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 Human Immunodeficiency Virus 1 Infected Treatment naïve Adults
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus, HIV Infections
Sponsor: ViiV Healthcare

 
                                                         Protocol 
 
Study ID:  204861 
 
Official Title of Study: A Phase III, randomised, double-blind, multicentre, 
parallelgroup, 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 
 
NCT ID: NCT0221148  
 
Date of Document: 14-Jun-2018  
 
 

2 0 1 5 N 2 4 2 9 7 8 _ 0 2
C O N FI D E N TI A L
Vii V H e alt h c ar e a n d t h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s
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Di visi o n: W orl d w i de De vel o p me nt
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt
Title:
A P hase III, ra n d o mise d, d o u ble- bli n d, m ultice ntre, parallel -
gr o u p, n o n -i nferi orit y st u d y e val uati n g t he efficac y, safety, a n d
t olera bilit y of d ol ute gra vir pl us la mi v u dine c o m pare d t o 
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C o p y ri g ht 2 01 8 Vii V Healt hcare a n d t he Gla x o S mit h Kli ne gr o u p of c o m pa nies.  All
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2015N242978_02
CONFIDENTIAL
ViiV Healthcare and the GlaxoSmithKline group of companies
204861
2
Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2015N242978_00
2016-APR-25
Original
2015N242978_01
2017-DEC-01
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.

2015N242978_02
CONFIDENTIAL
ViiV Healthcare and the GlaxoSmithKline group of companies
204861
3
2015N242978_02
2018-JUN-14
Amendment No. 2
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.

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5
M E DI C A L M O NI T O R/ S P O N S O R I N F O R M A T I O N P AG E
Me dic al M o nit or/ S A E C o nt act I nf or m ati o n:
R ol e
N a m e
D ay Ti m e P h o n e N u m b er a n d 
e m ail a d dr ess
Aft er -h o urs 
P h o n e/ C ell/
P a g er 
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M e dic al 
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a b ov e
T his st u d y  is s p o ns ore d b y Vii V Healt hcare.  P P D I nc. a n d Gla x o S mit h Kli ne are 
s u p p orti n g Vii V Healt hcare i n t he c o n d uct of t his st u d y. 
Gl o b al S p o ns or Le g al Re gistere d A d dress (e xcl u di n g U S): 
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9 8 0 Great West R oa d
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c o m p a n y le g al e ntit y.  I n t hese i nst a nces, t he a p pr o pri ate c o m p a n y t o be i de ntifie d 
as s p o ns or m ust be a gree d wit h t he gl o b al Vii V He a lt hc are cli nic al te a m a n d si g ne d 
off b y t he V P a n d He a d , Gl o b al Rese arc h a n d Me dic al Str ate g y.    
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2015N242978_02
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6
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204861
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

2015N242978_02
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7
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204861......................................................11
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................17
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Treatment Arms and Duration.....................................................................20
4.3.
Type and Number of Subjects.....................................................................21
4.4.
Design Justification.....................................................................................22
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................22
4.6.1.
Risk Assessment .........................................................................23
4.6.2.
Benefit Assessment.....................................................................28
4.6.3.
Overall Benefit:Risk Conclusion...................................................28
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............28
5.1.
Inclusion Criteria.........................................................................................29
5.2.
Exclusion Criteria........................................................................................31
5.3.
Screening Failures......................................................................................32
5.4.
Withdrawal/Stopping Criteria.......................................................................33
5.4.1.
Virologic Criteria for Subject Management and Viral 
Resistance Testing ......................................................................34
5.4.1.1.
Virologic Withdrawal Criteria.......................................34
5.4.1.2.
Managing Subjects Meeting Suspected 
Virologic Withdrawal Criteria.......................................35
5.4.1.3.
Managing Subjects Meeting Confirmed 
Virologic Withdrawal Criteria.......................................36
5.4.1.4.
Managing subjects with HIV-1 RNA 50 c/mL 
at Weeks 24, 48, 96 and 144......................................37
5.4.2.
Liver Chemistry Stopping Criteria ................................................37
5.4.2.1.
Study Treatment Restart ............................................38
5.5.
Subject and Study Completion....................................................................39
6.
STUDY TREATMENT ............................................................................................39
6.1.
Investigational Product and Other Study Treatment....................................39
6.2.
Treatment Assignment................................................................................42
6.3.
Blinding.......................................................................................................43
6.3.1.
Emergency Unblinding.................................................................43
6.3.2.
Scheduled Unblinding..................................................................44
6.4.
Packaging and Labeling..............................................................................44
6.5.
Preparation/Handling/Storage/Accountability..............................................44
6.6.
Compliance with Study Treatment Administration.......................................44
6.7.
Treatment of Study Treatment Overdose....................................................45
6.8.
Treatment after the End of the Study ..........................................................45

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8
6.9.
Concomitant Medications and Non-Drug Therapies....................................45
6.9.1.
Permitted Medications and Non-Drug Therapies..........................46
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................46
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................47
7.1.
Time and Events Table...............................................................................48
7.2.
Screening and Critical Baseline Assessments ............................................52
7.2.1.
Screening Assessments ..............................................................52
7.2.2.
Baseline Assessments.................................................................53
7.3.
Efficacy.......................................................................................................53
7.4.
Safety .........................................................................................................54
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........54
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................54
7.4.1.2.
Method of Detecting AEs and SAEs ...........................55
7.4.1.3.
Follow-up of AEs and SAEs........................................55
7.4.1.4.
Cardiovascular and Death Events ..............................55
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................55
7.4.1.6.
Regulatory Reporting Requirements for SAEs............56
7.4.2.
Pregnancy ...................................................................................56
7.4.3.
Physical Exams ...........................................................................57
7.4.4.
Electrocardiogram (ECG).............................................................57
7.4.5.
Clinical Safety Laboratory Assessments ......................................57
7.4.6.
Suicidal Risk Monitoring...............................................................59
7.5.
Biomarkers .................................................................................................60
7.6.
HIV-1 Polymerase Viral Genotyping and Phenotyping ................................61
7.6.1.
HIV-1 Exploratory Analyses .........................................................61
7.7.
Value Evidence and Outcomes...................................................................61
7.7.1.
Value Evidence and Outcomes Endpoints ...................................62
8.
DATA MANAGEMENT ...........................................................................................62
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................62
9.1.
Hypotheses.................................................................................................62
9.2.
Sample Size Considerations.......................................................................63
9.2.1.
Sample Size Assumptions ...........................................................63
9.2.1.1.
Rationale for non-inferiority margin.............................63
9.2.1.2.
Response rate assumptions .......................................63
9.2.2.
Sample Size Sensitivity................................................................63
9.2.3.
Sample Size Re-estimation or Adjustment...................................64
9.3.
Data Analysis Considerations .....................................................................64
9.3.1.
Analysis Populations....................................................................64
9.3.1.1.
Intent-to-Treat Exposed (ITT-E) Population ................64
9.3.1.2.
Per Protocol (PP) Population......................................64
9.3.1.3.
Safety Population .......................................................64
9.3.2.
Analysis Data Sets.......................................................................65
9.3.3.
Treatment Comparisons ..............................................................65
9.3.3.1.
Primary Comparison of Interest ..................................65
9.3.3.2.
Other Comparisons of Interest....................................65
9.3.3.3.
Secondary comparisons .............................................65
9.3.4.
Interim Analyses ..........................................................................66

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9
9.4.
Key Elements of Analysis Plan ...................................................................66
9.4.1.
Efficacy Analyses.........................................................................66
9.4.2.
Safety Analyses...........................................................................68
9.4.3.
Viral Genotyping/Phenotyping Analyses ......................................68
9.4.4.
Other Analyses ............................................................................69
10. STUDY GOVERNANCE CONSIDERATIONS........................................................69
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............69
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................69
10.3.
Quality Control (Study Monitoring) ..............................................................69
10.4.
Quality Assurance.......................................................................................70
10.5.
Study and Site Closure ...............................................................................70
10.6.
Records Retention......................................................................................71
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................71
10.8.
Independent Data Monitoring Committee....................................................72
11. REFERENCES.......................................................................................................73
12. APPENDICES........................................................................................................77
12.1.
Appendix 1: Abbreviations and Trademarks................................................77
12.2.
Appendix 2: Child-Pugh Classification ........................................................80
12.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................81
12.4.
Appendix 4: Liver Safety – Study Treatment Restart Guidelines.................84
12.5.
Appendix 5: CDC Classification for HIV-1 Infection (2014)..........................88
12.6.
Appendix 6: Division of AIDS table for Grading Severity of Adult and 
Pediatric Adverse Events............................................................................90
12.7.
Appendix 7: Definition of and Procedures for Recording, Evaluating, 
Follow-up and Reporting of Adverse Events .............................................118
12.7.1.
Definition of Adverse Events......................................................118
12.7.2.
Definition of Serious Adverse Events.........................................119
12.7.3.
Definition of Cardiovascular Events ...........................................120
12.7.4.
Sentinel Events..........................................................................121
12.7.5.
Recording of AEs and SAEs ......................................................121
12.7.6.
Evaluating AEs and SAEs..........................................................122
12.7.7.
Reporting of SAEs and other events to ViiV 
Healthcare/GSK/PPD.................................................................123
12.8.
Appendix 8: Toxicity Management ............................................................125
12.8.1.
Specific Toxicities/Adverse Event Management.........................126
12.8.1.1.
Liver Chemistry Stopping and Follow-up 
Criteria......................................................................126
12.8.1.2.
Restarting Study Drug ..............................................126
12.8.1.3.
Decline in Renal Function.........................................127
12.8.1.4.
Proteinuria................................................................127
12.8.1.5.
Allergic reaction........................................................128
12.8.1.6.
Rash.........................................................................128
12.8.1.7.
Hypertriglyceridemia/Hypercholesterolemia..............129
12.8.1.8.
Creatine Phosphokinase (CPK) Elevation ................129
12.9.
Appendix 9: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.....................130

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12.9.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ............130
12.9.2.
Collection of Pregnancy Information ..........................................130
12.10. Appendix 10: Country-specific Requirements ...........................................132
12.11. Appendix 11: Protocol Changes................................................................133
12.11.1. Protocol Amendment 01 ............................................................133
12.11.2. Protocol changes for Amendment 02 (14-JUN-2018) from 
Amendment 01 (01-DEC-2017) .................................................149

2015N242978_02
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11
1.
PROTOCOL SYNOPSIS FOR STUDY 204861
Rationale
Study 204861 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, 205543, will be conducted in parallel with Study 204861 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

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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 205543.
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).  

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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 
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 

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telomerase leading to accelerated shortening of telomere length in activated PBMCs 
[Leeansyah, 2013; Stella-Ascariz, 2017]. 
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 204861 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 [BHIVA, 2015; DHHS, 2016; EACS, 2015; IAS-USA, 
2014] in HIV-1-infected, ART-naïve subjects.  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 

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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). 
An identical sister study, 205543, will be conducted in parallel with Study 204861 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 

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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-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;

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Objectives
Endpoints
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
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

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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 
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 

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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.
Figure 1
204861 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

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
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.  
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 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.
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.

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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].  
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 will initially 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).

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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, 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.
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). 

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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: 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:

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Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea 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.

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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY
1.
Women who are breastfeeding or plan to become pregnant or breastfeed during the 
study;
2.
Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 
3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring systemic 
therapy 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 
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.

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The following guidelines should be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results:

Confirmatory testing should be scheduled 2 to 4 weeks following resolution of any 
intercurrent illness, during which time the subject should receive full doses of all 
study drugs.

Confirmatory testing should be scheduled 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.

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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.  
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
Liver Chemistry Stopping and Increased Monitoring Algorithm

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Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 
5xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
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:

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.

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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, 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 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 (Day1) 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 :

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.

For fasting glucose assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast 
is acceptable for subjects with afternoon appointments.

Direct bilirubin will be reflexively performed for all total bilirubin values >1.5× ULN.

Glomerular filtration rate (GFR) will be estimated by the central laboratory using the CKD-EPI 
method [Levey, 2009].

For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is 
acceptable for subjects with afternoon appointments.

For subjects meeting virologic withdrawal criteria, plasma samples will be analysed in attempt to 
obtain genotype/phenotype data.

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.

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.
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 

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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.  
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 

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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 
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 

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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:
H0:  rd - rf ≤ -10%                   H1: rd - rf > -10%

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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 (MSD=F) 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 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.
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.

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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).
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.

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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.
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.  

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
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.

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 

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the suspension or premature discontinuation of the study and the reason(s) for the 
action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed (e.g. 
for a ViiV 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.

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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.
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 
205543.  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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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 
2014. 20th International AIDS Conference. 20-25 July 2014. Melbourne, Australia. 
Abstract TUAB0101.
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.
TIVICAY Product Information (dolutegravir), March 2017.
Truvada Product Information (emtricitabine/tenofovir disaproxil fumarate), April 2017. 
U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for Industry: Human 
Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. 
November 2015. Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm355128.pdf. Accessed 6 April 2016.

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Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir Plus Abacavir/Lamivudine 
for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 
and Week 144 Results from the SINGLE Randomized Clinical Trial. J Acquir Immune 
Defic Syndr. 2015;70:515–519
Walmsley SL, Antela A, Clumeck N, et al; SINGLE Investigators. Dolutegravir plus 
abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369:1807-
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/behaviour, 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. 

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Principal Investigator Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of drug 
restart, as required. 

If drug re-initiation VSLC-approved, the 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

Coccidioidomycosis, disseminated or extrapulmonary 

Cryptococcosis, extrapulmonary 

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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≤ 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.
Dermatologic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALL
Y LIFE-
THREATENIN
G
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 
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)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALL
Y LIFE-
THREATENIN
G
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 
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
applicable
Localized rash
Diffuse rash
OR Target
lesions
Diffuse rash
AND Vesicles 
or limited 
number of bullae 
or superficial
ulcerations of
mucous 
membrane 
limited to one 
site
Extensive or
generalized bullous
lesions OR Ulceration
of mucous membrane 
involving two or
more distinct mucosal 
sites OR Stevens-
Johnson syndrome 
OR Toxic epidermal 
necrolysis
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions 
section. 

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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 
interference with 
usual social & 
functional
activities OR 
Thyroid 
replacement
therapy indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
Life-threatening 
consequences 
(e.g., myxedema 
coma)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Lipoatrophy4
Detectable by
study 
participant, 
caregiver, or 
physician
AND Causing
no or
minimal
interference 
with usual
social & 
functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
Lipohypertrophy5
Detectable by
study 
participant, 
caregiver, or 
physician
AND Causing
no or
minimal
interference 
with usual
social &
functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and 
abdomen.

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Gastrointestinal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Anorexia
Loss of
appetite 
without
decreased oral
intake
Loss of appetite 
associated with 
decreased oral
intake without
significant 
weight loss
Loss of appetite 
associated with 
significant weight
loss
Life-threatening 
consequences OR
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total
parenteral nutrition)
Ascites
No symptoms
Symptoms AND
Intervention
indicated (e.g.,
diuretics, 
therapeutic 
paracentesis)
Symptoms 
recur or persist
despite 
intervention
Life-
threatening 
consequencs
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)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
< 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 
pseudomembrane
s or ulcerations
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma
Life-threatening 
consequences 
(e.g., aspiration, 
choking) OR 
Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal 
bleeding
Nausea
Transient (< 
24 hours) or 
intermittent 
AND No or 
minimal 
interference 
with oral 
intake
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours
Persistent nausea 
resulting in 
minimal oral intake
for > 48 hours OR 
Rehydration 
indicated (e.g., IV 
fluids)
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)
Pancreatitis
NA
Symptoms with 
hospitalization not 
indicated
Symptoms with 
hospitalization 
indicated
Life-threatening 
consequences 
(e.g., circulatory 
failure, 
hemorrhage, 
sepsis)
Perforation
(colon or rectum)
NA
NA
Intervention 
indicated
Life-threatening 
consequences

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

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

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6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific 
Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World 
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 
2007: Printed by the University of Sheffield.
Neurologic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute CNS IschemiaNA
NA
Transient
ischemic 
attack
Cerebral vascular 
accident (e.g.,
stroke with
neurological 
deficit)
Altered Mental
Status (for
Dementia, see 
Cognitive,
Behavioral, or 
Attentional
Disturbance below)
Changes 
causing no or
minimal 
interference
with usual
social & 
functional
activities
Mild lethargy or 
somnolence 
causing greater
than minimal 
interference
with usual
social & 
functional
activities
Confusion,
memory 
impairment,
lethargy, or 
somnolence 
causing inability
to perform usual
social & 
functional
activities
Delirium OR
Obtundation
OR Coma
Ataxia
Symptoms 
causing no or
minimal 
interference
with usual
social & 
functional
activities OR
No symptoms 
with ataxia 
detected on
examination
Symptoms 
causing greater
than minimal 
interference
with usual
social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Disabling symptoms 
causing inability to 
perform basic self-
care functions
Cognitive,
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention 
deficit disorder)
Specify type, if
applicable
Disability
causing no or
minimal 
interference
with usual
social & 
functional
activities OR
Specialized 
resources not 
indicated
Disability
causing greater
than minimal 
interference
with usual
social & 
functional
activities OR
Specialized 
resources on
part- time basis 
indicated
Disability
causing 
inability to
perform usual
social & 
functional
activities OR
Specialized 
resources on a 
full- time basis 
indicated
Disability causing 
inability to
perform basic self-
care functions OR
Institutionalization 
indicated

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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Neurosensory 
Alteration (includes 
paresthesia and 
painful neuropathy)
Specify type, if 
applicable
Minimal 
paresthesia 
causing no or 
minimal 
interference 
with usual 
social & 
functional 
activities OR 
No symptoms 
with sensory 
alteration on 
examination
Sensory 
alteration or 
paresthesia 
causing greater 
than minimal 
interference 
with usual 
social & 
functional 
activities
Sensory 
alteration or 
paresthesia 
causing 
inability to
perform usual 
social & 
functional 
activities
Disabling sensory 
alteration or 
paresthesia 
causing inability 
to perform basic 
self-care functions
Seizures
New Onset Seizure
≥ 18 years of age
NA
NA
1 to  3 seizures
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to 
control (e.g., 
refractory 
epilepsy)
< 18 years of age 
(includes new or pre-
existing febrile 
seizures)
Seizure lasting 
< 5 minutes 
with < 24 
hours postictal 
state
Seizure lasting 
5 to < 20 
minutes with
< 24 hours 
postictal state
Seizure lasting 
≥ 20 minutes 
OR > 24 hours 
postictal state
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to 
control (e.g., 
refractory 
epilepsy)
Pre-existing Seizure
NA
Increased 
frequency from 
previous level 
of control 
without change 
in seizure 
character
Change in 
seizure 
character 
either in 
duration or 
quality (e.g., 
severity or 
focality)
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to 
control (e.g., 
refractory 
epilepsy)
Syncope
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope)
Loss of 
consciousness 
with no 
intervention 
indicated
Loss of 
consciousness 
AND 
Hospitalizatio
n or 
intervention 
required
NA

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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

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

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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
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)

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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Cytokine Release
Syndrome9
Mild signs and 
symptoms AND
Therapy (i.e.,
antibody 
infusion)
interruption not
indicated
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND
Responds promptly 
to symptomatic 
treatment OR
Prophylactic 
medications 
indicated for ≤24 
hours
Prolonged
severe signs 
and symptoms 
OR Recurrence 
of symptoms
following 
initial
improvement
Life-
threatening 
consequences 
(e.g., requiring
pressor or 
ventilator
support)
Fatigue or Malaise
Report only one
Symptoms 
causing no or
minimal 
interference
with usual social
& functional
activities
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform 
usual social
& functional
activities
Incapacitating
symptoms of fatigue 
or malaise causing
inability to perform
basic self-care 
functions
Fever (non-
axillary 
temperatures 
only)
38.0 to < 38.6°C 
or 100.4 to <
101.5°F
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F
≥ 39.3 to < 
40.0°C or ≥ 
102.7 to <
104.0°F
≥ 40.0°C or ≥ 104.0°F
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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
2 to 5 years of age
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
loss)
NA
5 to < 9% loss in 
body weight from 
baseline
≥ 9 to < 20%
loss in body
weight from 
baseline
≥ 20% loss in body
weight from baseline 
OR Aggressive 
intervention indicated
(e.g., tube feeding,
total parenteral 
nutrition)
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

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Site Reactions to Injections and Infusions
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain or
Tenderness
Report only one
Pain or
tenderness 
causing no or 
minimal
limitation of
use of limb
Pain or
tenderness 
causing greater
than minimal
limitation of use 
of limb
Pain or
tenderness 
causing inability
to perform usual
social & 
functional
activities
Pain or tenderness 
causing inability to 
perform basic self-
care function OR
Hospitalization
indicated
Injection Site 
Erythema or 
Redness13
Report only one
> 15 years of age
2.5 to < 5 cm in 
diameter OR
6.25 to < 25
cm2 surface 
area AND
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
≥ 5 to < 10 cm in 
diameter OR ≥ 
25 to < 100 cm2
surface area OR 
Symptoms 
causing greater
than minimal
interference with
usual social & 
functional
activities
≥ 10 cm in
diameter OR ≥ 
100 cm2 surface 
area OR
Ulceration OR
Secondary 
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage OR
Symptoms 
causing inability
to perform usual
social & 
functional
activities
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis 
involving
dermis or 
deeper tissue)
≤ 15 years of age
≤ 2.5 cm in
diameter
> 2.5 cm in
diameter with < 
50% surface area 
of the extremity 
segment
involved (e.g.,
upper arm or 
thigh)
≥ 50% surface 
area of the 
extremity
segment involved
(e.g., upper arm
or thigh) OR
Ulceration OR
Secondary
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis 
involving
dermis or 
deeper tissue)
Injection Site
Induration or 
Swelling
Report only one
> 15 years of
age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15
years of age

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≤15 years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Injection Site 
Pruritus
Itching localized
to the injection
site that is 
relieved 
spontaneously or
in < 48 hours of 
treatment
Itching beyond
the injection site 
that is not
generalized OR
Itching localized
to the injection
site requiring ≥ 
48 hours 
treatment
Generalized 
itching causing
inability to 
perform usual
social & 
functional
activities
NA
13Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or 
measured surface area.
Laboratory Values
Chemistries
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acidosis
NA
pH ≥ 7.3 to < LLN
pH < 7.3
without life-
threatening 
consequences
pH < 7.3 with
life-
threatening 
consequences
Albumin, Low
(g/dL; g/L)
3.0 to < LLN
30  to < LLN
≥ 2.0 to < 3.0
≥ 20  to < 30
< 2.0
< 20
NA
Alkaline 
Phosphatase, 
High
1.25 to <
2.5 x ULN
2.5  to < 5.0 x ULN
5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Alkalosis
NA
pH > ULN to ≤ 7.5
pH > 7.5
without life-
threatening 
consequences
pH > 7.5 with
life-
threatening 
consequences
ALT or SGPT,
High
Report only one
1.25 to <
2.5 x ULN
2.5 to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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
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
Preterm 
Neonates
See Appendix A. 
Total Bilirubin
for Term and
Preterm 
Neonates
See 
Appendix A. 
Total
Bilirubin for 
Term and
Preterm 
Neonates
See Appendix A.
Total Bilirubin for
Term and Preterm
Neonates
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age
10.6  to < 11.5
2.65 to < 2.88
11.5 to < 12.5
2.88 to < 3.13
12.5  to < 13.5
3.13 to < 3.38
≥ 13.5
≥ 3.38
< 7 days of age
11.5 to < 12.4
2.88 to < 3.10
12.4 to < 12.9
3.10 to < 3.23
12.9 to < 13.5
3.23 to < 3.38
≥ 13.5
≥ 3.38
Calcium (Ionized), 
High
(mg/dL; mmol/L)
> ULN to < 6.0
> ULN  to < 1.5
6.0 to < 6.4
1.5 to < 1.6
6.4 to < 7.2
1.6 to < 1.8
≥ 7.2
≥ 1.8
Calcium, Low
(mg/dL; mmol/L)
≥ 7 days of age
7.8  to < 8.4
1.95  to < 2.10
7.0   to < 7.8
1.75  to < 1.95
6.1  to < 7.0
1.53  to < 1.75
< 6.1
< 1.53
< 7 days of age
6.5  to < 7.5
1.63  to < 1.88
6.0 to < 6.5
1.50  to < 1.63
5.50  to < 6.0
1.38  to < 1.50
< 5.50
< 1.38
Calcium (Ionized),  
Low
(mg/dL; mmol/L)
< LLN  to 4.0
< LLN to 1.0
3.6 to < 4.0
0.9 to < 1.0
3.2 to < 3.6
0.8 to < 0.9
< 3.2
< 0.8
Cardiac Troponin 
I, High
NA
NA
NA
Levels consistent with
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 < 
27.75
> 500
≥ 27.75
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age
55  to 64
3.05  to 3.55
40  to < 55
2.22  to < 3.05
30  to < 40
1.67 to < 2.22
< 30
< 1.67
< 1 month of age
50 to 54
2.78  to 3.00
40 to < 50
2.22 to < 2.78
30 to < 40
1.67 to < 2.22
< 30
< 1.67
Lactate, High
ULN to  < 2.0
x ULN without 
acidosis
≥ 2.0 x ULN without 
acidosis
Increased lactate 
with pH < 7.3 
without life-
threatening 
consequences
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences
Lipase, High
1.1  to < 1.5 x ULN 1.5  to < 3.0 x ULN
3.0  to < 5.0 x 
ULN
≥ 5.0 x ULN
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol, 
Fasting, High
≥ 18 years of age
200  to < 240
5.18  to < 6.19
240  to < 300
6.19  to < 7.77
≥  300
≥  7.77
NA
< 18 years of age
170  to < 200
4.40  to < 5.15
200  to < 300
5.15  to < 7.77
≥  300
≥  7.77
NA
LDL, Fasting, 
High
130  to < 160
160 to < 190
≥ 190
NA

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≥ 18 years of age
3.37  to < 4.12
4.12  to < 4.90
≥ 4.90
> 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
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.

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Haematology
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 x109
400 to 599
0.400 x 109 to
0.599 x109
< 400
< 0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to
1.500 x 109
1,000 to 1,249
1.000 x 109 to
1.249 x109
750 to 999
0.750 x 109 to
0.999 x109
< 750
< 0.750 x 109
≤ 1 day of age
4,000 to 5,000
4.000 x 109 to
5.000 x 109
3,000 to 3,999
3.000 x 109 to
3.999 x109
1,500 to 2,999
1.500 x 109 to
2.999 x109
< 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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≥ 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 
1.1  to < 1.66 x 
ULN
1.66 to < 2.33 x 
ULN
2.33 to < 3.00 x 
ULN
≥  3.00 x ULN
Platelets, Decreased
(cells/mm3; cells/L)
100,000  to
< 124,999
100.000 x 109  to
< 124.999 x 109
50,000  to
< 100,000
50.000 x 109  to
< 100.000 x 109
25,000  to
< 50,000
25.000 x 109  to
< 50.000 x 109
< 25,000
< 25.000 x 109
PT, High
(not on 
anticoagulation
therapy)
1.1  to < 1.25 x 
ULN
1.25  to < 1.50 x 
ULN
1.50  to < 3.00 x 
ULN
≥  3.00 x ULN
WBC, Decreased
(cells/mm3; cells/L)
> 7 days of age
2,000 to 2,499
2.000 x 109 to 
2.499 x 109
1,500 to 1,999
1.500 x 109 to 
1.999 x109
1,000 to 1,499
1.000 x 109 to 
1.499 x109
< 1,000
< 1.000 x 109

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≤ 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 x109
< 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
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, diarrhoea, 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: Division of AIDS table for Grading Severity of Adult and 
Pediatric Adverse Events, 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 

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information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to 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

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
If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
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. 

2 0 1 5 N 2 4 2 9 7 8 _ 0 2
C O N FI D E N TI A L
2 0 4 8 6 1
1 3 4

T o c orrect a n o missi o n, sta n dar d pr oce d ure s f or f or war di n g pre g na nc y i nf or mati o n 
t o t he A ntiretr o viral Pre g na nc y Re gister were a d de d.

F or clarificati o n p ur p oses, t he A E se verit y gra di n gs i n A p pe n di x 7, Secti o n 1 2. 7. 6 
( E val uati n g A Es a n d S A Es) were u p date d t o be c o nsiste nt wit h A p pe n di x 6, 
Secti o n 1 2. 6. ( Di visi o n of AI D S ta ble f or Gra di n g Se verit y  of A d ult a n d Pe diatric 
A d verse E ve nts).  T his c ha n ge has n o i m pact o n t he i n vesti gat or’s e val uati o n of 
a d verse e ve nts .

Mi n or re v isi o ns were ma de t o t he te xt t o pr o vi de u p date d i nf or mati o n, c orrect err ors 
an d i m pr o ve acc urac y .
LI S T O F S P E CI FI C C H A N G E S
U nless st ate d ot her wise, ne w te xt is re prese nte d i n b ol d f o nt, a n d delete d te xt i n 
stri ket hr o u g h f o nt.

A ut h ors
A m e n de d te xt:

Me dic al m o nit or/ S p o ns or I nf or m ati o n P a ge
A m e n de d te xt
S ec o n d ary 
M e dic al 
M o nit or
M D
Vii V H e alt hc ar e
9 8 0 Gr e at W est 
R o a d, Br e ntf or d, 
Mi d dl es ex, T W 8 
9 G S, U K
M ailst o p U P 4 4 1 0
C oll e g evill e, P A 
( U S A)

Secti o n 1. Pr ot oc ol S y n o psis; O ver all Desi g n
A m e n de d te xt: 
T he st u d y  i nitiall y will e nr ol a p pr o xi matel y 1 0 0 s u bjects wit h a Scree ni n g HI V-1 R N A of 
1 0 0 0 t o 1 0 0, 0 0 0 c/ m L .  Acc u m ulate d data fr o m ot her cli nical trials i n vesti gati n g t he 
D T G pl us 3 T C d ual re gi me n will u n der g o i n de pe n de nt re vie w.   If t he i n de pe n de nt re vie w 
is s u p p orti ve of e val uati n g t he d ual re gi me n’s efficac y i n s u bjects wit h a Scree ni n g viral 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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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; 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.

2 0 1 5 N 2 4 2 9 7 8 _ 0 2
C O N FI D E N TI A L
2 0 4 8 6 1
1 4 9

Secti o n 1 2. 9. 2. C ollecti o n of Pre g n a nc y I nf or m ati o n
A d diti o n al te xt:
G S K’s ce ntral safet y de part me nt will als o f or war d t his i nf or mati o n t o t he A ntiretr o viral 
Pre g na nc y  Re gistr y. T he i nter nati o nal re gistr y is j oi ntl y s p o ns ore d b y ma n ufact urers or 
lice nsees of a ntiretr o viral pr o d ucts. A d diti o nal i nf or mati o n a n d a list of partici pati n g 
ma n ufact urers/lice nsees are a vaila ble fr o m htt p:// w w w.a pre gistr y .c o m/.
1 2. 1 1. 2.
Pr ot o c ol c h a n g e s f or A m e n d m e nt 0 2 ( 1 4 -J U N -2 0 1 8 ) fr o m 
A m e n d m e nt 0 1 ( 0 1 -D E C -2 0 1 7)
T his gl o b al a me n d me nt is a p plic a ble t o all p artici p ati n g sites.
S u m m ar y of C h a n ges i n Pr ot oc ol A me n d me nt 0 2 a n d R ati o n ale:
C ha n ges were ma de t o t he pr ot oc ol t o ma na ge a n d miti gate ris ks f oll o wi n g i de ntificati o n 
of a p ote nt ial safet y iss ue relate d t o ne ural t u be defects i n i nfa nts b or n t o w o me n wit h 
e x p os ure t o d ol ute gra vir at t he ti me of c o nce pti o n.  C ha n ges were als o ma de t o u p date 
t he refere nces t o t he D T G I B t o reflect t he m ost c urre nt versi o ns.

T he Ris k Assess me nt ta ble ( Secti o n 4. 6. 1 ) was u p date d t o i ncl u de la n g ua ge re gar di n g 
ris k a n d miti gati o n of ne ural t u be defects.

T he wit h dra wal criteria ( Secti o n 5. 4 ) were u p date d t o i ncl u de a re mi n der t hat fe males 
of re pr o d ucti ve p ote ntial w h o c ha n ge t heir mi n ds a n d desire t o be p re g na nt, or w h o 
state t he y n o l o n ger are willi n g t o c o m pl y wit h t he a p pr o ve d pre g na nc y a v oi da nce 
met h o ds, s h o ul d als o be wit h dra w n fr o m t he st u d y.

T he Ti me a n d E ve nts ta ble ( Secti o n 7. 1 ). was u p date d t o i ncl u de a re mi n der f or 
i n vesti gat ors t o c hec k at e very visit t hat fe males of re pr o d ucti ve p ote ntial are 
a v oi di n g pre g na nc y.

T he m o difie d list of hi g hl y  effecti ve met h o ds f or a v oi di n g pre g na nc y i n F R P ( Secti o n
1 2. 9. 1 ) was u p date d t o e xcl u de t he d o u ble barrier met h o d of c o ntrace pti o n, w hic h 
d oes n ot meet u p da te d G S K/ Vii V criteria f or a hi g hly effecti ve met h o d.
LI S T O F S P E CI FI C C H A N G E S
U nless st ate d ot her wise, ne w te xt is re prese nte d i n b ol d f o nt, a n d delete d te xt i n 
stri ket hr o u g h f o nt.
Title P a ge, A ut h ors:
U p date d te xt:
 
 
P P D
P P D

2 0 1 5 N 2 4 2 9 7 8 _ 0 2
C O N FI D E N TI A L
2 0 4 8 6 1
1 5 0
Secti o n 4. 6. 1: Ris k Ass ess me nt
D T G: 
Ne ur al t u be 
defects
I n o ne o n g oi n g birt h o utc o me 
s ur veill a nce st u d y i n B ots w a n a, 
e arl y res ults fr o m a n u n pl a n ne d 
i nteri m a n al ysis s h o w t h at 4/ 4 2 6 
( 0. 9 %) of w o me n w h o were t a ki n g 
D T G w he n t he y bec a me pre g n a nt 
h a d b a bies wit h ne ur al t u be defects
c o m p are d t o a b ac k gr o u n d r ate of 
0. 1 %.
1.
A fe m ale s u bject is 
eli gi ble t o p artici p ate if 
s he is n ot pre g n a nt, n ot 
l act ati n g, a n d, if s he is a 
fe m ale of re pr o d ucti ve 
p ote nti al, a grees t o 
f oll o w o ne of t he 
o pti o ns liste d i n t he 
M o difie d List of Hi g hl y 
Effecti v e Met h o ds f or 
A v oi di n g Pre g n a nc y i n 
Fe m ales of 
Re pr o d ucti ve P ote nti al 
( F R P) (see A p pe n di x 9, 
Secti o n 1 2. 9. 1) fr o m 3 0 
d a ys pri or t o t he first 
d ose of st u d y 
me dic ati o n a n d f or at 
le ast 2 wee ks after t he 
l ast d ose of st u d y 
me dic ati o n.
2.
W o me n w h o are 
bre astfee di n g or pl a n t o 
bec o me pre g n a nt or 
bre astfee d d uri n g t he 
st u d y are e xcl u de d;
3.
W o me n w h o bec o me 
pre g n a nt, or w h o desire 
t o be pre g n a nt w hile i n 
t he st u d y, or w h o st ate 
t he y n o l o n ger are 
willi n g t o c o m pl y wit h 
t he a p pr o ve d 
pre g n a nc y a v oi d a nce 
met h o ds, will h a ve 
st u d y tre at me nt 
disc o nti n ue d a n d will 
be wit h dr a w n fr o m t he 
st u d y.
4.
Fe m ales of 
re pr o d ucti ve p ote nti al 
are re mi n de d re: 
P P D

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pregnancy avoidance 
and adherence to 
contraception 
requirements at every 
study visit.
5. Pregnancy status is 
monitored at every 
study visit
Section 5.1 Inclusion Criteria:
Updated inclusion criterion 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.

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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.