A Phase III, Randomized, Multicenter, Open-label, Non-inferiority Study Evaluating the Efficacy, Safety and Tolerability of Switching to Dolutegravir/Lamivudine Fixed Dose Combination in HIV-1 Infected Adults Who Are Virologically Suppressed
Phase: PHASE3
Conditions: HIV Infections
Sponsor: ViiV Healthcare

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

2017N331008_06
CONFIDENTIAL
ViiV Healthcare group of companies
208090
2
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity.  In these instances, the appropriate company to be identified 
as Sponsor must be agreed with the global ViiV Healthcare clinical team and signed 
off by the Vice President, Global Research and Medical Strategy
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline and PPD are supporting 
ViiV Healthcare in the conduct of this study.  
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): US IND: 127475/ EudraCT: 2018-000177-
72

1
Fr o m:
S e nt:
W e d n es d a y, M a y 6, 2 0 2 0 1 2: 2 2 A M
T o:
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F W: Pr ot- A m e n d 4- 2 0 8 0 9 0-s p o nsi g n
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Pl e as e fi n d s p o ns or a p pr o v al b el o w f or 2 0 8 0 9 0 a m e n d m e nt 0 4. 
 
Ki n d r e g ar ds, 
 
Fr o m:  S h er e n e Mi n 
 
S e nt:  T u es d a y, M a y 0 5, 2 0 2 0 1: 3 8 P M 
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D e ar  
, 
 
I a p pr o v e t h e pr ot oc ol a m e n d m e nt. 
Ki n d r e g ar ds, 
S h er e n e 
 
S h er e n e S h a ki b Mi n, M D, M P H 
V P, H e a d of Cli nic al D e v el o p m e nt 
 
Vii V H e alt hc ar e 
Fi v e M o or e Dri v e 
P P D
R T P, N C. 2 7 7 0 9 
 
M:
 
P P D
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2
 
 
Fr o m:  
  
S e nt:  M o n d a y, M a y 0 4, 2 0 2 0 1: 3 1 P M 
T o:  S h er e n e Mi n
S u bj ect:  Pr ot- A m e n d 4- 2 0 8 0 9 0-s p o nsi g n 
 
De ar S p o ns or, 
T o a p pr o ve t he cli nical pr ot oc ol i n dicate d bel o w, re pl y t o t his e mail a n d state y o ur a p pr o val. 
P R O T O C O L N U M B E R: 2 0 8 0 9 0  
D O C U M E N T I D E N TI FI E R:  2 0 1 7 N 3 3 1 0 0 8 _ 0 6  
A M E N D M E N T N U M B E R:  0 4 P R O T O C O L TI T L E: A P hase II I, ra n d o mize d, m ultice nter, o pe n-la bel, n o n-
i nferi orit y st u d y e val uati n g t he efficacy, safet y a n d t olera bilit y of s witc hi n g t o d ol ute gra vir/la mi v u di ne fi xe d 
d ose c o m bi nati o n i n HI V- 1 i nfecte d a d ults w h o are vir ol o gicall y s u p presse d 
Na me of S p o ns or Si g nat or y: 
S here ne S ha ki b Mi n, M D, M P H 
Title of S p o ns or Si g nat or y: 
 
Vice Presi de nt a n d Hea d of Cli nical  De vel o p me nt, Vii V Healt hcare 
 
P P D
P P D

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

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

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Section # and Name
Description of Change
Brief Rationale
Preparation/Handling/Storage/Accountability
Section 7.1.1.1, Participants Meeting Virologic 
Management Criteria
Section 8, Study Assessments and Procedures 
Section 8.2.4, Clinical Safety Laboratory Assessments
Section 8.3, Adverse events (AE) and serious adverse 
events (SAEs)
Section 11.7, Appendix 7: Clinical Laboratory Tests
body of the 
protocol
Section 6.8, Treatment after the end of the study
Removed text, Added text
To correct an 
administrative 
error and to aid 
clarity
Section 10, References
Added references
To reflect new
text added to the 
amendment
Section 11.6, Appendix 6, Prohibited Medications
Added fampridine and 
related text and clarifications
To align with 
current 
Investigator 
Brochure version 
13 and aid clarity
Section 11.9.1, Liver Chemistry Stopping Criteria: 
Required Actions and Follow up Assessments
Added laboratory 
assessments
To align with 
updated 
guidance
Section 11.13, Appendix 13: Country-specific 
Requirements
Added new sections to 
describe previous country 
specific amendments for 
Sweden/Denmark and 
China. Sweden/Denmark will 
now be incorporated into this 
global amendment. 
To consolidate 
Sweden/Denmark 
into the global 
amendment and 
provide clarity on 
past country 
specific protocol 
amendments
Section 11.14, Appendix 14: COVID-19 Pandemic and 
Clinical Trial Continuity
Added appendix
To summarize 
COVID-19 related 
patient 
management 
updates that 
were previously 
communicated in 
a memo to 
investigators

2017N331008_06
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7
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES.................................................4
1.
PROTOCOL SUMMARY........................................................................................11
1.1.
Synopsis.....................................................................................................11
1.2.
Schema ......................................................................................................15
1.3.
Schedule of Activities (SoA)........................................................................16
2.
INTRODUCTION....................................................................................................21
2.1.
Study Rationale ..........................................................................................22
2.2.
Background ................................................................................................23
2.3.
Benefit/Risk Assessment ............................................................................25
2.3.1.
Risk Assessment .........................................................................26
2.3.2.
Benefit Assessment.....................................................................30
2.3.3.
Overall Benefit: Risk Conclusion..................................................30
3.
OBJECTIVES AND ENDPOINTS...........................................................................31
4.
STUDY DESIGN ....................................................................................................33
4.1.
Overall Design ............................................................................................33
4.2.
Number of Participants ...............................................................................34
4.3.
Participant and Study Completion...............................................................34
4.4.
Scientific Rationale for Study Design ..........................................................35
4.5.
Justification for Dose ..................................................................................36
5.
STUDY POPULATION...........................................................................................38
5.1.
Inclusion Criteria.........................................................................................38
5.2.
Exclusion Criteria........................................................................................40
5.3.
Lifestyle Restrictions...................................................................................43
5.4.
Screen Failures...........................................................................................43
6.
STUDY INTERVENTION........................................................................................43
6.1.
Study Interventions Administered ...............................................................45
6.2.
Dose Modification .......................................................................................45
6.3.
Method of Treatment Assignment ...............................................................45
6.4.
Blinding.......................................................................................................46
6.5.
Preparation/Handling/Storage/Accountability..............................................46
6.6.
Treatment Compliance................................................................................47
6.7.
Concomitant Therapy..................................................................................47
6.7.1.
Permitted Medications and Non-Drug Therapies..........................47
6.8.
Treatment after the End of the Study ..........................................................48
7.
DISCONTINUATION CRITERIA.............................................................................49
7.1.
Discontinuation of Study Intervention..........................................................49
7.1.1.
Virologic Criteria for Participant Management and Viral 
Resistance Testing ......................................................................49
7.1.1.1.
Participants Meeting Virologic Management 
Criteria........................................................................49

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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3. Documented evidence of at least two plasma HIV-1 RNA measurements 
<50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month 
window, and one within 6 months prior to Screening.
4. Plasma HIV-1 RNA <50 c/mL at Screening.
5. Must be on uninterrupted current regimen (either the initial or second cART 
regimen) for at least 3 months prior to Screening.  
Any prior switch, defined as a change of a single drug or multiple drugs 
simultaneously, must have occurred due to tolerability and/or safety concerns or 
access to medications, or convenience/simplification and must NOT have been 
done for suspected or established treatment failure. The following switches, if 
they are the only switches, would not be considered a change in regimen:
a.
A switch from a PI boosted with RTV to the same PI boosted with cobicistat 
is allowed (and vice versa).
b. A switch from lamivudine (3TC) to emtricitabine (FTC) (and vice versa)
c.
A switch from tenofovir disoproxil fumarate (TDF) to tenofovir 
alafenamide (TAF) (and vice versa)”
Acceptable stable cART regimens prior to Screening include 2 NRTIs plus:

INI (either the initial or second cART regimen)

NNRTI (either the initial or second cART regimen)

Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second PI-based 
cART regimen)
NOTE: Combination triple ART 10 days with any antiretroviral agent following a 
diagnosis of HIV-1 infection is not considered a prior cART regimen. 
Sex
6. Male and Female
a. Female participants: 
A female participant is eligible to participate if she is not pregnant [as confirmed by 
a negative serum human chorionic gonadotrophin (hCG) test at screen and a negative 
urine hCG test at Randomization (a local serum hCG test at Randomization is 
allowed if it can be done, and results obtained, within 24 hours prior to 
randomization)], not breastfeeding, and at least one of the following conditions 
applies:

Not a woman of childbearing potential (WOCBP) as defined in
Section 11.4.1
OR
A WOCBP who agrees to follow the contraceptive guidance in Section 11.4.2
during the treatment period from 28 days prior to the first dose of study 

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

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Note: Participants positive for anti-HBc (negative HBsAg status) and positive for 
anti-HBs (past and/or current evidence) are immune to HBV and are not excluded.  
Anti-HBc must be either total anti-HBc or anti-HBc immunoglobulin G (IgG), and 
NOT anti-HBc IgM.  Participants with a documented history of chronic HBV and 
current undetectable HBV DNA while on a TAF/TDF regimen are excluded.
6. Anticipated need for any hepatitis C virus (HCV) therapy during the randomized 
phase of the study, or anticipated need for HCV therapy with a potential for adverse 
drug-drug interactions with DTG or 3TC. 
7. Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without 
clear documentation of treatment).  Participants who are at least 7 days post 
completed treatment are eligible.
8. History or presence of allergy or intolerance to the study interventions or their 
components or drugs of their class.
9. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile 
intraepithelial neoplasia.
10. Participants who in the investigator’s judgment, poses a significant suicidality risk
11. Any pre-existing physical or mental condition which, in the opinion of the 
Investigator, may interfere with the participant’s ability to comply with the dosing 
schedule and/or protocol evaluations or which may compromise the safety of the 
participant.
12. Any condition which, in the opinion of the Investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the study interventions or render 
the participant unable to take oral medication.
Exclusionary Treatments Prior to Screening or Day 1
13. Use of any regimen consisting of single or dual ART (peri-partum treatment with 
single dose nevirapine is allowed). 
14. Current use of stavudine, didanosine, or nelfinavir
15. Participants receiving any prohibited medication listed in Section 11.6 and who are 
unwilling or unable to switch to an alternate medication
16. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
17. Treatment with any of the following agents within 28 days of Screening

radiation therapy

cytotoxic chemotherapeutic agents

any systemic immune suppressant
18. Exposure to an experimental drug or experimental vaccine within either 28 days, 5 
half-lives of the test agent, or twice the duration of the biological effect of the test 
agent, whichever is longer, prior to the first dose of IP.

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

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

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

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

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Randomization and study intervention assignment will be facilitated by the interactive 
voice/web recognition system (IVRS/IWRS). Following confirmation of fulfilment of 
study entry criteria, study site personnel will be required to contact the IVRS/IWRS to 
register participants. Participants will be randomized in a 1:1 ratio to DTG/3TC FDC or 
the CAR arm, in accordance with the computer-generated randomization schedule. To 
control for treatment related factors that may impact study outcomes, randomization will 
be stratified by baseline third agent class (protease inhibitor [PI], integrase inhibitor 
[INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]).  Each participant will 
be assigned a unique identifier (designating the participant’s randomization code) and a 
unique treatment number which matches the randomized treatment assignment. 
Participants who are randomly assigned into the trial and subsequently withdrawn may 
not be rescreened.  Once a randomisation number has been assigned it must not be 
re-assigned.
6.4.
Blinding
This is an open-label study; potential bias will be reduced by the following steps: central 
randomization. No summaries of the study data according to actual randomized treatment 
groups will be available to sponsor staff prior to the planned Week 24 preliminary 
analysis. Public presentation of the Week 24 analysis will not be done until after the last 
participant completes their last visit for the primary Week 48 analysis.
6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study intervention is required.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM. 

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
ViiV/GSK.

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
IP accountability will be evaluated using pill counts of unused DTG/3TC FDC only 
and not CAR.  This assessment will be conducted each time the participant receives a 
new (refill) supply of DTG/3TC FDC through the Withdrawal visit or study 
completion. IP accountability records must be maintained throughout the course of 
the study.  These data will be recorded in the participant’s eCRF but will not be 
summarised for analysis purposes.

Please refer to Appendix 14 in Section 11.14 for study management information 
during the COVID-19 pandemic.
6.6.
Treatment Compliance
When participants self-administer study interventions at home, compliance with
DTG/3TC FDC or CAR will be assessed through querying the participant during the site 
visits and documented in the source documents and eCRF.  A record of the number of 
DTG/3TC FDC tablets dispensed to and taken by each participant must be maintained 
and reconciled with study intervention and compliance records.  Intervention start and 
stop dates, including dates for treatment delays will also be recorded in the case report 
form (eCRF) for both DTG/3TC FDC and CAR.
6.7.
Concomitant Therapy
Refer to Appendix 6 for a full list of prohibited medications. The Medical Monitor should 
be contacted if there are any questions regarding concomitant or prior therapy.
Participants should be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
DDIs between such treatments and the study interventions. The investigator should 
evaluate any potential DDIs at every visit, including reviewing the most current version 
of the U.S. or local prescribing information for DTG, 3TC and CAR, especially if any 
new concomitant medications are reported by participants.  All concomitant medications 
(including oral contraception, implants or oral or topical hormone replacement therapy)
taken during the study will be recorded in the eCRF.  The minimum requirement is that 
the drug name, route, and the dates of administration are to be recorded.
Concomitant medications (prescription and non-prescription) should be prescribed by the 
relevant health care provider/investigator and administered only as medically necessary 
during the Randomized and Continuation phases of the study (except prohibited 
medications described in Section 11.6).  Chemoprophylaxis for HIV-associated 
conditions is encouraged, if appropriate, at the discretion of the participant and their 
physician. All concomitant medications, blood products, and vaccines taken during the 
study will be recorded in the eCRF with dates of administration.
6.7.1.
Permitted Medications and Non-Drug Therapies
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 plasma 
RNA, it is highly recommended that a vaccine, if necessary, be given during or 
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when scheduled visits are ≥4 weeks apart.  This approach will minimize the risk of non-
specific increases in the level of HIV-1 plasma RNA at the next scheduled assessment.
DTG/3TC FDC should be administered 2 hours before or 6 hours after taking antacid or 
laxative products containing polyvalent cations (e.g. aluminium and magnesium),
sucralfate, or calcium supplements.  Proton pump inhibitors and H2-antagonists may be 
used in place of antacids with no scheduling restrictions.  Concurrent administration with 
multivitamins is acceptable.  Iron supplements can be taken with IP provided that all are 
taken together with a meal. Under fasted conditions, DTG +3TC should be given 2 hours 
prior to OR 6 hours after iron supplements.
Metformin concentrations may be increased by DTG.  A dose adjustment of metformin 
should be considered when starting and stopping co-administration of dolutegravir with 
metformin, to maintain glycaemic control.
Clinical monitoring is recommended for participants taking methadone, as methadone 
maintenance therapy may need to be adjusted in some participants.
Non-protocol defined treatments or medical interventions (e.g., physical therapy, 
radiotherapy, surgical procedures) are permitted during the study for appropriate medical 
management of the participant. 
6.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not ViiV is providing
specific post-study treatment.
All participants on DTG/3TC FDC who successfully complete 52 weeks of treatment will 
have the opportunity to receive DTG/3TC FDC once daily in a Continuation Phase until:
DTG and 3TC are each locally approved for use as part of a 2-drug regimen, and 
each of the single entities of DTG and 3TC are available to participants (e.g., 
through public health services or through their usual health insurance payer), or
the actual DTG/3TC FDC tablet, if required by local regulations, is available, or
the participant no longer derives clinical benefit, or 
the participant meets a protocol-defined reason for discontinuation, or 
development of the DTG plus 3TC 2-drug regimen is terminated.
The Continuation Phase is not applicable for participants in Sweden and Denmark. 
The purpose of the Continuation Phase is to ensure provision of DTG/3TC FDC.  
Assessments during the Continuation Phase are limited and will include some safety 
laboratory assessments.

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

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

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

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

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

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

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
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent;

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records;

At the request of, GSK or ViiV Healthcare;

The participant requires concurrent prohibited medications during the course of the 
study.  The participant may remain in the study if in the opinion of the Investigator 
and the medical monitor, such medication will not interfere with the conduct or 
interpretation of the study or compromise the safety of the participant.
Participants must be discontinued from the study for any of the following reasons:

Virologic withdrawal criteria as specified in Section 7.1.1 are met

Participant is identified as having been mistakenly screened/randomized with 
exclusionary resistance (see Section 7.1.1)

Participant requires substitution or dose modification of DTG, 3TC or any 
component of CAR. For participants on CAR, a switch from a PI boosted with 
ritonavir to the same PI boosted with cobicistat (and vice versa) and a switch from 
lamivudine to emtricitabine (and vice versa) is permitted per protocol.

Liver toxicity where stopping criteria specified in Section 7.1.2 are met and no 
compelling alternate cause is identified

Allergic reaction or Rash criteria as described in Section 11.3.1.5 and Section 
11.3.1.6 are met and no compelling alternate cause is identified

Renal toxicity as specified in Section 11.3.1.3 are met and no compelling alternate 
cause is identified

Grade 4 clinical or laboratory AE considered causally related to study intervention

Pregnancy (intrauterine), regardless of termination status of pregnancy (Section 
8.2.6).  As a reminder, females of reproductive potential who change their minds and 
desire to be pregnant, or who state they no longer are willing to comply with the 
approved pregnancy avoidance methods, should also be withdrawn from the study.
Refer to the Schedule of Activities (SoA) (Section 1.3) for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed.
All data from the Withdrawal visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any participant from the study.   An 
in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of study 
medication for participants with ongoing AEs, serious adverse events (SAEs) regardless 

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of attributability, and any laboratory abnormalities that are considered to be AEs or 
potentially harmful to the participant, at the last on-study visit.
Participants are not obligated to state the reason for withdrawal.  However, a reason for 
withdrawal must be documented by the Investigator on the Completion/Withdrawal 
section of the electronic case report form (eCRF).  Every effort should be made by the 
Investigator to follow-up participants who withdraw from the study.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 

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

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will complete the Screening period up to 28 days prior to Baseline (Day 1) during which 
all clinical and laboratory assessments of eligibility must be performed and reviewed.  
The Screening period of up to 28 days is to accommodate availability of all Screening 
assessment results, completion of source document verification to satisfy the Inclusion 
and Exclusion Criteria including the required previous HIV-1 RNA values, and 
scheduling.  All Screening results must be available prior to randomization. 
All information about the participant’s current and any past regimen must be 
available for review by the Principal Investigator or designee prior to 
randomization.  Source documents from other medical facilities must be 
located/received during the 28-day screening period and under no circumstances 
may the participant be randomized in the absence of source documentation, even if 
there are delays in receipt of this information. A participant may be re-screened if 
the source documentation is obtained after the screening window closes.
Details regarding prior resistance data must be noted in the source documentation.  
Resistance testing reports with genotypic data must be provided to ViiV after screening 
and before randomization for review by ViiV.  Sites must wait for the study virologists to 
confirm the lack of exclusionary resistance mutations, which will be provided to the site 
before the screening window closes. Details for tracking historic resistance report 
availability and sending to ViiV Virology for evaluation are described in the SRM.  
Details regarding baseline or prior resistance data must be noted in the source 
documentation.  If a participant is identified as having been mistakenly 
screened/randomized with exclusionary resistance, they will be withdrawn.
Participants with chronic active hepatitis B virus infection are excluded.  Evidence of 
Hepatitis B virus (HBV) infection is based on the results of testing at Screening for 
Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B 
surface antibody (anti-HBs), and HBV DNA.  HBV DNA testing will only be performed 
for participants with positive anti-HBc and negative HBsAg and negative anti-HBs (past 
and/or current evidence).
All participants will be screened for syphilis at screening. Participants with untreated 
syphilis infection, defined as a positive Rapid Plasma Reagin (RPR) without clear 
documentation of treatment, are excluded unless they complete treatment during the 
28-day screening window and 7 days prior to randomization. Participants who complete 
treatment after the screening window closes may be rescreened.
Participants who meet all entry criteria are randomized and assigned a randomization 
number. Participants not meeting all inclusion and exclusion criteria at initial screen may 
be rescreened and receive a new participant number one time unless they were excluded 
for reason of having exclusionary historic genotypic resistance or for a viral load 
≥50c/mL at time of screening.  Participants who are randomized into the trial and 
subsequently withdrawn from the study for any reason may not be rescreened.

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

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

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

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investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behaviour. Participants presenting with new 
onset/treatment emergent depression should be advised to contact the investigator 
immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop, because medical intervention and discontinuation of the study 
medication may be required.
Assessment of treatment-emergent suicidality will be monitored during this study using 
the electronic version of the Columbia Suicidality Severity Rating Scale (eC-SSRS). The 
definitions of behavioural suicidal events used in this scale are based on those used in the 
Columbia Suicide History Form [Posner, 2007].  Questions are asked on suicidal 
behaviour, suicidal ideation, and intensity of ideation.  Day 1 (Baseline) visit questions 
will be in relation to lifetime experiences and current experiences (within the past 
2 months); all subsequent questioning is in relation to the last assessment. The eC-SSRS 
is to be administered as a participant completed questionnaire specified in the SoA. The 
eC-SSRS will be conducted electronically by telephone or by computer/tablet connected 
to the internet.
Additionally, the investigator will collect information using the Possible Suicidality-
Related AE (PSRAE) eCRF form in addition to the AE (non-serious or SAE) eCRF form 
on any participant that experiences a possible suicidality-related AE while participating 
in this study.  This may include, but is not limited to, an event that involves suicidal 
ideation, a preparatory act toward imminent suicidal behaviour, a suicide attempt, or a 
completed suicide.  The investigator will exercise his or her medical and scientific 
judgment in deciding whether an event is possibly suicide-related. PSRAE forms should 
be completed and reported to ViiV/GSK within 1 week of the investigator diagnosing a 
possible suicidality-related AE.
8.2.6.
Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
intervention and ending at the final Follow-up visit.  If a pregnancy is reported, the 
investigator should inform ViiV/GSK/PPD within 2 weeks of learning of the pregnancy 
and should follow the procedures outlined in Section 11.4.3.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and child(ren). Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE.  Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and must be reported.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the participant has completed the study and considered by the investigator 
as possibly related to the study intervention must be reported promptly to ViiV/GSK (or
designee).
GSK’s central safety department will forward this information to the ART Pregnancy 
Registry.  The international registry is jointly sponsored by manufacturers or licensees of 

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ARV products.  Additional information and a list of participating manufacturers/licensees 
are available from http://www.apregistry.com/.  
8.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 8.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
Please refer to Appendix 14 in Section 11.14 for study management information during 
the COVID-19 pandemic.
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 1.3).  However, any SAEs assessed 
as related to study participation (e.g., study intervention, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a 
ViiV/GSK product will be recorded from the time a participant consents to 
participate in the study.

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (eCRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in
Appendix 8. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in
Appendix 8.

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8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest will be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is given in Appendix 8.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 11.8.3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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10.
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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
11.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B Core Antibody
ARV
Antiretroviral
ART
Antiretroviral therapy
ATV
Atazanavir
ATV/r
Atazanavir/ritonavir
AST
Aspartate aminotransferase
AUC
Area under the curve
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
c/mL
Copies/milliliter
CAR
Current ART regimen
cART
Combination ART 
CDC
Centers for Disease Control and Prevention
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum concentration
CMH
Cochran-Mantel Haenszel
CRF
Case Report Form
CI
Confidence interval
ConART
Concomitant ART therapy
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CV
Cardiovascular
CVW
Confirmed Virologic Withdrawal
DAIDS
Division of Acquired Immunodeficiency Syndrome
DDI
Drug-Drug Interaction
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DTG
Dolutegravir, TIVICAY
E/C/F/TAF
Elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide
ECG
Electrocardiogram
eCRF
Electronic case report form
eC-SSRS
Electronic Columbia Suicidality Severity Rating Scale
EFV
Efavirenz

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

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

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

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

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

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

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

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Participants with asymptomatic Grade 3 laboratory abnormalities should be investigated 
for all potential non-drug related causes, and, following discussion with the medical 
monitor, may continue study intervention if the investigator has compelling evidence that 
the toxicity is not related to study intervention.
Exceptions are noted for lipid abnormalities in Section 11.3.1.7 and rash in Section 
11.3.1.6.
Grade 4 Toxicity/Adverse Event
Participants who develop a Grade 4 AE or toxicity should have study intervention 
discontinued.  However, if the investigator has compelling evidence that the AE is not 
causally related to the study interventions, dosing may continue after discussion with and 
assent from the medical monitor.  Participants should be rechecked each week until the 
AE returns to Grade 2.
Participants experiencing Grade 4 AEs requiring permanent discontinuation of study 
intervention should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal and follow-up study evaluations as noted above.
Participants with asymptomatic Grade 4 laboratory abnormalities should be investigated 
for all potential non-drug related causes, and, following discussion with the medical 
monitor, may continue therapy if the investigator has compelling evidence that the 
toxicity is not related to study intervention.  Exceptions are noted for lipid abnormalities 
in Section 11.3.1.7.  An in-clinic Follow-Up visit will be conducted approximately 
4 weeks after the last dose of study medication for participants with ongoing AEs, serious 
adverse events (SAEs) regardless of attributability, and any laboratory abnormalities that 
are considered to be AEs or potentially harmful to the participant, at the last on-study 
visit.
11.3.1.
Specific Toxicities/Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be 
related or possibly related to study intervention are provided below.
Participants who permanently discontinue study intervention for reasons of toxicity 
should be followed weekly until resolution of the AE and encouraged to complete the 
withdrawal and Follow-up study evaluations (see Section 7.2).
11.3.1.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure participant 
safety and to evaluate liver event aetiology during administration of study intervention 
and the follow-up period. For a complete listing of stopping and follow-up criteria refer 
to Section 11.9.1.

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11.3.1.2.
Restarting Study Intervention
Refer to Section 11.9.2 for details on drug restart following transient resolving liver 
events not related to study intervention.
11.3.1.3.
Decline in Renal Function
Participants who experience an increase in serum creatinine from Baseline of 
45 micromoles/liter (Mol/L) (or 0.5 milligrams/deciliter [mg/dL]) should return for a 
confirmatory assessment within 2 to 4 weeks.  A urinalysis, urine albumin/creatinine and 
urine total protein/creatinine ratios, serum cystatin C and an estimated GFR using the 
CKD-EPI (cystatin C) [Inker, 2012] should also be done at this confirmatory visit.  If the 
creatinine increase is confirmed, the investigator should contact the study medical 
monitor to discuss additional follow-up and medical management.
Participants who experience progression to an estimated GFR (using the CKD-EPI-
creatinine) of <30 mL/min/1.73m2 must return for a confirmatory assessment within 
2 weeks [Levey, 2009].  A urinalysis, urine albumin/creatinine and urine 
protein/creatinine ratios, serum cystatin C and an estimated GFR using the CKD-EPI 
(cystatin C) [Inker, 2012] should be done at this confirmatory visit.  If an estimated GFR 
of <30 mL/min/1.73m2 is confirmed using the CKD-EPI (cystatin C), then study 
intervention should be discontinued and the participant withdrawn from the study (as 
dose adjustment is needed for NRTIs, which is not possible in a study of a fixed-dose 
combination tablet).
11.3.1.4.
Proteinuria
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, >300 mg/g, or 
>34 mg/mmol) that represents a change from Baseline and no associated increase in 
creatinine, should have a repeat spot urine albumin/creatinine ratio performed within 2-4 
weeks.  If confirmed, then consideration should be given to additional evaluation after 
consultation with the study medical monitor. Additional evaluation may include a 24-
hour urine protein and creatinine measurement and nephrology referral.
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, 300 mg/g, or 
>34 mg/mmol and representing a change from Baseline) and a serum creatinine increase 
>45 μmol/L (or 0.5 mg/dL) should have confirmation of both results within 2 weeks. If 
confirmed, the study medical monitor should be contacted immediately.  Agreement on 
further management should be agreed between the investigator and medical monitor.
11.3.1.5.
Allergic reaction
Participants may continue study intervention for Grade 1 or 2 allergic reactions at the 
discretion of the Investigator.  The participant should be advised to contact the 
Investigator immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop.  Antihistamines, topical corticosteroids, or antipruritic agents 
may be prescribed. 

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

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

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11.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
11.4.1.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.   

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
11.4.2.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 3.
The list does not apply to FRP with same sex partners or for participants who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 

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

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

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

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

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

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

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

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

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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
11.8.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred, or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 

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baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
11.8.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization

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

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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to ViiV/GSK. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to 
ViiV/GSK/PPD.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by ViiV/GSK/PPD to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide ViiV/GSK with a copy of any 
post-mortem findings including histopathology.

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

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

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

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

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

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associated with human leukocyte antigen (HLA) marker of liver injury, when liver 
chemistries improve to within 1.5x baseline and ALT<3xULN) (Table 6, Figure 4).
Drug Restart
Phase III “drug restart” can be approved by the VSLC for transient, defined non-drug-
induced liver injury if no evidence of:
•
immunoallergic injury /HLA association with injury
•
drug-induced liver injury (DILI)
•
alcoholic hepatitis
Study intervention is held while labs and evaluation is completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval (Figure 4):

PI requests consideration of drug re-initiation for a participant stable or improving on 
study intervention, who exhibits liver chemistry elevation meeting participant 
stopping criteria, which is transient, non-drug-related, and liver chemistries improve 
to within 1.5x baseline and ALT< 3xULN. 

In setting of a definitive non-study-drug-related diagnosis (e.g., acute viral or 
syphilitic hepatitis), restart will be considered once ALT <3x ULN (for 
participants with baseline ALT <1.5x ULN) or < 3x baseline ALT value (for 
participants with baseline ALT >1.5x ULN).

Medical monitor and Clinical Safety Physician to review the participant’s diagnosis, 
restart risk factors and complete checklist (Table 6).
The LOC medical director (ViiV Healthcare and GSK where applicable) should 
be informed that study intervention restart is under consideration and of the final 
decision, whether or not to proceed.
Table 6
Checklist for Phase III drug restart after well-explained liver injury 
(e.g., biliary, pancreatic, hypotensive events, congestive heart 
failure, acute viral hepatitis), improving to liver chem.1.5x baseline 
& ALT<3xULN
Yes
No
Was participant stable or improving on study intervention?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (AST>ALT, typically <10xULN)

study intervention has an HLA genetic marker associated with liver injury 
(e.g., lapatinib, abacavir, amoxicillin/clavulanate)
Previous drug history

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

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
The Safety Review Team must record restart outcomes and the GCSP Physician 
must send these to the VSLC
All severe reactions (restart associated with bilirubin>2xULN or jaundice, or 
INR1.5), SAEs or fatalities with drug restart must be immediately reported to 
Line Management, VSLC Chair, VP Global Medical Strategy and EU Qualified 
Person for Pharmacovigilance. 
Principal Investigator Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of drug 
restart, as required. 

If drug re-initiation VSLC-approved, the participant must provide informed consent 
with a clear description of possible benefits and risks of drug administration 
including recurrent, more severe liver injury or possible death.

The participant’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed once weekly for ‘restart’ cases for one month or 
for as long as clinically indicated following drug re-initiation.  If participant exhibits 
protocol-defined liver chemistry elevations, study intervention should be 
discontinued as protocol specified.
VSLC and the IRB/IEC must be informed of the participant’s outcome following 
drug restart.
Restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting participant stopping criteria

2 = recurrent liver chemistry elevation meeting participant stopping criteria

3 = serious adverse event

4 = fatality
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009; 8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010; 
52:2216-2222. 
Papay JI, Clines D, Rafi R, et al.  Drug-induced liver injury following positive drug 
rechallenge.  Regul Tox Pharm. 2009; 54:84-90. 

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

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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
11.10.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
11.10.5.
Committees Structure
Full details of the methods, timing, decision criteria and operating characteristics of the 
Independent Data Monitoring Committee (IDMC) will be pre-specified in the IDMC 
Charter.
11.10.6.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

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
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
11.10.7.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
ViiV/GSK site or other mutually-agreeable location.

ViiV/GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with 
ViiV/GSK Policy.
11.10.8.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 

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11.10.9.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
11.10.10. Study and Site Closure
ViiV/GSK or its designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of ViiV/GSK. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents 
and study supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development

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11.11.
Appendix 11:  Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events Version 2.1, 
March 2017
VERSION 2.1, March 2017
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term.
Estimating Severity Grade for Parameters Not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as grade 5
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Clinical adverse
event NOT
identified 
elsewhere in
the
grading table
Mild symptoms
causing no or 
minimal 
interference
with
usual social & 
functional
activities with
intervention not
indicated
Moderate symptoms
causing greater
than minimal
interference with
usual social &
functional
activities with
intervention 
indicated
Severe symptoms
causing inability
to perform usual
social & 
functional
activities
with
intervention or 
hospitalization 
indicated
Potentially life-
threatening
symptoms causing
inability to perform
basic self-care 
functions with
intervention
indicated to prevent 
permanent impairment, 
persistent disability, or
death
Major Clinical Conditions Cardiovascular
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Arrhythmia
(by ECG or physical
examination)
Specify 
type, if 
applicable
No symptoms
AND No
intervention 
indicated
No symptoms AND
Non-urgent 
intervention 
indicated
Non-life-
threatening 
symptoms 
AND Non-
urgent
intervention
indicated
Life-threatening 
arrhythmia OR
Urgent intervention
indicated

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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11.12.
Appendix 12:  CDC Classification for HIV-1 Infection (2014)

Note that the CD4+ T-lymphocyte count takes precedence over the CD4+ T-
lymphocyte percentage in HIV infection stages 1, 2, and 3.  The CD4+ T-
lymphocyte percentage should only be considered if the count is missing.

HIV infection, stage 0

Indicates early HIV infection, inferred from a negative or indeterminate HIV test 
result within 180 days of a positive result.  The criteria for stage 0 supersede and are 
independent of criteria used for other stages.

HIV infection, stage 1

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of ≥500 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%.

HIV infection, stage 2

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of 200 to 499 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%.

HIV infection, stage 3 (AIDS)

Laboratory confirmation of HIV infection, and
o
CD4+ T-lymphocyte count of <200 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or
o
Documentation of an AIDS-defining condition (see below).

Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte 
count of >200 cells/L and a CD4+ T-lymphocyte percentage of total lymphocytes 
of >14%. 

HIV infection, stage unknown

Laboratory confirmation of HIV infection, and
o
No information on CD4+ T-lymphocyte count or percentage, and
o
No information on presence of AIDS-defining conditions.

Stage-3-defining opportunistic illnesses in HIV infection

Candidiasis of bronchi, trachea, or lungs 

Candidiasis of oesophagus 

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary 

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

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

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

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11.14.
Appendix 14: COVID-19 Pandemic and Clinical Trial 
Continuity
Background
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participant’s ability to attend clinic visits.  In some places, medical 
visits are occurring, and in others, research clinics are operating with only emergency 
staff.
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in HIV-1 
treatment for participants enrolled in this clinical study, through continuous access to 
antiretroviral therapy.
In order to maintain the scientific integrity of the study, and adhere to updated guidance 
from regulators, procedures have also been put into place to ensure that the actions taken 
to mitigate against any impact of COVID-19 are well documented in the trial database.
A “Memo to Dolutegravir Clinical Trial Investigators and Study Staff” was issued on 
March 25th, 2020 and served as a record of approved emergency actions being taken 
within this clinical trial to manage issues related to COVID-19.  That memo continues to 
serve as record of approved actions which can be fully implemented by Investigators, in 
advance of this protocol guidance.  This appendix will remain consistent with the 
guidance provided within the March 25, 2020 “Memo to Dolutegravir Clinical Trial 
Investigators and Study Staff” and will also serve to provide additional protocol 
documentation requirements and procedures.
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect patient safety and to ensure the integrity of the clinical trial, as a 
result of COVID-19 only. These measures may be implemented in accordance with any 
requirements and expectations set out by local Independent Review Boards/Independent 
Ethics Committees and National Competent Authorities, as necessary.
This appendix does not apply to participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19. 
11.14.1.
Changes to Study Visits and Study Procedures

When site staff resources are limited due to COVID-19, abbreviated study visits 
may proceed without conducting all protocol-specified additional assessments 
(e.g. lab tests, questionnaires, etc.). If laboratory testing will be missed for more 
than one consecutive visit, medical monitor pre-notification is required, and all 
efforts should be made to find alternative approaches for lab testing. 

Consider alternative travel options for participants, if possible. 

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
When central laboratory testing is not possible at a particular visit, tests for 
management of participant safety, including HIV-1 RNA may be performed at an 
appropriately authorised/accredited local laboratory (or other relevant clinical 
facility), if this can be done within local restrictions on physical distancing. The 
site should proactively inform PPD/the sponsor about such instances. Local 
laboratory results done as per routine follow-up, including HIV-1 RNA, may be 
used to inform safety and patient management decisions.  Results should be 
retained in source records and added to the eCRF.
o
If labs are collected on site and cannot be processed (either via central lab 
shipping, or local labs), freeze (and maintain at correct temperature for 
later processing) those samples that are sent frozen. Please safely discard 
ambient samples per site standards.

When on-site visits are reduced, it is important that the investigator continue 
collecting relevant clinical information, including AEs/SAEs, from the participant 
through alternative means, e.g. by telephone contact. The assessment should 
include inquiries to determine if the participant has been impacted by COVID-19.  
Other protocol assessments and procedures as specified in the Schedule of 
Activities should be completed where possible (e.g. answer questions, update 
concomitant medications, emphasize adherence, plan/schedule participants return 
for next scheduled visit). This information should be placed in source records and 
entered into the eCRF when next possible. If the eC-SSRS assessment is able to 
be completed as part of the remote telephone visit, participants can complete the 
eC-SSRS at home by providing them with the activation code and the phone 
number or URL.  Where possible, the site should be in contact with the participant 
before and after the completion of the assessment to ensure proper follow-up of 
positive alerts and have plans in place for addressing any positive results, and 
referring for care as necessary. The HIV TSQ and SDM questionnaires may be 
completed over the phone.

There may be cases where the current principal investigator (PI) of a site is 
indisposed for a period and may need to delegate parts of his/her duties 
temporarily, e.g. to a sub-investigator. Any such changes should be documented 
in the site’s source records. Any permanent changes in PI should be 
communicated to the sponsor.

There may also be circumstances where immediate actions are required by the 
sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the National 
Competent Authority (NCA)/IRB/IEC regulations.
11.14.2.
Changes to Informed Consent
Informed consent should continue per normal procedure and as described in the main 
body of the protocol, to the extent possible. However, there may be circumstances where 
re-consent of participants is needed, and a physical signature on site is not possible. In 
these cases, alternative ways of obtaining such re-consent should be considered, such as 

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

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listed in the study guide should be evaluated and documented. Proper 
documentation of the shipment should be maintained. In all cases IP 
accountability must be maintained, and all DTP dispensing documentation should 
be reflected in source records and dispensing logs per GCP.

Please refer to your CRA or local study manager for support with the DTP 
process, ensuring reference to current sponsor guidance and arrangement of a 
courier that can support shipment of IP directly to participants.

Remember that any courier deliveries can be affected by limitations of 
movements imposed by governments in relation to COVID-19. 

Local courier vendors should be equipped to reduce risks of COVID-19 
contamination during transportation.
11.14.4.
COVID-19 Experimental Agents
If any treatments for COVID-19 are planned for a study participant, please consult with 
the study medical monitor to ensure that relevant drug interactions are considered and to 
ensure that continued study participation remains appropriate.
If any participants are being considered for enrolment into clinical studies for COVID-19 
treatment or vaccinations, please consult with the study medical monitor to ensure that 
relevant drug interactions are considered and to ensure that continued study participation 
remains appropriate. The protocols do not allow for enrolment in other interventional 
studies, though, there may be exceptions in this pandemic. Please discuss with the study 
team and Medical monitor.
11.14.5.
COVID-19 Specific Data Capture
11.14.5.1. Capturing COVID-19 Specific Protocol Deviations
In order to summarise the impact of COVID-19 in a systematic way and in line with 
regulatory authorities’ recommendations, any study-level impact around COVID-19 will 
be documented as a protocol deviation. This will include the permissible actions 
summarized in this Appendix, which are taken to protect patient safety, including DTP 
supply of IP and remote study visits as well as missed visits and assessments as a result 
of logistical challenges resulting from COVID-19.
Although the conduct of remote visits and the continuity of antiretroviral therapy, via 
DTP supply of IP, are being utilized to protect patient safety, these events fall outside of 
the intent of the original protocol design, may have an impact on data interpretation, and 
thus will be characterized as protocol deviations for the purposes of data summary and 
analysis.
Any protocol deviations resulting from COVID-19 should be clearly identified as such 
within the protocol deviation description and summarised separately. 

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

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WHO Case Definition (March 20, 2020 Version) (https://www.who.int/publications-
detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov)): 
Suspected case: 
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset; 
OR 
B. A patient with any acute respiratory illness AND in contact (see definition of 
“contact” below) with a confirmed or probable COVID-19 case (see definition of 
contact) in the last 14 days prior to symptom onset; 
OR 
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation. 
Probable case: 
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory). 
OR 
B. A suspect case for whom testing could not be performed for any reason. 
Confirmed case: 
A person with laboratory confirmation of COVID-19 infection, irrespective of clinical 
signs and symptoms. 
Covid-19 Contact:
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case: 
1. Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes; 
2. Direct physical contact with a probable or confirmed case; 
3. Direct care for a patient with probable or confirmed COVID-19 disease without 
using proper personal protective equipment; OR 
4. Other situations as indicated by local risk assessments. 

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Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation.

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

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

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

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

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

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

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