists ≥2 weeks 
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ALT ≥8×ULN 
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ALT ≥3×ULN  (if 
baseline ALT is <ULN) 
or ALT ≥3 fold increase 
from baseline value (if
baseline ALT >ULN) 
with appearance or 
worsening of symptoms 
of hepatitis or 
hypersensitivity
24 hoursa
Liver Event eCRFb
24 hours
Updated Liver Event 
eCRFb
a. The Medical Monitor must be contacted at onset of liver chemistry elevations to discuss subject safety.
b. Liver event documents (i.e., “Liver Event eCRF” and updates, “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, 
as applicable) should be completed as soon as possible.


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12.8.
Appendix 8: 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 12.6). Additional information 
regarding detecting, documenting and reporting AEs and SAEs are available in Section 
12.7.
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 minimise 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 12.8.1.7 and rash in Section 
12.8.1.6.
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 12.8.1.7.  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.
12.8.1.
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 as noted in Appendix 7, Section 12.7.
12.8.1.1.
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 Appendix 3, 
Section 12.3.
12.8.1.2.
Restarting Study Drug
Refer to Appendix 4, Section 12.4 for details on drug restart following transient resolving 
liver events not related to study treatment.


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12.8.1.3.
Decline in Renal Function
Subjects who experience an increase in serum creatinine from Baseline of 45 
micromoles/litre (Mol/L) (or 0.5 milligrams/decilitre [mg/dL]) should return for a 
confirmatory assessment within 2 to 4 weeks.  A urinalysis and urine albumin/creatinine 
and urine total protein/albumin ratios should also be done at this confirmatory visit.  If 
the creatinine increase is confirmed, the investigator should contact the study Medical 
Monitor to discuss additional follow-up and medical management.
Subjects who experience progression to an estimated GFR (using the CKD-EPI method) 
of <50 mL/min/1.73 m2 must return for a confirmatory assessment within 2 weeks 
[Levey, 2009].  A urinalysis and urine albumin/creatinine and urine protein/creatinine 
ratios should be done at this confirmatory visit.  If an estimated GFR of <50 mL/min/1.73 
m2 is confirmed, 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 this 
blinded study).
Proximal Renal Tubule Dysfunction
Proximal Renal Tubule Dysfunction (PRTD) is defined as:

Confirmed rise in serum creatinine of ≥0.5 mg/dL from Baseline AND serum 
phosphate <2.0 mg/dL;

Either of the above accompanied by any two of the following:

Glycosuria (≥250 mg/dL) in a non-diabetic;

Low serum potassium (<3 mEq/L);

Low serum bicarbonate (<19 mEq/L).
Subjects meeting criteria for PRTD must return for a confirmatory assessment within 2 
weeks of diagnosis. A urinalysis should also be performed at the time of the confirmatory 
assessment.  If PRTD is confirmed subjects must be withdrawn from the study.
12.8.1.4.
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 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.


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12.8.1.5.
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, topical 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.
12.8.1.6.
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. [GlaxoSmithKline Document Number RM2007/00683/11, 
GlaxoSmithKline Document Number 2017N352880_00, GlaxoSmithKline 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, Appendix 6, Section 12.6).


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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. 
12.8.1.7.
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.
12.8.1.8.
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.
References  
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure, Version 11. October 2017.
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.
Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular 
filtration rate.  Ann Int Med. 2009; 150: 604-612.


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12.9.
Appendix 9: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.9.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
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.
1.  Contraceptive subdermal implant
2.  Intrauterine device or intrauterine system
3.  Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.  Injectable progestogen [Hatcher, 2011]
5.  Contraceptive vaginal ring [Hatcher, 2011]
6.  Percutaneous contraceptive patches [Hatcher, 2011]
7.  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.
12.9.2.
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/Healthcare/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/Healthcare/GSK/PPD.  Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. 

GSK’s central safety department will also 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/.


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
Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.    

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 Appendix 7, Section 12.7. While the investigator is 
not obligated to actively seek this information in former study participants, he or she 
may learn of an SAE through spontaneous reporting.
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. 


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12.10.
Appendix 10 – Country-specific Requirements
United Kingdom
This requirement has been included based on requests from the Medicines and Healthcare 
products Regulatory Agency (MHRA) to include information on the specific duration of 
the Continuation Phase/Study Treatment for similar Phase III trials being conducted with 
dolutegravir.
Study Duration
In this study, the date of last study treatment administration in the UK will be determined 
by the completion of the 148 week 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 March 2017, and hence the last study treatment 
administration will occur by January 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 December 2020, 
when the dual regimen of DTG plus 3TC is anticipated to be approved).


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12.11.
Appendix 11: Protocol Changes
12.11.1.
Protocol Amendment 01
This global amendment is applicable to all participating sites.
Summary of Changes in Protocol Amendment 01 and Rationale:

The double barrier method of contraception (male condom combined with a vaginal 
spermicide) was added in this study as a permitted method for preventing pregnancy 
in females of reproductive potential.  All study medications have full marketing 
approval, and based on animal studies, have a very low risk for embryofetal toxicity. 
The use of the double barrier method is considered to be an acceptable method of 
contraception with very low failure rates.  

Exclusion criterion #15 (limitations on investigational drug use) was broadened to 
include additional countries as needed.  Inclusion of Portugal was required by the 
Portuguese National Ethics Committee for Clinical Research.

Assessment of weight at Weeks 96 and 144 was added to monitor the incidence of 
significant weight gain with dolutegravir use.

Assessment of inflammation biomarkers (IL-6, hs-CRP), at Day 1, and Weeks 48, 96 
and 144, was added as a new exploratory endpoint. Elevated levels of inflammation 
may be associated with the occurrence of non-AIDS-defining events such as 
cardiovascular disease, liver disease and cancer. Changes from Baseline between the 
2-drug and 3-drug regimen will be evaluated.

Assessment of telomere length at Day 1, and Weeks 96 and 144, was added as a new 
exploratory endpoint. Telomere length may be a marker for accelerated aging, and
perturbations in this marker may be associated with aging-related morbidities. Where 
possible, changes from Baseline between the 2-drug and 3-drug regimen will be 
evaluated.

For clarification purposes, the ‘peripheral blood mononuclear cell (PBMC)’ sample
in Section 7.1 (Time and Events table) and Section 7.6.1 (HIV-1 Exploratory 
Analyses) was renamed as a ‘whole blood’ sample. 

The Day 1 ‘PBMC’ sample (now named ‘whole blood’ sample) originally designated 
for virology use was additionally designated for telomere length measurement, where 
possible.  Additional whole blood samples were added for measurement of telomere 
length at Week 96 and Week 144.

A description of commercial image dolutegravir tablets was added to Section 6.1 
(Investigational Product and Other Study Treatment) to allow use of commercial
material as well as clinical trial material during the study.

The physical description for open-label lamivudine in Section 6.1 was corrected. 


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
To correct an omission, standard procedures for forwarding pregnancy information 
to the Antiretroviral Pregnancy Register were added.

For clarification purposes, the AE severity gradings in Appendix 7, Section 12.7.6 
(Evaluating AEs and SAEs) were updated to be consistent with Appendix 6, 
Section 12.6. (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.
LIST OF SPECIFIC CHANGES
Unless stated otherwise, new text is represented in bold font, and deleted text in 
strikethrough font.

Authors
Amended text:
 

Medical monitor/Sponsor Information Page
Amended text:
Secondary 
Medical 
Monitor
MD
ViiV Healthcare
980 Great West 
Road, Brentford, 
Middlesex, TW8 
9GS, UK
Mailstop UP4410
Collegeville, PA 
(USA)

Section 1. Protocol Synopsis; Overall Design
Amended text: 
The study initially will enrol approximately 100 subjects with a Screening HIV-1 RNA of 
1000 to 100,000 c/mL.  Accumulated data from other clinical trials investigating the 
DTG plus 3TC dual regimen will undergo independent review.  If the independent review 
is supportive of evaluating the dual regimen’s efficacy in subjects with a Screening viral 
PPD
PPD


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load of up to 500,000 c/mL, recruitment will be opened to subjects with a Screening 
HIV-1 RNA of 1000 to 500,000 c/mL.  If the review does not support enrolment of such 
subjects, the Screening viral load will remain capped at 100,000 c/mL. This 
independent review of accumulated data on the DTG plus 3TC dual regimen was 
supportive, enabling an increase in the Screening viral load cap to ≤500,000 c/mL
for subjects screened on/after 5 November 2016.

Section 2.1. Study Rationale
Amended text: 
Current HIV treatment guidelines recommend first-line antiretroviral (ARV) regimens 
consisting of two nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) 
as a “backbone” combined with a third agent from the non-nucleoside reverse 
transcriptase inhibitor (NNRTI), protease inhibitor (ritonavir-boosted) (PI/RTV), or 
integrase strand transfer inhibitor (INSTI) classes [BHIVA, 2015; DHHS, 2016; EACS, 
2015; IAS-USA, 2014].  While these regimens are highly efficacious and generally well 
tolerated, there is growing concern about long-term toxicities, and great interest from 
patients and clinicians in unique regimens that might avoid such toxicities, and to provide 
effective long-term ART with the most streamlined regimens possible.
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 
immuno-deficiency syndrome (AIDS)-defining events such as cardiovascular 
disease, liver disease and cancer. These non-AIDS-defining events are now the 
leading causes of morbidity and mortality among treated HIV-infected persons. The 
aetiologies of these non-AIDS-defining events are multi-factorial and 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. 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 


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found to produce the most significant inhibition of telomerase leading to accelerated 
shortening of telomere length in activated PBMCs [Leeansyah, 2013; Stella-Ascariz, 
2017].

Section 2.2. Brief Background
Amended text: 
Limited data are also available from two pilot studies to evaluate the dual regimen 
of DTG plus 3TC:

An ongoing investigator-initiated 48-week pilot study, the PADDLE trial 
(NCT02211482), is being has been conducted in 20 HIV treatment-naïve subjects 
with no genotypic resistance to 3TC and a viral load of 100,000 c/mL at Screening 
and has provided notable early data on the efficacy of a once-daily DTG plus 3TC 
two-drug regimen.  Subjects were enrolled in two separate groups of 10, allowing 
close evaluation of response while employing a set of stopping rules with intensive 
follow-up in each cohort.  By Week 8, all 20 subjects, including 4 subjects with a 
Baseline HIV-1 RNA of >100,000 c/mL, had reached a viral load of <50 c/mL and all 
maintained virologic suppression through Week 24 [Figueroa, 2015]. At Week 48, 
18/20 (90%) of subjects achieved the primary endpoint of plasma HIV-1 RNA 
<50 copies/mL using the FDA snapshot algorithm for the intention to treat –
exposed (ITT-E) population [Cahn, 2017].

The ongoing ACTG A5353 trial is a Phase II, single-arm pilot study of once-
daily DTG plus 3TC in treatment-naïve HIV-1-infected participants with a viral 
load of ≥1000 to <500,000 c/mL.  Virologic efficacy (plasma HIV-1 RNA 
<50 c/mL using the FDA Snapshot) at Week 24 was 108/120 (90%) with no 
significant difference between the low (≤100,000 c/mL) and high (>100,000 c/mL) 
viral load strata: 90% and 89%, respectively [Taiwo, 2017].

Section 3. Objectives and Endpoints

Additional text: 
Objectives
Endpoints
Exploratory

To evaluate inflammation biomarkers 
in subjects treated with DTG+ 3TC 
compared to DTG + TDF/FTC
Change from Baseline in inflammation 
biomarkers at Weeks 48, 96 and 144
To evaluate telomere length in subjects 
treated with DTG + 3TC compared to 
DTG + TDF/FTC
Change from Baseline in telomere 
length at Weeks 96 and 144


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
Section 4.1. Overall Design, and Section 4.3. Type and Number of Subjects
Amended text: 
The study initially will enrol approximately 100 subjects with a Screening HIV-1 RNA of 
1000 to 100,000 c/mL.  Accumulated data from other clinical trials investigating the 
DTG plus 3TC dual regimen will undergo independent review.  If the independent review 
is supportive of evaluating the dual regimen’s efficacy in subjects with a Screening viral 
load of up to 500,000 c/mL, recruitment will be opened to subjects with a Screening 
HIV-1 RNA of 1000 to 500,000 c/mL.  If the review does not support enrolment of such 
subjects, the Screening viral load will remain capped at 100,000 c/mL. This 
independent review of accumulated data on the DTG plus 3TC dual regimen was 
supportive, enabling an increase in the Screening viral load cap to ≤500,000 c/mL
for subjects screened on/after 5 November 2016.

Section 5.2. Exclusion Criteria
Amended text:
15. Subjects enrolled in France (and other countries as required by local regulations 
or ethics committees/IRBs): the subject has participated in any study using an 
investigational drug during the previous 60 days or 5 half-lives, or twice the duration 
of the biological effect of the experimental drug or vaccine, whichever is longer, prior 
to screening for the study or the subject will participate simultaneously in another 
clinical study.


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
Section 6.1. Investigational Product and Other Study Treatment
Amended text: 
Study Treatment 
(Double-blind Randomised Phase, Day 1 to Week 96)
Product name:
Dolutegravir, DTG
Lamivudine, 3TC
Tenofovir disoproxil 
fumarate/emtricitabine 
fixed-dose combination, 
TDF/FTC FDC
Formulation 
description:
Commercial supply
or 
Clinical trial material, which is 
the same formulation as the 
commercial material with the 
exception of the film coat 
colour
Over-encapsulated 
commercial supply 
tablet to visually match 
over-encapsulated 
TDF/FTC FDC tablet
Over-encapsulated 
commercial supply tablet 
to visually match over-
encapsulated 3TC tablet
Dosage form:
Tablet
Capsule
Capsule
Unit dose 
strength(s)/Dosage 
level(s):
50 mg
300 mg
300 mg TDF/200 mg FTC
Route of 
Administration:
Oral
Oral
Oral
Dosing instructions:
Take one tablet once daily 
with or without food
Take one capsule once 
daily with or without 
food
Take one capsule once 
daily with or without food
Physical 
description:
Commercial supply: 
Yellow, round, film-coated, 
biconvex tablets debossed 
with “SV 572” on one side 
and “50” on the other side.  
The tablets are packaged 
into HDPE bottles with 
induction seals and child-
resistant closures, each 
containing 30 tablets.
Clinical trial supply: White, 
round, biconvex, film-coated 
tablets debossed on one side 
with “SV 572” and on the 
other side with “50”.  The 
tablets are packaged into 
high density polyethylene 
(HDPE) bottles with induction 
seals and child-resistant 
closures. Each 45 ml bottle 
contains 30 tablets and a 
desiccant.
Swedish Orange, size 
AA elongated double-
blind hydroxypropyl 
methylcellulose 
(HPMC) capsules.  The 
capsules are packaged 
into HDPE bottles with 
induction seals and 
child- resistant
closures.   Each 150 
mL bottle contains 
30 capsules and a 
desiccant.
Swedish Orange, size AA 
elongated double-blind 
HPMC capsules.  The 
capsules are packaged 
into HDPE bottles with 
induction seals and child-
resistant closures.   Each 
150 mL bottle contains 
30 capsules and a 
desiccant.


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Study Treatment 
(Open-label Randomised Phase, Week 96 to Week 148)
Product name:
Dolutegravir, DTG
Lamivudine, 3TC
Tenofovir disoproxil 
fumarate/emtricitabine 
fixed-dose combination, 
TDF/FTC FDC
Formulation 
description:
Commercial supply
or
Clinical trial material, 
which is the same 
formulation as the 
commercial material with 
the exception of the film 
coat colour
Commercial supply
Commercial supply
Dosage form:
Tablet
Tablet
Tablet
Unit dose 
strength(s)/Dosage 
level(s):
50 mg
300 mg
300 mg TDF/200 mg FTC
Route of 
Administration:
Oral
Oral
Oral
Dosing instructions:
Take one tablet once daily 
with or without food
Take one tablet once 
daily with or without food
Take one tablet once daily 
with or without food
Physical 
description:
Commercial supply: 
Yellow, round, film-
coated, biconvex tablets 
debossed with “SV 572” 
on one side and “50” on 
the other side.  The 
tablets are packaged 
into HDPE bottles with 
induction seals and 
child-resistant closures, 
each containing 
30 tablets.
Clinical trial supply:
White, round, biconvex, 
film-coated tablets 
debossed on one side with 
“SV 572” and on the other 
side with “50”.  The tablets 
are packaged into HDPE 
bottles with induction seals 
and child-resistant 
closures. Each 45 ml 
bottle contains 30 tablets 
and a desiccant.
Gray, diamond-shaped, 
film-coated tablets 
engraved with “GX 
EJ7” on one side and 
plain on the reverse 
side.  White, diamond-
shaped, scored, film-
coated tablets debossed 
with “GX CJ7” on both 
sides.  The tablets are 
packed into over-labelled
HDPE bottles with child-
resistant closures each 
containing 30 tablets. 
Blue, capsule-shaped, 
film-coated tablet, 
debossed on one side with 
“GILEAD” and on the other 
side with “701”.  The 
tablets are packed in over-
labelled HDPE bottles with 
polypropylene child-
resistant closures each 
containing 30 tablets and 
a desiccant.


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Study Treatment 
(Continuation Phase)
Product name:
Dolutegravir, DTG
Lamivudine, 3TC
Formulation 
description:
Commercial supply
or 
Clinical trial material, which is the 
same formulation as the commercial 
material with the exception of the 
film coat colour
Commercial supply
Dosage form:
Tablet
Tablet
Unit dose 
strength(s)/Dosage 
level(s):
50 mg
300 mg
Route of 
Administration:
Oral
Oral
Dosing instructions:
Take one tablet once daily with or 
without food
Take one tablet once daily with or without 
food
Physical description:
Commercial supply: 
Yellow, round, film-coated, 
biconvex tablets debossed with 
“SV 572” on one side and “50” on 
the other side.  The tablets are 
packaged into HDPE bottles with 
induction seals and child-
resistant closures, each 
containing 30 tablets.
Clinical trial supply:
White, round, biconvex, film-coated 
tablets debossed on one side with 
“SV 572” and on the other side with 
“50”.  The tablets are packaged into 
HDPE bottles with induction seals 
and child-resistant closures. Each 
45 ml bottle contains 30 tablets and 
a desiccant.
Gray, diamond-shaped, film-coated 
tablets engraved with “GX EJ7” on 
one side and plain on the reverse side.  
White, diamond-shaped, scored, film-
coated tablets debossed with “GX CJ7” 
on both sides.  The tablets are packed 
into over-labelled HDPE bottles with 
child-resistant closures each containing 
30 tablets. 

Section 7.1. Time and Events Table
The Time and Events Table was amended as follows: 

Assessment of weight was added at Weeks 96 and 144.

Assessment of inflammation biomarkers (IL-6, hs-CRP) was added at Day 1, and 
Weeks 48, 96 and 144. 

The ‘peripheral blood mononuclear cell (PBMC)’ sample was renamed as a ‘whole 
blood’ sample. 

The Day 1 ‘PBMC’ sample (now renamed ‘whole blood’ sample) will also be used 
for telomere length measurement, where possible.

Additional whole blood samples were added for measurement of telomere length at 
Weeks 96 and 144.

Addition of footnote ‘v’ required original footnote ‘v’ to be renamed footnote ‘w’.


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Amended text:
Procedures
Screening Visita
Double-blind Randomised Phase
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline / Day 1
Week
Every 12 
weeks after 
Week 148
4
8
12
16
24
28b
36
48
52b
60
72
84
96
100b
108
120
132
144
148
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
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
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
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symptom Directed 
Physical Exam/Medical 
Decision Makingi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGj
X


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Procedures
Screening Visita
Double-blind Randomised Phase
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline / Day 1
Week
Every 12 
weeks after 
Week 148
4
8
12
16
24
28b
36
48
52b
60
72
84
96
100b
108
120
132
144
148
Adverse events
X
X
X
X
X
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
X
X
X
X
X
EQ-5D-5Ll
X
X
X
X
X
X
X
Laboratory Assessments
Plasma for HIV 
genotyping
X
Quantitative plasma HIV-
1 RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xm
X
X
Lymphocyte subset 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for 
storage/inflammation 
biomarkersn
X
X
X
X
X
X
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
X
X
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and 
glucoseo
X
X
X
X
X
Xp
Urinalysis and spot urine 
for protein analysisq
X
X
X
X
X
X
X
Pregnancy testr
S
U
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
HBsAg, anti-HBc, anti-
HBs, and HBV DNAs
X
HCV antibody
X
RPR
X


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Procedures
Screening Visita
Double-blind Randomised Phase
Open-label Randomised Phase
Continuation 
Phasec
Withdrawal
Follow-upd
Baseline / Day 1
Week
Every 12 
weeks after 
Week 148
4
8
12
16
24
28b
36
48
52b
60
72
84
96
100b
108
120
132
144
148
Renal and bone marker 
analytes (blood/urine)t
X
X
X
X
X
X
PBMCsWhole blood for 
virology/telomere 
lengthu
Xu
Xu
Xu
Whole blood for 
telomere lengthv
X
X
Study Treatment
IVRS/IWRSvw
X
X
X
X
X
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
X
X
X
X
Study treatment 
accountability (pill 
counts)
X
X
X
X
X
X
X
X
X
X
X
X
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, ECG = electrocardiograph, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus type 1, INR = international 
normalised ratio, IVRS = interactive voice recognition system, IWRS = interactive web recognition system, PBMC = peripheral blood mononuclear cell, PT = prothrombin time, RNA = 
ribonucleic acid, RPR = rapid plasma reagin
a.
Randomisation may occur as soon as all Screening results are available.
b.
Subjects with plasma HIV-1 RNA levels 50 c/mL at Week 24, Week 48 and Week 96 must have HIV-1 levels re-assessed by a second measurement performed four weeks later 
at the Week 28, Week 52 visit and Week 100 visit, respectively. Subjects should have received full doses of study treatment for at least 2 weeks at the time of HIV-1 RNA re-
assessment for any HIV-1 RNA level 50 c/mL.  Subjects with plasma HIV-1 RNA levels <50 c/mL at Week 24, Week 48 and Week 96 should not attend the Week 28 visit,  Week 
52 visit and Week 100 visit, respectively.
c.
Subjects randomised to DTG plus 3TC who complete through Week 148 may 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.


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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.
f.
Full medical history will be conducted prior to randomisation 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.
At Screening, 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. Body mass index (BMI) will be calculated within the eCRF.  At Week 96 and Week 144, only weight will be 
measured.
h.
On Day 1, the electronic Columbia Suicidality Severity Rating Scale (eC-SSRS) is to be administered prior to randomisation. 
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 Healthcare/GSK product will be collected between obtaining informed consent and administration 
of study drug at Day 1.
l.
The questionnaire is recommended to be administered at the beginning of the visit before any other assessments are conducted.  Only conduct the questionnaire at Withdrawal if 
occurring prior to Week 144. 
m.
At Week 148, repeat HIV-1 RNA testing will only be performed for subjects with HIV-1 RNA 50 c/mL at Week 144. 
n.
Plasma samples for storage will be collected at each visit, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  Additionally, these samples will 
be used when needed such as when samples are lost or arrive at the laboratory unevaluable or as a priority need for genotypic and/or phenotypic analyses when subjects meet 
CVW criteria. Additionally, inflammation biomarkers (IL-6, hs-CRP) will be measured at Day 1, Week 48, Week 96 and Week 144 using stored plasma samples.
o.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
p.
Only collect fasting lipids and glucose if the Withdrawal visit occurs at Week 24, Week 48, Week 96 or Week 144.
q.
A morning specimen is preferred. To assess renal biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
r.
Pregnancy testing will be conducted (females of reproductive potential only) on serum (S) samples with the exception of Day 1, which must be a urine (U) test to confirm status 
prior to administration of study treatment.
s.
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.
t.
Blood samples for renal and bone biomarker assessments: Renal: Cystatin C; Beta-2 Microglobulin; Retinol Binding Protein (RBP); Bone: bone specific alkaline phosphatase, 
procollagen type I N-terminal propeptide, type I collagen cross-linked C-telopeptide, osteocalcin, 25-hydroxyvitamin D. Urine sample for renal biomarker assessments: RBP and 
Beta-2-Microglobulin.  Only collect at the Withdrawal visit if it occurs at Week 24, Week 48, Week 96 or Week 144.
u.
Whole bloodPBMC collection samples may be used for virologic analyses as described in the protocol; a sample at Day 1 and a second sample at either Week 148 or at 
Withdrawal (if a subject is withdrawn prior to Week 148) will be taken for all subjects. Additionally, where possible, stored whole blood from Day 1 will be used for telomere 
length evaluation (while telomere length evaluation at Week 96 and Week 144 require a separate whole blood sample).
v.
Whole blood samples for telomere length evaluation will be taken at Week 96 and Week 144 (where possible, the Day 1 evaluation will be done from the stored whole 
blood ‘virology/telomere length’ sample in footnote ‘u’).
w.
At Screening, a subject number will be generated.


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
Section 7.4.5. Clinical Safety Laboratory Assessments, Table 1.
Amended text: 
Other 
Laboratory 
Tests

Plasma HIV-1 RNA 6

CD4+ cell counts

Hepatitis B (HBsAg, anti-HBc, anti-HBs, HBV DNA)

Hepatitis C (anti-HCV)

RPR

PT/INR 

Serum hCG pregnancy test (as needed for females of reproductive 
potential) 7

Urinalysis, urine albumin/creatinine ratio, and urine 
protein/creatinine ratio, urine phosphate

Renal biomarkers including Cystatin C (blood), Retinol Binding 
Protein (RBP, blood/urine); and Beta-2 Microglobulin (B2M, 
blood/urine) 8

Bone biomarkers including: bone-specific alkaline phosphatase, 
procollagen type I N-terminal propeptide, type I collagen cross-
linked C-telopeptide, osteocalcin, 25-hydroxyvitamin D 8

Inflammation biomarkers including IL-6 and hs-CRP 8

Telomere length 8
ALT = alanine aminotransferase,  anti-HBc = hepatitis B core antibody, anti-HBs = hepatitis B surface 
antibody, anti-HCV = hepatitis C antibody, AST = aspartate aminotransferase,  BUN = blood urea nitrogen, 
CO2 = carbon dioxide, HBsAg = hepatitis B surface antigen, HBV DNA = hepatitis B virus 
deoxyribonucleic acid, HDL = high density lipoprotein, LDL = low density lipoprotein, MCH = mean 
corpuscular haemoglobin, MCV = mean corpuscular volume, PT/INR = prothrombin time/international 
normalised ratio, RBC = red blood cells, RPR = rapid plasma reagin, WBC = white blood cells, IL-6 = 
interleukin 6, hs-CRP = high-sensitivity C-reactive protein

Section 7.5. Biomarkers
Amended text: 
Blood and/or urine are being collected to perform evaluations of renal, and bone and
inflammation biomarkers, and telomere length biomarker assessments as outlined in 
Section 7.1.  
Renal biomarkers include: 

Cystatin C (blood)

Retinol Binding Protein (RBP, blood/urine),

Beta-2-Microglobulin (B2M, blood/urine), 

urine albumin/creatinine ratio, 

urine protein/creatinine ratio, 

urine phosphate, and 

serum creatinine.  


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Bone biomarkers (blood) include:

bone-specific alkaline phosphatase, 

procollagen type 1 N-propeptide, 

type 1 collagen cross-linked C-telopeptide, 

osteocalcin, and 

25-hydroxyvitamin D.  
Inflammation biomarkers include:

interleukin-6 (IL-6, blood)

high-sensitivity C reactive protein (hs-CRP, blood)
Telomere length (whole blood)

Section 7.6.1. HIV-1 Exploratory Analyses
Amended text: 
Additional virologic analyses for HIV-1 may, for example, be carried out on peripheral 
blood mononuclear cell (PBMC) whole blood samples collected at Baseline or on study 
per Time and Events Table (Section 7.1), and/or on stored plasma samples from other 
relevant time points.

Section 11. References
Amended text: 
EPIVIR Product Information (lamivudine), September 20157.
GlaxoSmithKline Document Number RM2007/00683/0911: GSK1349572 Clinical 
Investigator's Brochure, version 0911. October 20157.
TIVICAY Product Information (dolutegravir), August 2015March 2017
Truvada Product Information (emtricitabine/tenofovir disaproxil fumarate), March 2016 
April 2017
Additional Notes: 
References to the Investigator’s Brochure were updated in Section 2.1., Section 2.2., 
Section 4.6., Section 12.8.1.6., and Section 12.8. (References).
References to the product information for EPIVIR, TIVICAY and Truvada were updated 
in Section 2.1. and Section 6.7.


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
Section 11. References
Additional text (references):
Cahn P, Rolón MJ, Figueroa MI, et al. Dolutegravir-lamivudine as initial therapy in HIV-
Infected, ARV-naïve patients, 48 Week results of the PADDLE (Pilot Antiretroviral 
Design with Dolutegravir LamivudinE) study. J.Int AIDS Society 2017, 20:21678.
Leeansyah E, Cameron PU, Solomon A, et al. Inhibition of telomerase activity by human 
immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential 
factor contributing to HIV-associated accelerated aging. J Infect Dis. 2013;207:1157–65.
Solomon A, Tennakoon S, Leeansyah E, et al. No Difference in the Rate of Change in 
Telomere Length or Telomerase Activity in HIV-Infected Patients after Three Years of 
Darunavir/Ritonavir with and without Nucleoside Analogues in the MONET Trial. PLoS 
ONE. 2014;9(11): e109718. Available at: 
http://journals.plos.org/plosone/article/asset?id=10.1371/journal.pone.0109718.PDF. 
Accessed 15 November 2017.
Stella-Ascariz N, Montejano R, Pintado-Berninches P, et al. Brief Report: Differential 
effects of tenofovir, abacavir, emtricitabine, and darunavir on telomerase activity in vitro. 
J. Acquir Immune Defic Syndr 2017;74:91-94.
Taiwo BO, Zheng L, Nyaku AN, et al. ACTG A5353: a pilot study of dolutegravir 
(DTG) + lamivudine (3TC) for initial treatment of HIV-1-infected participants with HIV-
1 RNA <500,000 copies/mL. IAS 2017, 9th IAS Conference on HIV Science. Paris, 
France. Abstract TULBPEB21.

Section 12.1. Appendix 1: Abbreviations and Trademarks
Additional text (abbreviations):
hs-CRP
High-sensitivity C-reactive protein
IL-6
Interleukin-6


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
Section 12.7.6. Evaluating AEs and SAEs
Amended 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 following categories in the Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(“DAIDS AE Grading Table”) in Appendix 6, Section 12.6.:

Grade 1 / Mild  An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.

Grade 2 / Moderate:  An event that is sufficiently discomforting to interfere with 
normal everyday activities

Grade 3 / 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 utilised 
for rating the intensity of an event; and both AEs and SAEs can be assessed as 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 12.8.1.4. Proteinuria
Amended 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.

Section 12.9.1. Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP)
Additional text (i.e., an additional method was added to the list of methods for 
avoiding pregnancy):
In addition, male condom combined with a vaginal spermicide (foam, gel, film, 
cream, or suppository) [Hatcher, 2011] is included in this study as a permitted 
method of contraception.


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
Section 12.9.2. Collection of Pregnancy Information
Additional text:

GSK’s central safety department will also forward this information to the 
Antiretroviral Pregnancy Registry. The international registry is jointly 
sponsored by manufacturers or licensees of antiretroviral products. Additional 
information and a list of participating manufacturers/licensees are available 
from http://www.apregistry.com/.
12.11.2.
Protocol changes for Amendment 02 (14-JUN-2018) from   
Amendment 01 (29-NOV-2017)
This global amendment is applicable to all participating sites.
Summary of Changes in Protocol Amendment 02 and Rationale:
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 update 
the references to the DTG IB to reflect the most current versions.

The Risk Assessment table (Section 4.6.1) was updated to include language 
regarding risk and mitigation of neural tube defects.

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.

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.

The modified list of highly effective methods for avoiding pregnancy in FRP 
(Section 12.9.1) was updated to exclude the double barrier method of contraception, 
which does not meet updated GSK/ViiV criteria for a highly effective method.
LIST OF SPECIFIC CHANGES
Unless stated otherwise, new text is represented in bold font, and deleted text in 
strikethrough font.
Title Page, Authors: 
Updated text: Man, Choy; Sievers, Jorg; Urbaityte, Rimgaile; Currie, Alexander; Davis, 
Karen; Pappa, Keith; Ward, Paulina; Brandon, Daisy; Underwood, Mark; Curtis, Lloyd; 


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Murray, Miranda; Tenorio, Allan; Wynne, Brian; Gartland, Martin; Case, Laura; 
Fettiplace, Anna; Blair, Elizabeth.
Section 4.6.1: Risk Assessment
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 9, Section 
12.9.1) 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


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Section 5.1 Inclusion Criteria:
Updated inclusion criterion 4: b.  Reproductive potential and agrees to follow one of the 
options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP) (see Appendix 9, Section 12.9.1) from 30 
days prior to the first dose of study medication and for at least 2 weeks after the last 
dose of study medication. until the last dose of study medication and completion of the 
Follow-up visit.
Section 5.4: Withdrawal/Stopping Criteria

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
Footnote S added: 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 11: 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 12.9.1: Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
In addition, male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository) [Hatcher., 2011] is included in this study as a permitted method of 
contraception.