Clinical trial NCT04880395
Conditions: HIV-1-infection
Keywords: antiretroviral naive triple therapy. Dolutegravir-Lamivudine dual-therapy
Sponsor: Fundación Huésped
Start date: 2021-05-17; Completion date: 2024-05-07
Enrollment: 265 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Protocol Title: DOLCE: Dolutegravir-Lamivudine for naïve HIV-Infected Patients with ≤200 CD4/mm3

Protocol Number: FH-57

Study Objectives: To assess the antiviral activity at week 48 of DTG+3TC among naïve HIV patients with a CD4 count ≤200 cells /mm3.

Detailed description:
Primary endpoint: Proportion of patients with viral load \< 50 copies/mL at week 48 using the ITT-exposed analysis (FDA snapshot) for the intent-to-treat exposed (ITT-E) population.

Secondary Objectives:

* To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC at week 24
* To evaluate the safety and tolerability of DTG+3TC and DTG+TDF/XTC over time
* To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC at week 48 in patients with baseline viral load \>100,000 c/mL
* To evaluate immunological activity (CD4+ lymphocyte \[CD4 counts\]) at Week 24 and Week 48
* To assess the development of HIV-1 resistance in patients with virologic failure or viral rebound treated with DTG+3TC or DTG+TDF/XTC
* To evaluate the incidence of disease progression (HIV-associated conditions, AIDS and death) of DTG + 3TC and DTG + TDF/XTC over time.

Secondary endpoints:

* Proportion of patients treated with DTG+3TC and DTG+TDF/XTC with HIV-1 levels of less than 50 copies/mL at week 24
* Frequency, type and severity of adverse events and laboratory abnormalities and proportion of patients who discontinue DTG+3TC or DTG+TDF/XTC due to adverse events or death
* Proportion of patients with baseline HIV-1 RNA \>100,000 c/mL that achieve virological suppression at week 48 weeks,
* Changes in CD4 count, CD8 count and CD4/CD8 ratio between baseline and 48 weeks
* Number and type of resistance mutations in case of virologic failure (defined as a confirmed viral above 200 copies/mL after week 24 copies/mL or viral rebound at any timepoint)
* Incidence of IRIS and disease progression (HIV associated conditions, AIDS and death).

Tertiary objectives:

● TDF/XTCTo explore change in health-related quality-of-life for subjects treated with DTG plus 3TC and DTG + TDF/XTC

Tertiary endpoints:

● Change from Baseline in health-related quality of life using EQ-5D-5L and PHQ9 at Weeks 24, and 48

Patient Population:

HIV-1-infected subjects aged \>18 years who are naïve to antiretroviral therapy with ≤200 CD4 cell/mm3

Study Design:

Prospective, Phase IV, randomized, multicenter, parallel group study design

Regimens:

Dolutegravir 50 mg /lamivudine 300 mg QD FDC. Dolutegravir 50 mg QD plus tenofovir 300 mg/emtricitabine 200mg or plus tenofovir 300 mg/ lamivudine 300 mg.

Duration: 48 weeks

Sample size:230 subjects

Arms: arm 1: DOVATO: Dolutegravir 50mg/lamivudine 300 mg, FDC, 1 coformulated tablet QD arm 2: Unit Dose:

* TDF/FTC 300/200 mg, 1 coformulated tablet QD (FDC) plus Dolutegravir 50 mg, 1 tablet QD OR
* TDF/3TC 300/300 mg, 1 coformulated tablet QD (FDC) plus Dolutegravir 50 mg, 1 tablet QD
Interventions: intervention 1: Intervention Arm: dolutegravir/lamivudine intervention 2: Comparator ARM: TDF/XTC plus Dolutegravir (XTC stand for lamivudine OR emtricitabine)
Intervention descriptions: intervention 1: 1 pill QD intervention 2: 1 pill of each QD

Protocol documents:
Prot_SAP_000.pdf: 
DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
_________________________________________________________________________________________ 
Confidential Information – Not for distribution 
DOLCE (FH-57) 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤ 
200 CD4. 
Phase IV 
Protocol version 3.0, December 13th, 2021 
 
Principal Investigators:  
Dr. María Inés Figueroa, MD, PhD 
Fundación Huésped (Argentina)  
 
Dr. Carlos Brites, MD, PhD 
Universidade Federal de Bahia (Brazil)  
 
 
Version Number: 3.0 
Date: December 13th, 2021 
 
 
 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
_________________________________________________________________________________________ 
 
Signature Page 
 
Investigator Signature: 
I have read this protocol and agree to conduct this study in full accordance with all 
applicable regulations and Good Clinical Practice. 
 
Signed: __________________________________   Date: _________________​
     
Signed: __________________________________   Date: _________________​
 
 
Sponsor’s signature: 
 
I have read and approve this protocol. I assure that this study will be conducted 
according to all stipulations of the protocol, including all statements regarding 
confidentiality. 
 
 
Signed: _________________________________   Date: _________________​
 
 
 
 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
_________________________________________________________________________________________ 
 
Sponsor Information Page 
This study is sponsored by Fundación Huésped and funded by an Investigator grant 
from ViiV.  
 
Sponsor: 
Fundación Huésped 
Carlos Gianantonio, (Ex Angel Peluffo) 3932 (C1202ABB) 
Buenos Aires, Argentina 
 
Sponsor contact: 
UEM-Gardel Multicentric Studies Unit  
Fundación Huésped 
Carlos Gianantonio, (Ex Angel Peluffo) 3932 (C1202ABB) 
Buenos Aires, Argentina 
Telephone +54 11 4981-1855/7777 
Fax +54 11 4982 4024 
E-mail: UEMgardel@huesped.org.ar 
 
 
 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
_________________________________________________________________________________________ 
 
Clinical Study Protocol 
DOLCE: Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. 
Protocol version 3.0, December 13rd, 2021   
Protocol Number: 
FH-57 
​
Investigational Product: 
​
Dolutegravir-Lamivudine 
Development Phase: 
Phase IV 
 
Study Design:           
.  
Randomized, non-comparative, open, multicenter study 
 
Authors 
 
Omar Sued, MD, PhD 
Carlos Brites, MD, PhD 
 
Sponsor 
Fundación Huésped  
The study will be supported by an Investigator-Initiated 
Research Grant from ViiV.  
 
Clinicaltrials.gov: 
(Registry number) 
NCT04880395 
 
This study will be conducted in compliance with the protocol, Good Clinical 
Practice and all other applicable regulatory requirements, including the US and 
Argentinean regulations.  
 
 
 
 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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TABLE OF CONTENTS 
 
1.​
INTRODUCTION​
8 
1.1.​
BACKGROUND INFORMATION​
8 
1.2.​
RATIONALE​
8 
2.​
OBJECTIVES​
10 
2.1.​
PRIMARY OBJECTIVE:​
10 
2.1.1.​
PRIMARY ENDPOINT:​
10 
2.2.​
SECONDARY OBJECTIVES:​
10 
2.2.1.​
SECONDARY ENDPOINTS:​
10 
2.3.​
TERTIARY OBJECTIVES:​
11 
2.3.1.​
TERTIARY ENDPOINTS:​
11 
3.​
INVESTIGATIONAL PLAN​
11 
3.1.​
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION​
11 
3.2.​
TREATMENT ARMS AND DURATION​
11 
4.​
SUBJECTS SELECTION AND WITHDRAWAL CRITERIA​
13 
4.1.​
STUDY POPULATION​
13 
4.2.​
MANAGEMENT OF WOMEN OF CHILD BEARING POTENTIAL AND PREGNANCY​
13 
4.3.​
SAMPLE SIZE​
13 
4.4.​
INCLUSION CRITERIA​
15 
4.5.​
EXCLUSION CRITERIA​
17 
4.6.​
WITHDRAWAL CRITERIA​
18 
4.7.​
MANAGEMENT OF INDIVIDUALS WHO FAILS TO ATTEND THE CLINIC FOR A PLANNED CLINICAL VISIT:​
19 
4.8.​
VIROLOGIC WITHDRAWAL CRITERIA FOR SUBJECT MANAGEMENT AND VIRAL RESISTANCE TESTING​
20 
4.9.​
SCREENING FAILURES​
21 
5.​
STUDY TREATMENT​
21 
5.1.​
DOSAGE AND ADMINISTRATION OF STUDY DRUGS​
21 
5.2.​
TREATMENT ASSIGNMENT​
21 
5.3.​
DRUG PROVISION​
22 
5.4.​
PREPARATION/HANDLING/STORAGE:​
23 
5.5.​
PACKAGING AND LABELING​
24 
5.6.​
PRODUCT ACCOUNTABILITY​
24 
5.7.​
TREATMENT COMPLIANCE​
24 
5.8.​
TREATMENT OVERDOSE​
24 
5.9.​
TREATMENT AFTER THE END OF STUDY​
24 
5.10.​ CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES​
25 
5.11.​
PERMITTED AND PROHIBITED MEDICATIONS AND NON-DRUG THERAPIES​
25 
5.12.​ PROHIBITED MEDICATIONS AND NON-DRUG THERAPIES​
26 
6.​
STUDY ASSESSMENTS AND PROCEDURES​
27 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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7.​
EFFICACY OUTCOMES​
32 
7.1.​
PLASMA HIV-1 RNA​
32 
7.2.​
LYMPHOCYTE SUBSETS​
32 
7.3.​
FAT DISTRIBUTION​
32 
7.4.​
QUALITY OF LIFE AND DEPRESSION​
32 
8.​
SAFETY​
32 
8.1.​
ADVERSE EVENTS​
32 
8.2.​
SERIOUS ADVERSE EVENTS​
34 
8.3.​
OTHER EVENTS THAT SHOULD BE REPORTED​
36 
8.3.1.​
CARDIOVASCULAR EVENTS​
36 
8.3.2.​
NEW AIDS EVENT AND AIDS RELATED DEATHS​
36 
8.3.3.​
SUICIDAL IDEATION OR BEHAVIORS​
36 
8.3.4.​
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)​
37 
9.​
TOXICITY MANAGEMENT​
38 
9.1.​
ALLERGIC REACTION​
39 
9.2.​
RASH​
39 
9.3.​
TOXICITY GRADE 1-2:​
41 
9.4.​
TOXICITY GRADE 3-4:​
41 
9.5.​
LIVER CHEMISTRY STOPPING AND FOLLOW UP CRITERIA​
42 
9.6.​
HYPERGLYCEMIA​
44 
9.7.​
CPK ELEVATION​
44 
9.8.​
HYPERTRIGLYCERIDEMIA/HYPERCHOLESTEROLEMIA​
45 
9.9.​
DECLINE IN RENAL FUNCTION​
45 
10.​ REPORTING​
45 
10.1.​ OBSERVATION PERIOD FOR ADVERSE EVENT REPORTING:​
45 
10.2.​ PREGNANCY REPORTING​
45 
10.3.​ EVENTS REPORTING TIME PERIODS FOR SAES AND PREGNANCY REPORT​
46 
11.​ DATA MANAGEMENT​
46 
11.1.​
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS​
47 
11.1.1.​
HYPOTHESES​
47 
11.1.2.​
ANALYSIS POPULATIONS​
47 
11.1.3.​
ANALYSIS DATA SETS​
47 
11.1.4.​
TREATMENT COMPARISONS​
48 
11.2.​
INTERIM ANALYSIS​
48 
11.3.​
STATISTICAL PLAN​
48 
11.3.1.​
EFFICACY ANALYSES​
48 
11.3.2.​
SAFETY​
49 
11.4.​
PROCEDURE FOR HANDLING MISSING, UNUSED, AND SPURIOUS DATA​
50 
11.5.​
PROCEDURES FOR REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN​
50 
12.​ STUDY CONDUCT CONSIDERATIONS​
50 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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12.1.​ POSTING OF INFORMATION AND RESULTS ​
50 
12.2.​ REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING THE INFORMED CONSENT PROCESS​
50 
12.3.​ DATA HANDLING AND RECORD KEEPING​
51 
12.4.​ QUALITY CONTROL​
51 
12.5.​ QUALITY ASSURANCE​
52 
12.6.​ STUDY AND SITE CLOSURE​
52 
13.​ REFERENCES​
53 
APPENDICES​
55 
14.​ APPENDIX 1. PROTOCOL SYNOPSIS​
55 
15.​ APPENDIX 2. CDC CLASSIFICATION SYSTEM FOR HIV-1 INFECTIONS (1993)​
57 
16.​ APPENDIX 3: MODIFIED LIST OF HIGHLY EFFECTIVE METHODS FOR AVOIDING PREGNANCY IN FEMALES OF 
REPRODUCTIVE POTENTIAL​
61 
17.​ APPENDIX 4: ESSENTIAL ELEMENTS OF INFORMED CONSENT​
62 
18.​ APPENDIX 5: ADHERENCE QUESTIONNAIRES​
64 
19.​ APPENDIX 6: QUALITY OF LIFE QUESTIONNAIRES​
67 
20.​ APPENDIX 7: MENTAL HEALTH QUESTIONNAIRE​
70 
21.​ APPENDIX 8: DTG+3TC RISK ASSESSMENT​
72 
 
 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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1.​ Introduction 
1.1.​Background Information 
Dolutegravir (DTG), a second generation integrase inhibitor (INI) is one of the most 
potent antiviral drugs: - with IC50 values in the nanomolar rage (2.7 to 12.6nM) in 
vitro and in vivo 10-day monotherapy, with 50 mg of DTG, resulting in 2.48 log10 
copies/mL decline in HIV viral load. Large clinical trials showed non-inferior efficacy 
and a safety profile of DTG similar to raltegravir (RAL) with 88% of participants 
virologically suppressed at 48 weeks1, and superiority when compared with 
efavirenz2. DTG has been shown to have a high genetic barrier as in randomized 
clinical trials the emergence of INI resistant mutation among failing patient is 
extremely rare.3 
Lamivudine is cheap, well tolerated and with a very low potential of drug interactions, 
it allows also a once daily dosing.4 
Dual therapy based on dolutegravir + lamivudine (DTG+3TC) has been developed 
for initial treatment or as simplification of treatment-experienced, virologically 
suppressed 
individuals. The PADDLE study5 and the ACTG5353 study6 
demonstrated that DTG+3TC resulted in potent antiviral activity. GEMINI 1&2 trials 
demonstrated non-inferiority compared to a dolutegravir based three-drug regimen at 
both week 48 (primary endpoint) and week 96. 7,8 The combination has also been 
shown to be effective and safe as a simplification strategy among suppressed 
patients, switching from TAF based regimens in the TANGO study.9 
1.2.​Rationale 
Dolutegravir plus lamivudine has been included as a recommended regimen for 
antiretroviral treatment naïve patients in both the DHHS10 and EACS11, although 
EACS guideline still requires >200 CD4/mm3 for this indication. The combination has 
the potential of becoming a first-line preferred therapy across multiple geographies 
globally and could represent a new global standard of care for ART expansion. In 
fact, WHO is proposing the transition of ART programs to DTG based 
combinations12,13 that contain tenofovir. Avoiding tenofovir might reduce costs, pill 
size and need for renal monitoring. DTG+3TC can be proposed as a preferred 
combination for several reasons. DTG is an extremely potent antiviral compound 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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with proven clinical efficacy in both treatment- naïve and treatment-experienced 
HIV-infected patients. The genetic barrier of DTG resistance is higher than other first 
generation 
INIs. 
Metabolism 
primarily 
by 
uridine 
diphosphate 
glucuronosyltransferase (UGT)1A1 anticipates no significant drug–drug interactions 
and the pharmacokinetic profiles support once day dosing. 3TC is a safe and well 
tolerated drug and the presence of the M184V resistance mutation might not 
preclude anti-viral activity. DTG+3TC allows a once a day dosing schedule. In 
addition, this combination does not require preliminary testing (with the exception of 
testing for hepatitis B infection in order to avoid lamivudine monotherapy in those 
with chronic infection), dose adjustment in moderated renal disease or special 
monitoring needs. DTG+3TC is an attractive combination from a safety perspective 
as it is not associated with many of the toxicities described for other drugs (lipid 
alterations in PIs; CNS toxicity, liver toxicity or rash in NNRTI; mitochondrial toxicity 
in NRTI; and renal and bone disease in tenofovir). However, the information about 
efficacy in patients with advanced HIV disease is limited.  
One third of new HIV diagnosis is identified with advanced HIV disease: In Brazil, 
30% of new diagnosed individuals have less than 200 CD4 cells/mm3,14 while in 
Argentina the figure is similar, with 32.6%.15 Therefore, it is critical to demonstrate 
that this new intervention is effective in this sub-population. In previous studies, 
three-drug regimens based on Dolutegravir performed well and even better than the 
comparator arm among participants with less than 200 CD4 cells/mm3: in SPRING2 
the response in the DTG arm was 78% vs 68% in the RAL arm. In the SINGLE Study 
it was 79% in the DTG arm vs 77% in the EFV arm, and in the FLAMINGO it was 
91% in the DTG arm vs 79% in the Darunavir arm.16 However, the sub-samples for 
these studies were small (less than 60 participants in each one). For patients with 
CD4≤ 200 cells/mm3 in the GEMINI study the dual therapy arm achieved a 
percentage of viral suppression at 48 weeks similar to previous studies with 79% of 
success, but the comparator (DTG-TDF-FTC) achieved 93% of viral suppression.7 
Whilst caution needs to be taken interpreting these results due to the small numbers 
(9% of the Gemini 1&2 populations) and the fact that majority of those patients with 
low CD4 cell counts considered snapshot failures were due to non-treatment related 
reasons, this finding makes it imperative to explore further the efficacy of DTG+3TC 
dual therapy in this sub-population.  
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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2.​ Objectives  
2.1.​Primary objective: 
To assess the antiviral activity at week 48 of DTG+3TC among ART-naïve HIV 
patients with a CD4 count ≤200 cells/mm3. 
2.1.1.​ Primary endpoint:  
Proportion of patients with viral load < 50 copies/mL at week 48 using the 
ITT-exposed analysis (FDA snapshot) for the intent-to-treat exposed (ITT-E) 
population. 
2.2.​Secondary objectives:  
●​ To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC (TDF/FTC or 
TDF/3TC) at week 24  
●​ To evaluate the safety and tolerability of DTG+3TC and DTG+TDF/XTC over 
time 
●​ To assess the antiviral activity of DTG+3TC and DTG+TDF/XTC at week 48 in 
patients with baseline viral load >100,000 c/mL  
●​ To evaluate immunological activity (CD4+ lymphocyte [CD4 counts]) at Week 
24 and Week 48 
●​ To assess the development of HIV-1 resistance in patients with virologic 
failure or viral rebound whilst being treated with DTG+3TC or DTG+TDF/XTC 
●​ To evaluate the incidence of disease progression (HIV-associated conditions, 
AIDS and death) with DTG+3TC and DTG + TDF/XTC treatment over time 
2.2.1.​ Secondary endpoints:  
●​ Proportion of patients treated with DTG+3TC and DTG+TDF/XTC with HIV-1 
levels of less than 50 copies/mL at week 24 
●​ Frequency, type and severity of adverse events and laboratory abnormalities 
and proportion of patients who discontinue DTG+3TC or DTG+TDF/XTC due 
to adverse events or death 
●​ Proportion of patients with baseline HIV-1 RNA >100,000 c/mL that achieve 
virological suppression at week 48  
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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●​ Changes in CD4 count, CD8 count and CD4/CD8 ratio between baseline and 
48 weeks 
●​ Number and type of resistance mutations in case of virologic failure (defined 
as a confirmed viral above 200 copies/mL on or after week 24 or confirmed 
viral rebound at any time-point)  
●​ Incidence of IRIS or disease progression (HIV associated conditions, AIDS 
and death) 
2.3.​Tertiary objectives:  
●​ To explore change in health-related quality-of-life and depression, for subjects 
treated with DTG+3TC and DTG+TDF/XTC. 
2.3.1.​ Tertiary endpoints: 
●​ Change from Baseline in health-related quality of life using EQ-5D-5L and 
PHQ9 at Weeks 24, and 48.  
3.​ Investigational Plan 
3.1.​Overall Study Design and Plan: Description 
This is a phase IV randomized, open-label study describing the antiviral efficacy, 
safety and tolerability of dual therapy with DTG+3TC as initial therapy among naïve 
HIV-1 subjects with CD4 ≤200 cells/mm3. 
3.2.​Treatment arms and duration 
The study will include 230 HIV-1-infected subjects, meeting all inclusion criteria and 
not meeting any exclusion criteria for this study. They will be randomly assigned in a 
2:1 ratio to receive DTG plus 3TC or DTG plus TDF/XTC. Randomization will be 
stratified by country and by screening plasma HIV-1 RNA (> or ≤ 100.000 
copies/mL).  
This study will consist of a screening period of up to 10 days, a 48-week treatment 
period, followed by a 4-week post-treatment follow-up (FU) period to document late 
adverse events.  
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Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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At the screening visit, subjects must be willing and able to give written informed 
consent (signed and dated) prior to any study-specific procedure. Participants will 
receive a unique screening number and will undergo all the study procedures 
corresponding to the screening visit.  
The investigator will document in the clinical record the informed consent process, 
provide a signed copy to the participant, and evaluate and document whether the 
subject meets all eligibility criteria. All the laboratory results should be evaluated and 
signed by the investigator or a sub-investigator. Women of child bearing potential 
should be fully informed about the potential risk of using dolutegravir during 
conceptional period (refer to Section 4.2).  
At the Baseline Visit, subjects will undergo the study procedures identified in Table 1 
and will initiate DTG+3TC for 48 weeks, or DTG+3TC/TDF depending on the 
assigned arm. Subjects will receive instructions about the study medications and the 
dosing schedule. The participants should begin taking their study medication within 
24 hours of the Baseline Visit. Subjects will return to the investigator's site for the 
study visits and procedures. Subjects who prematurely discontinue from the study 
must return for a Final /Discontinuation Visit. 
After finishing or discontinuing the protocol, the investigator will make all efforts to 
ensure continuity of treatment through her/his regular care provider in order to avoid 
unnecessary interruptions. For patients that discontinue due to virological failure or 
toxicity, efforts will be made to ensure a proper switch to an effective treatment, or a 
safe regimen, as appropriate, and as early as possible. 
A DSMB will be instituted to ensure external review of efficacy and safety in order to 
protect the scientific and ethical interest and wellbeing of subjects.  
4.​ Subjects selection and withdrawal criteria 
4.1.​Study population  
Subjects will be HIV-1-infected patients without ARV experience (naïve), who are 
willing to start ARV therapy, with ≥ 18 years of age, and who meet all inclusion 
criteria and do not meet any of the exclusion criteria. 
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Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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4.2.​Management of Women of Child Bearing Potential and pregnancy 
Study participants should be informed that an observational study identified a 
potential risk of neural tube defects in infants born to women who were taking DTG 
when they became pregnant. These defects happen early in pregnancy, before many 
women even know they are pregnant.   
Women who are pregnant or breastfeeding, or women who plan to become pregnant 
in the next year are excluded from this study. Women of reproductive potential 
should be counselled on the importance of avoiding pregnancy, safer sexual 
practices and the proper use of their chosen contraceptive methods in accordance 
with the applicable contraceptive product label, or, for non-product methods, as 
determined by the investigator, and reminded about this at every study visit.  
The subject’s chosen contraceptive method must be used for an adequate time 
period (at least 10 days) before dosing with the DTG-containing study medication is 
initiated and continued throughout the treatment- and post-treatment- periods until it 
is predicted that a clinically insignificant amount of study medication(s) is present in 
the subject (i.e., 30 days or one month after stopping DTG).  
4.3.​Sample Size 
This study is designed to assess the antiviral effect of DTG+3TC in naïve HIV 
individuals with CD4 ≤200 cells/mm3. No formal comparative statistical hypothesis 
testing will be performed. The study will include 230 HIV-1-infected subjects, meeting 
all inclusion criteria and not meeting any exclusion criteria for this study. Assuming 
an 80% response rate for DTG+3TC, a sample size of 153 subjects would have > 
85% power to detect a response rate of greater than 70%.  
In this study, though comparing DTG+3TC to DTG+TDF/XTC is not the primary 
objective, it will still be randomized to include a group of patients on DTG + TDF/XTC 
using a 2:1 allocation ratio (DTG+3TC: DTG+ TDF/XTC).  
A total sample size of 230 (153+77) would be recommended for the study. 
Although the objective of the study is not to test a statistical hypothesis between the 
two treatment groups, the sample size has been chosen to provide an adequate 
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Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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number of subjects for assessing the antiretroviral activity of DTG+3TC in this patient 
group. 
 
 
 
Figure A: relationship between study power and sample size required 
assuming a response rate of 80% against a pre-specified target response rate 
of 70%. 
 
 
 
Figure B: relationship between minimum sample size required and the 
assumed response rate against the pre-specified response rate of 70%; 
different targets for power (80% and 90%) are considered. 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
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Deviations from inclusion and exclusion criteria will not be allowed. Subjects will be 
allowed to re-screen for this study one time except where exclusionary HIV-1 
resistance was present. A single repeat test (re-test) per analyte or assessment is 
allowed during the screening period to determine eligibility  
4.4.​Inclusion Criteria 
A subject will be eligible for study participation if he/she meets ALL of the following 
criteria:  
1.​ Subject has voluntarily signed and dated an informed consent form, approved 
by an Institutional Review Board (IRB) / Independent Ethics Committee (IEC), 
after the nature of the study has been explained and the subject has had the 
opportunity to ask questions.  
2.​ Documented HIV-1 infection defined as a positive rapid test or ELISA plus a 
plasma HIV-1 RNA (>1,000 copies/mL) or a positive western blot. A previous 
result performed on the last 30 days can be used.   
3.​ ≥18 years of age. 
4.​ Naïve to ARV therapies (defined as ≤ 10 days of prior therapy with any 
antiretroviral therapy following an HIV diagnosis). Previous use of PrEP or 
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DOLCE 
Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤200 CD4. Protocol version 3.0, 13 Dec ,  2021 
_________________________________________________________________________________________ 
PEP is allowed if there is documented HIV seronegativity between the last 
prophylactic dose and the date of HIV diagnosis. 
5.​ HIV RNA at screening visit > or = 1,000 copies/mL. A previous result 
performed on the last 30 days can be used.   
6.​ CD4 at screening < or = 200 cells/mL. A previous result performed on the last 
30 days can be used. 
7.​ Subjects can comply with protocol requirements.  
8.​ Subject agrees not to take any medication during the study, including 
over-the-counter medicines or herbal preparations, without the approval of the 
trial physician. 
9.​ Subject’s general medical condition, in the investigator’s opinion, does not 
interfere with assessments and completion of the study. 
10.​A female may be eligible to enter and participate in the study if she is not 
pregnant (as confirmed by serum pregnancy test negative at screening, and a 
urine negative test at baseline), not lactating and at least one of the following 
condition applies:  
a)​ Women with non-reproductive potential, defined as pre-menopausal females 
with documented tubal ligation or hysterectomy, or bilateral oophorectomy; or 
as post-menopausal women defined as 12 months of spontaneous 
amenorrhea, and ≥45 years of age in women without hormonal replacement 
therapy. 
b)​ Women with reproductive potential and agrees to follow one of the 
contraceptive options listed in the Appendix 3 from at least 15 days prior to 
the first dose of medication and until at least 30 days after the last dose of 
study medication and completion of the follow-up visit.  
Any contraception method must be used consistently, in accordance with the 
approved product label. All subjects participating in the study should be 
counselled on safer sexual practices including the use of effective barrier 
methods and the choice of effective contraceptive method should be 
documented in the eCRF.  
4.5.​Exclusion Criteria 
Patients will NOT be selected to be part of this study if they meet ANY of the 
following criteria:  
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1.​ Women who are pregnant or breastfeeding, or women who plan to become 
pregnant in the next year. 
2.​ Subjects testing positive for Hepatitis B surface antigen (+HBsAg) at 
screening, or anticipated need for Hepatitis C virus (HCV) therapy with drugs 
with potential drug-drug interaction during the study.  
3.​ Subjects with severe hepatic impairment (Child-Pugh class C), or unstable 
liver disease (ascites, encephalopathy, coagulopathy, or oesophageal or 
gastric varices) or cirrhosis. 
4.​ Opportunistic infections that impede to start ART immediately (specifically 
tuberculosis, meningeal tuberculosis or cryptococcosis within the first month 
of specific treatment). Subjects with other suspected or confirmed active 
opportunistic infections and subjects with cryptococcal disease after the initial 
period can be included if she/he can follow the protocol and if her/his 
participation could benefit the subject. A clear documentation of these aspects 
must to be done in the clinical chart of the participant. 
5.​ Subjects who in the investigator’s judgment, pose a significant suicidality risk.  
6.​ History or presence of allergy to the study drugs or their components or drugs 
of their class. 
7.​ Treatment with any of the following agents within 28 days of screening: 
radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators 
that alter immune responses; or treatment with an HIV-1 immunotherapeutic 
vaccine within 90 days of screening; or 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 investigational product. 
8.​ Any previous evidence of resistance to dolutegravir (defined as the presence 
of G118R, Q148 H/K/R or R263K), to lamivudine (presence of the mutation 
M184V) or resistance to tenofovir (mutation K65R or more than 3 TAMs) with 
a Sanger sequence method or using next-generation sequencing (NGS) at a 
frequency >15%. If the subject does not have a previous resistance test, 
samples will be taken at the screening visit and the subject can be 
randomized and start the study. while awaiting the results (see section 4.8). 
9.​ Any verified Grade 4 abnormality.  
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10.​Alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (ULN), or 
ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (with >35% direct bilirubin). 
11.​Creatinine clearance of <50mL/min via Cockroft-Gault method  
4.6.​Withdrawal Criteria  
Subjects discontinuing study treatments before week 48 are considered withdrawn 
from the study. A subject may withdraw from study treatment at any time at his/her 
request or may be withdrawn at any time at the discretion of the investigator for 
safety, or other reasons. Those subjects will not be replaced. The study might allow 
temporary interruptions for management of toxicities or other reasons. Consultation 
with the medical monitor is required.  
 Subjects may be withdrawn from the study if: 
1.​ Subject non compliance, as evaluated by the investigator;  
2.​ At the request of the subject, the investigator, the IRB, or the sponsor; 
3.​ The subject requires concurrent prohibited medication; 
4.​ The investigator considers that, for safety reasons, it is in the best interest of 
the subject that he or she is withdrawn;  
5.​ The resistance test shows evidence of resistance to dolutegravir (defined as 
the presence of G118R, Q148 H/K/R or R263K), to lamivudine (presence of 
the M184V mutation) or to tenofovir (K65R mutation or more than three 
TAMs), should be discussed with the study medical monitor. In this case, the 
researcher will evaluate the risk of keeping the patients in the study 
depending on the type of mutations and the virological evolution. The opinion 
of the study medical monitor should be sought for any resistance test with 
mutations to any study drugs.  
Subjects must be withdrawn from the study if: 
1.​ The subject meets virological failure criteria 
2.​ Subject requires dose modification of DTG, 3TC, TDF or FTC 
3.​ Individual meets liver toxicity stopping rules  
4.​ Subjects with an adverse event Grade ≥4 that is considered causally related 
to the investigational product(s) 
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5.​ Pregnancy  
6.​ For certain other toxicities (see Section 9) 
If a subject is prematurely withdrawn from the study, all procedures specified for the 
withdrawal visit should be performed. The date and the reason for discontinuation 
must be noted on the case report form (CRF). If possible, perform the follow up visit 
after 4 weeks after the last dose of study.  
4.7.​Management of individuals who fails to attend the clinic for a planned 
clinical visit:  
The site should attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 
Counselling should be provided at each visit to identify individuals experiencing 
challenges to continue in the study. 
In cases where the subject is considered lost to follow up, the investigator team 
should document in the medical chart that they had performed at least 3 telephone 
calls, had sent 1 certified letter, and had tried to contact them through social 
networks.  
4.8.​Virologic Withdrawal Criteria for Subject Management and Viral 
Resistance Testing  
Patients will have a HIV resistance test at the time of inclusion in the study. They 
may be randomized without having the results of resistance tests, due to the urgency 
of initiating treatment and the low risk of primary resistance. The situation will be 
re-evaluated upon receiving the results. Those participants whose resistance test 
shows evidence of resistance to dolutegravir (defined as the presence of G118R, 
Q148 H / K / R, or R263K), lamivudine (presence of the M184V mutation), or 
resistance to tenofovir (K65R mutation or more than three TAMs) should be 
discussed with the study medical monitor and followed according instructions. For 
mutations that do not predict decreased efficacy of dolutegravir, the investigator may 
consider performing a viral load to assess response before making the decision to 
exclude the participant. 
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Subjects with confirmed virological rebound or virological non-response will be 
considered to have met virological withdrawal criteria. For clinical management 
virological rebound is defined as a confirmed (repeated within 4 weeks of the first 
measurement) rebound in plasma HIV-1 RNA levels ≥ 200 c/mL after prior virological 
suppression to ≤ 200 c/mL. Non response is defined as a decrease in plasma HIV-1 
RNA of less than 1 log10 c/mL by week 12, with subsequent confirmation, unless 
plasma HIV-1RNA is ≤ 200 c/mL; or by a confirmed plasma HIV-RNA levels ≥ 200 
c/mL on, or after week 24.  
For confirmation, investigators should not schedule re-assessment 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 vaccinations. Subjects should have received full doses of 
investigational product for at least 2 weeks at the time of HIV-1 RNA re-assessment. 
In all participants meeting virological withdrawal criteria a genotypic test and plasma 
storage should be requested. Sites should discuss cases with Medical Monitor 
before withdrawing individuals.  
4.9.​Screening Failures  
A subject is considered a screening failure if after providing informed consent, the 
subject’s circumstances or conditions change or the outcome of a test or 
assessment becomes available which results in the subject’s failure to meet one or 
more of the entry criteria, or results in the investigator deciding that the subject is no 
longer an appropriate study candidate. Subjects are allowed to re-screen for this 
study one time; this will require a new subject number. There is no timeline restriction 
for re-screening. A single repeat test (re-test) per analyte or assessment is allowed 
during the screening period to determine eligibility (with the exception of a 
disqualified screening genotype, which may not be retested).  
5.​ Study Treatment  
The term investigational product (IP) is used to describe any combination of products 
received by the subject as per the protocol design. 
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5.1.​Dosage and Administration of study drugs 
 
Arm 
Dual therapy arm 
Triple therapy arm 
Product 
name 
Dolutegravir/lamivudine 
DTG+3TC FDC  
Tenofovir disoproxil fumarate/ 
emtricitabine 
TDF/FTC, 
or 
Tenofovir disoproxil fumarate/ 
lamivudine 
TDF/3TC 
Dolutegravir 
DTG 
Unit Dose 
50 mg DTG/300 mg 3TC 
300 mg TDF/200 mg FTC or 
300 mg TDF/300 mg 3TC, 
50 mg DTG 
Route 
Oral 
Oral 
Oral 
Frequency 
QD 
QD 
QD 
Dosing 
instructions 
With or without food 
With 
or 
without 
food 
in 
combination with DTG 
With or without 
food in combination 
with TDF/FTC or 
TDF/3TC 
5.2.​Treatment assignment 
Informed consent must be obtained prior to any study procedures. Subjects will be 
assigned to study treatment in accordance with the computer-generated 
randomization schedule. Randomization schedule will be generated by Fundación 
Huésped using REDCap. Subjects will be randomized in a 2:1 ratio to DTG+3TC or 
DTG plus TDF/XTC. After confirmation of fulfilment of study entry criteria, study site 
personnel will be required to randomize the participant using the REDCap 
randomization feature. Once randomized, and if subsequently the participant is 
withdrawn from the study, she/he cannot be rescreened. Randomization will be 
stratified on > or ≤ 100.000 copies/mL. 
Participant will maintain the assigned treatment group throughout the study. Efforts to 
avoid errors should be implemented in the clinic including but not limited to maintain 
a randomization list at the pharmacy, double verification of the treatment prescription 
and dispensation and internal audits.  
5.3.​Drug provision  
For Argentina: 
DTG 50mg will be provided for Argentina in local commercial bottles with fill count of 
30 tablets. DTG+3TC (as a single pill fixed dose combination) will be provided for 
Argentina in local commercial bottles with fill count of 30 tablets. For storage 
conditions, refer to the package insert leaflet provided with the local commercial 
packs.  
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For Brazil: 
DTG+3TC (as a single pill fixed dose combination) will be provided for Brazil in local 
commercial bottles with fill count of 30 tablets. For storage conditions, refer to the 
package insert leaflet provided with the local commercial packs. The comparator 
should be requested locally through the regular HIV provider. 
DTG/3TC. 
Product details can be found below:  
Dosage formulation: 
White, oval, film-coated tablets 
Unit dose strength(s)/Dosage level(s): 
50mg/300mg 
Route of Administration: 
Oral 
Dosing instructions: 
Take one tablet once a day 
Bottle specification from GSK/ViiV Healthcare 
The tablets are packed in high density 
polyethylene (HDPE) bottles with induction 
seals and child-resistant closures.  Each 60 mL 
bottle contains 30 tablets and a 2-gram silica 
gel desiccant. The bottle will only have a batch 
number.   
Storage Conditions 
Store up to 30° C (86°F), protect from moisture. 
Manufacturer 
GSK 
 
DTG 50mg (single entity) product details can be found below:  
Dosage formulation: 
yellow, biconvex, round, film-coated 
Unit dose strength(s)/Dosage level(s): 
50mg 
Route of Administration: 
Oral 
Dosing instructions: 
Take one tablet once a day 
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Bottle specification from GSK/ViiV Healthcare 
The tablets are packed in high density 
polyethylene (HDPE) bottles with induction 
seals and child-resistant closures.  Each 60mL 
bottle contains 30 tablets. The bottle will only 
have a date of manufacturer and batch number.   
Storage Conditions 
Between 15OC -30OC (59° to 86°F) 
Manufacturer 
GSK 
 
5.4.​Preparation/Handling/Storage: 
 
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. 
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. 
5.5.​Packaging and Labeling 
DTG+3TC (fixed dose combination) and DTG 50mg provided as single entity will be 
labeled as Investigational product by the Sponsor. The contents of the label will be in 
accordance with all applicable regulatory requirements and study protocol.  
5.6.​Product Accountability  
In accordance with local regulatory requirements, the investigator, designated site 
staff, or head of the medical institution must document the amount of investigational 
product dispensed and/or administered to study subjects and the amount returned by 
study subjects. Product accountability records must be maintained throughout the 
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course of the study. Returned tablets may (optionally) be re-dispensed to the same 
patient only once per container, indicating that he/she must first complete the intake 
of the container in use and then continue with the new container used during the 
visit. 
5.7.​Treatment Compliance  
Treatment compliance will be evaluated using ACTG adherence forms. This 
assessment will be conducted at each visit after baseline visit through the withdrawal 
visit or study completion. These data will be recorded in the subject’s CRF. 
Good adherence to treatment will be considered when at least 80% of daily intakes 
are completed (equivalent to ≥ 24 tablets per month). 
5.8.​Treatment overdose 
For the purposes of this study, an overdose is not an AE or SAE, unless it is 
accompanied by a clinical manifestation meeting AE or SAE criteria.  
5.9.​Treatment after the end of study 
At week 48 doctors will arrange the provision of antiretroviral treatment through the 
regular HIV provider of the participant. Investigators should do all needed for 
avoiding unnecessary discontinuation of treatments. Subjects randomized to receive 
DTG+3TC once daily and who successfully completed 48 weeks of treatment will be 
given the opportunity to continue receiving this regimen either as single entities or as 
the FDC (fixed dose combination), depending on which is available via the local HIV 
provider, unless the subject no longer derives clinical benefit.  
5.10.​ Concomitant Medications and Non-Drug Therapies  
Subjects should be advised to notify their Investigator of any current or proposed 
concomitant medication, whether prescribed or over the counter, because of the 
potential for interactions between such treatments and the study medications. 
Potential drug-drug interaction should be investigated for any concomitant therapy 
and act accordingly.  
Investigator should evaluate all concomitant medications that the participant took or 
is taken since the previous visit and all this information should be recorded in the 
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CRF. The minimum requirement is that the drug name and the dates of 
administration are to be recorded. 
5.11.​ Permitted and prohibited Medications and Non-Drug Therapies  
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study (except prohibited medications 
described below).  
Investigators are encouraged to prescribe all indicated chemoprophylaxis for HIV 
associated conditions, following local and international guidance, at discretion of the 
subject and their physician. All concomitant medications, including blood products, 
and vaccines taken during the study should be recorded in the CRF with dates of 
administration.  
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 
plasma RNA, it is recommended that a vaccine, if necessary, be given during or 
immediately after a scheduled visit after all laboratory tests have been drawn. This 
approach will minimize the risk of non-specific increases in the level of HIV-1 plasma 
RNA at the next scheduled assessment.  
DTG should be administered 2 hours before or 6 hours after taking antacid products 
or sucralfate containing divalent cations (e.g. aluminum and magnesium). Proton 
pump inhibitors and H2-antagonists may be used in place of antacids with no 
scheduling restrictions.  
Concurrent 
administration 
of 
multivitamins 
is 
acceptable. 
DTG 
can 
be 
co-administered with calcium or iron supplements if taken with a meal. Under fasted 
conditions, DTG should be given 2 hours prior to or 6 hours after calcium or iron 
supplements.  
Metformin concentrations may be increased by DTG. Subjects should be monitored 
during therapy and a metformin dose adjustment may be required. 
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5.12.​ Prohibited Medications and Non-Drug Therapies  
The following therapies are not permitted at any time during the study. Contact 
medical monitor for discussing the need of specific therapies present in this list, or 
alternative therapies: 
●​ HIV immunotherapeutic vaccines are not permitted at any time during the 
study. 
●​ Any experimental agents, others antiretroviral drugs, cytotoxic chemotherapy, 
or radiation therapy without authorization from the Medical Monitor.  
●​ Systemically administered immunomodulators that directly affect immune 
responses such as Interleukin or interferon. 
●​ HCV therapy that includes interferon, ribavirin or drugs with potential 
drug-drug interactions.  
●​ Acetaminophen is not to be used in patients with acute viral hepatitis. 
●​ Chronic use of glucocorticoids administered per oral or parenteral route. Short 
courses 
(less 
than 
14 
days) 
of 
oral 
prednisone, 
prednisolone, 
methylprednisolone are allowed.  
●​ Drugs that may cause decreased concentrations of DTG including: 
●​ Carbamazepine  
●​ Oxcarbazepine  
●​ Phenobarbital  
●​ Phenytoin  
●​ St. John’s wort  
●​ Rifampicin or rifapentine 
●​ Drugs that can cause toxicity in presence of DTG that include dofetilide, 
dalfampridine and pilsicainide as DTG may inhibit their renal tubular secretion 
resulting in increased concentrations and potential for toxicity. 
6.​ Study Assessments and Procedures 
Adherence to the study design requirements, including those specified in the Table 
1, is essential and required during the study conduction.  
6.1.​Study procedures 
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Written informed consent must be obtained from each potentially eligible subject (or 
his/her legal representative) by study site personnel prior to the initiation of any 
screening procedures as outlined in this protocol. The consent form must have been 
approved by the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC).  
After signing an informed consent, subjects will complete screening assessments to 
determine subject eligibility. Each subject being screened for study enrolment 
evaluation will be assigned a subject number. This number will be given sequentially 
in chronological order of subject presentation.   
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Table 1 Assessments and Procedures. 
Procedures 
SCR 
BSL Day 1 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
Final visit or 
Discont. Visit 
Window visits 
-10 days 
0 
+/-3days +/-7days 
+/-7days 
+/-7days 
+/-7days 
+/-7days 
Written informed consent 
X 
 
 
 
 
 
 
 
Demography, ART history, medical history, current 
medical conditions, vital signs, HIV risk factors and 
mode of transmission 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
review 
and 
documentation in the chart1.  
Randomization2 
X 
X 
 
 
 
 
 
 
CDC Classification 
X 
 
 
 
 
 
 
 
HIV associated conditions 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination # 
X 
X 
X 
X 
X 
X 
X 
X 
Waist circumference (WC), waist-to-hip ratio (WHR) 
and waist-to-height ratio (WHtR), Body Mass Index 
(BMI) 
 
X 
 
 
X 
 
X 
 
Vital Signs/ Weight measurement 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
Dispense medication 
 
X 
X 
X 
X 
X 
X 
 
Adherence (Baseline ACTG questionnaire) 
 
X 
 
 
 
 
 
 
Adherence (analogue scale and ACTG follow-up 
questionnaire)  
 
 
X 
X 
X 
X 
X 
 
EQ-5D-5L and PHQ93 
 
X 
 
 
X 
 
X 
 
Plasma and serum storage 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC storage4 
 
X 
 
 
X 
 
X 
 
Serum pregnancy test and contraception options 
counseling 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis and dipstick for proteins5 
X 
X 
 
 
X 
 
X 
 
HIV Genotype (PI, NRTI, NNRT) & INI genotype 
X 
 
 
 
 
 
 
 
Syphilis testing10 
X 
 
 
 
X 
 
X 
 
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HCV antibodies 
X 
 
 
 
 
 
 
 
HBV serology6  
X 
 
 
 
 
 
 
 
HIV-1 RNA10 
X 
X 
X 
X 
X 
X 
X 
 
CD4 and CD8 cell count10 
X 
X 
 
X 
X 
X 
X 
 
Hematology7 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistry8 
X 
X 
X 
X 
X 
X 
X 
 
Fasting lipids9 
 
X 
 
 
X 
 
X 
 
 
1)​
Inclusion/exclusion criteria will be initially collected at screening and fully assessed at the Day 1 previous to randomization. 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.  
2)​
Randomization may occur as soon as possible after having the required screening laboratories. 
3)​
The questionnaires are recommended to be administered at the beginning of the visit before any other assessments are conducted 
4)​
Whole blood/PBMC collection samples may be used for virologic analyses and for future research. 
5)​
A morning specimen is preferred.  
6)​
HBV: at screening HBsAg+HBs core, if negative participants should be vaccinated. If core is positive and HBsAg negative, a viral load should be requested.  
7)​
CBC, formula and platelets and eritrosedimentation rate 
8)​
Glucemia, urea, creatinine, creatinine clearence (Cockroft-Gault), AST, ALT, Alc Phost, Amylasemia, total bil, indirect bil, totel Chol, total protenin, uric acid.  
9)​
An overnight fast is preferred; however, a minimum of a 8-hour fast is acceptable. HDL, LDL, Total Cholesterol, TG. 
10)​ A laboratory result obtained within 30 days prior to the screening visit may be used, only for SCR visit. 
# ​
Physical Examination: Completed on screening visit and then directed on subsequent visits. 
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6.2.​Screening Assessments 
●​ Informed consent: No procedure can be performed until an informed consent 
form is signed and a copy provided to the participant.  
●​ Medical History. A complete medical history, including demography, ART history, 
current medical conditions, HIV risk factors, mode of transmission, history of 
tobacco, drug and alcohol use, opportunistic infections and previous allergies or 
drug adverse events will be obtained. 
●​ Concomitant medication review  
●​ Complete Physical Examination.  
●​ Height: This examination will serve as the baseline examination for the entire 
study.  
●​ Weight: Using a standard operating procedure, and calibrated weight scale.  
●​ Vital signs: Blood pressure, pulse and body temperature. 
●​ CDC category based on the 1993 classification, which should be documented in 
the medical record.  
●​ Laboratory determinations: 
▪​
HIV-1 genotype (a genotype performed in the last 90 days does not requires 
to be repeated). 
▪​
Plasma HIV-1 RNA (Abbott RT PCR). Previous results of this determination 
may be used if it is not more than 30 days old at the date of the screening 
visit. 
▪​
CD4 and CD8 cell counts. Previous results of these determinations may be 
used if they are not more than 30 days old at the date of the screening visit. 
▪​
Hematology, clinical chemistry panel and urinalysis.  
▪​
Serologies including syphilis screening (VDRL or RPR, and FTA Abs if 
reactive), HCV antibodies, HBV surface antigen and anti-core antibodies. If 
core antibodies are positive and HBV surface is negative, a viral load for HBV 
should be requested. Anti-Hbs should be requested for those with negative 
markers and, if needed vaccination should be offered. Previous results of 
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syphilis screening may be used if they are not more than 30 days old at the 
date of the screening visit. 
▪​
Serum pregnancy test (for women with fertile potential). 
▪​
Plasma and serum storage. 
●​ ECG: a 12-lead resting ECG will be obtained at the screening visit and as 
clinically indicated during the study. A qualified physician from the site will 
interpret, sign, and date all ECG tracings. The site physician will also provide 
his/her global interpretation as a written comment on the tracing using the 
following categories: 
▪​
Normal ECG 
▪​
Abnormal ECG - not clinically significant 
▪​
Abnormal ECG - clinically significant 
The results of all clinical evaluations during screening must be within clinically 
acceptable limits as defined by the test laboratory and reviewed by the investigator. 
6.3.​Baseline Visit procedures  
●​ Eligibility criteria review: all inclusion and exclusion criteria must be reviewed and 
documented in the clinical chart and verified by a second physician before 
proceeding to randomize a participant. 
●​ Medical History: will be updated prior to study drug administration and as 
necessary during the study. Pregnancy risk and contraceptive options counseling.  
●​ Concomitant medications: All new medications or changes in the medications 
recorded at screening visit should be recorded. 
●​ Any adverse event that could occur since the participant signed the Inform 
Consent.  
●​ Adherence (Baseline self-report ACTG questionnaire). 
●​ Changes in the Physical Examination. 
●​ Weight and vital signs (blood pressure, pulse and body temperature). 
Anthropometric parameters such as Body mass index (BMI) Waist circumference 
(WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) will be measured 
at baseline, 24 and 48 weeks. 
●​ Quality of life EQ-5D-5L questionnaire. 
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●​ Laboratory determinations:  
●​ Plasma HIV-1 RNA (Abbott RT PCR). 
●​ CD4+ and CD8 + cell counts.  
●​ Hematology, clinical chemistry panel and urinalysis.  
●​ Serum pregnancy test (for women with fertile potential). 
●​ PBMC storage.  
●​ Plasma y serum storage. 
●​ Fasting lipids and metabolic markers. Eight hours fasting blood samples 
(water is permitted) will be required for baseline visit and visits on week 24 
and 48. 
7.​ Efficacy outcomes 
7.1.​Plasma HIV-1 RNA  
Plasma for quantitative HIV-1 RNA will be collected using the Abbott RealTime HIV-1 
Assay with a lower limit of quantitation of 40 c/mL.  
7.2.​Lymphocyte Subsets  
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage, and absolute CD4 and CD8 cell counts). 
7.3.​Fat distribution 
Changes in body composition will be measured using weight, BMI, and 
anthropometry. 
7.4.​Quality of life and depression 
The EQ-5D-5L and PHQ9 assessment should be administered at the beginning of 
the visit at baseline, week 24 and week 48, prior to collection of blood for analysis 
and other scheduled assessments. These questionnaires include the European 
Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L), developed by EuroQol group, and 
the PHQ9, patient health questionnaire 9 items, developed by Columbia University.  
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8.​ Safety  
Safety will be assessed from adverse events, physical examination, vital signs and 
clinical laboratory data. 
8.1.​Adverse Events 
Throughout the course of the study (which begins when the Informed Consent is 
signed), the investigator will monitor each subject for the development of any clinical 
and/or laboratory evidence of an adverse event (AE). An adverse event is defined as 
any undesirable medical occurrence in a subject who participates in a study and 
includes those events/experiences which do not necessarily have a causal 
relationship to the study drug regimen. 
An adverse event may be a symptom, sign, or abnormal laboratory finding.  Any 
worsening of a pre-existing condition or intercurrent illness should be reported as an 
adverse event/experience.  A laboratory abnormality should be reported as an 
adverse event if action is required (e.g. study drug interruption, discontinuation, or 
treatment is required). The nature of the adverse sign or symptom, its date and time 
of onset, duration and severity, therapy employed (if any) and the investigator’s 
opinion of causality to study drug with an alternate etiology, if appropriate, must be 
documented.  For adverse events/experiences to be considered as intermittent or 
continuous, the events should be of similar nature and severity. 
The investigator will follow all adverse events to satisfactory clinical resolution 
or the establishment of a stable chronic stage upon study completion. 
For this study, the Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, version 2.1, Corrected version July 2017 will be used for 
grading events. The table can be found in the following link: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
If the event is not present in this table, the investigator will rate the severity of the 
adverse event according to the following definition:  
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Mild: 
The adverse event is transient and easily tolerated by the subject. 
Moderate: 
The adverse event causes the subject discomfort and interrupts the 
subject’s normal activities. 
Severe: 
The adverse event causes considerable interference with the 
subject’s 
normal 
activities 
and 
may 
be 
incapacitating 
or 
life-threatening. 
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE. When assessing causality, the investigator should 
determine if there is a "reasonable possibility" of being related to the study 
product, based on facts/evidence or arguments to suggest a causal relationship, 
rather than a relationship cannot be ruled out.  
The investigator will use clinical judgment to determine the relationship and 
alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.  
The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment.  
For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.  
The investigator may change his/her opinion of causality in light of follow-up 
information. 
8.2.​Serious Adverse Events 
The investigator will inform the Sponsor, the local IRBs, ViiV Healthcare and the 
appropriate Regulatory Agency within 24 hours of any serious adverse event 
reported in this study (see Table 4). A Serious Adverse Event (SAE) is an adverse 
drug experience that results in any of the following outcomes: 
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o​ Death. 
o​ Life-threatening situation — the subject was at risk of death at the time of 
the adverse event/experience.  It does not refer to the hypothetical risk of 
death if the AE were more severe or were to progress. 
o​ Inpatient hospitalization or prolongation of existing hospitalization. 
o​ Persistent or significant disability/incapacity — Any AE having an 
outcome that is associated with a substantial disruption of the ability to carry 
out normal life functions, including the ability to work.  This is not intended to 
include transient interruption of daily activities. 
o​ Congenital anomaly/birth defects — Any structural abnormality in subject’s 
offspring that occurs after intrauterine exposure to treatment. 
Important medical events/experiences that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse 
event/experience when, based on appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such medical 
events/experiences include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependence or drug abuse. 
Please note that a severe adverse event/experience is not necessarily serious, as 
the term severe is a measure of intensity while a serious adverse event is 
determined based on the aforementioned regulatory criteria. 
In addition to the above, any event meeting liver stopping criteria (as described in 
Table 2) should be reported as an SAE. 
Reporting of Suspected, Unexpected Serious Adverse Reactions (SUSARS) 
In addition, an SAE with onset after exposure to study drugs must be reported if the 
SAE meets the definition of unexpected given below: 
●​ Expected AEs are AEs that have been previously observed with use of the 
study drugs and are listed in the package insert. Expectedness is not based 
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on what might be anticipated from the pharmacological properties of the study 
agent. 
●​ Unexpected AEs are AEs for which the nature or severity (intensity) is not 
consistent with the applicable agent information (package insert). 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, until 
the condition stabilizes, until the event is otherwise explained, or until the subject is 
lost to follow-up. 
8.3.​ Other Events that should be reported 
8.3.1.​ Cardiovascular events 
Any cardiovascular event will be required to be reported in the Cardiovascular 
section of the CRF within one week of acknowledging the event. This will include 
Myocardial infarction/unstable angina, congestive heart failure, arrhythmias, new 
valvulopathy, pulmonary hypertension, cerebrovascular events/stroke and transient 
ischemic 
attack, 
peripheral 
arterial 
thromboembolism, 
deep 
venous 
thrombosis/pulmonary embolism and revascularization. 
8.3.2.​ New AIDS event and AIDS related deaths 
Any new AIDS defined condition (based on the CDC classification 1993) should be 
reported within one week of acknowledging the event. This will include information 
about laboratory tests, previous use of prophylaxis and diagnosis. Physicians are 
encouraged to use the best updated local guidelines to offer primary prophylaxis to 
these participants. In addition, chest X ray and cryptococcus antigen should be 
considered in the initial evaluation for patients with CD4 count below 100 cells/mm3.   
8.3.3.​ Suicidal Ideation or Behaviors 
Subjects with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour). In addition, there have been some 
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reports of depression, suicidal ideation and behaviour (particularly in patients with a 
pre-existing history of depression or psychiatric illness) in some patients being 
treated with integrase inhibitors, including DTG. Therefore, it is appropriate to 
monitor subjects for suicidality before and during treatment.  
Subjects should be monitored appropriately and observed closely for suicidal 
ideation and behaviour, or any other unusual changes in behaviour. It is 
recommended that the investigator consider mental health consultation or referral for 
subjects who experience signs of suicidal ideation or behaviour.  
The investigator will exercise his or her medical and scientific judgment in deciding 
whether an event is possibly suicide-related (PSRAE) and if it meets the SAE criteria 
in order to meet the timing for reporting (PSRAE within 1 week and SAE within 24 
hrs of becoming aware of the event). PSRAE may include, but is not limited to an 
event that involves suicidal ideation, a preparatory act toward imminent suicidal 
behavior, a suicide attempt, or a completed suicide. PSRAE forms should be 
completed and reported to Sponsor within one week of the investigator diagnosing 
and reporting a possible suicidality-related serious adverse event.  
8.3.4.​ Immune Reconstitution Inflammatory Syndrome (IRIS) 
Investigators need to carefully document and manage signs and symptoms that 
could be related to IRIS. In addition, the Medical Monitor will review the AE terms 
and HIV conditions in order to identify IRIS cases and might require additional 
information to characterize these events.  
To define IRIS, French criteria (2004) will be used, which requires 2 major criteria or 
1 major criterion plus 2 minor criteria 
Major criteria:  
A: atypical presentation of opportunistic infections or tumor´s in patients responding 
to ART, manifested by any of the following:  
●​ Localized disease 
●​ Exaggerated inflammatory reaction 
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●​ Atypical inflammatory response in affected tissues 
●​ Progression of organ dysfunction or enlargement of preexisting lesions 
after definitive clinical improvement with pathogen specific therapy prior to 
ART and exclusion of treatment toxicity and new diagnoses 
B: Decrease in plasma HIV RNA >1 log10 copies/mL 
Minor criteria 
●​ Increase in CD4 count after ART 
●​ Increase in an immune response specific to the relevant pathogen 
●​ Spontaneous resolution of disease with continuation of ART 
The diagnosis of this syndrome is a diagnosis of exclusion, after ruling out other 
diagnoses such as non-response to opportunistic infections treatments, poor 
adherence, recurrence of opportunistic infections, toxicity or drug reaction, 
neoplasia, or other causes of fever. In biological terms, the IRIS could be associated 
with a burst of specific Th1 CD4+ T cells to tuberculin purified protein derivative, 
detectable by ELISPOT for IFN-γ.  
 
9.​ Toxicity management 
Adverse events that occur during the study should be evaluated by the Investigator.  
IP may be interrupted at the discretion of the Investigator and according to the 
severity of the AE, but permanent discontinuation of the IP will require withdrawal of 
the participant from the study. IP 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 IP or temporary interruption of one or more 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 and can be discussed 
with the Medical Monitor. Guidance is provided below on general subject 
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management and IP interruptions based on the severity of the AE. All changes in the 
IP must be accurately recorded in the subject’s eCRF. No IP dose reductions will be 
allowed. 
In the event of a discontinuation of a DTG-containing product for suspected drug 
induced liver injury, other clinically significant liver chemistry elevations, severe skin 
reaction or hypersensitivity reaction, subjects should not be rechallenged with a 
DTG-containing product due to the risk of a recurrent reaction. These subjects 
should be withdrawn from study and seek/be reviewed for alternative antiretroviral 
therapy (but may continue on study, only for AE surveillance, but off study drug).  
Secondary syphilis should be ruled out in all participants presenting allergic reaction 
or rash during the study. 
9.1.​Allergic Reaction 
Subjects may continue investigational products for Grade 1 or 2 allergic reactions at 
the discretion of the Investigator. The subject should be advised to contact the 
Investigator immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic 
agents may be prescribed.  
Subjects with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the investigational product(s) should permanently discontinue the 
investigational product regimen and the subject should be withdrawn from the study. 
Subjects should be treated as clinically appropriate and followed until resolution of 
the adverse event. 
9.2.​Rash 
Mild to moderate rash is an expected adverse reaction for DTG-containing 
antiretroviral therapy. 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. The index case of a hypersensitivity reaction with 
DTG involved a profuse, purpuric and coalescing leukocytoclastic vasculitis as well 
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as clinically significant liver chemistry elevations. Other than this case, no other 
instances of serious skin reaction, including Stevens-Johnson Syndrome, toxic 
epidermal necrolysis and erythema multiforme have been reported for DTG in clinical 
trials. 
Subjects with an isolated Grade 1 rash may continue investigational product at the 
Investigator’s discretion. The subject should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
worsen, or if mucosal involvement develops. 
Subjects may continue investigational product for an isolated Grade 2 rash. 
However, investigational product (and all other concurrent medication(s) suspected 
in the Investigators causality assessment) should be permanently discontinued for 
any Grade 2 rash that is associated with an increase in ALT. The subject should be 
advised to contact the physician immediately if rash fails to resolve (after more than 
two weeks), if there is any worsening of the rash, if any systemic signs or allergic 
symptoms develop, or if mucosal involvement develops. 
Subjects should permanently discontinue investigational product (and all other 
concurrent medication(s) suspected in the Investigators causality assessment) for an 
isolated Grade 3 or 4 rash, and the subject should be withdrawn from the study. 
Subjects should be treated as clinically appropriate and followed until resolution of 
the adverse event. 
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 Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, version 
2.1, corrected version July 2017). 
If the etiology of the rash can be diagnosed as being unrelated to investigational 
product and due to a specific medical event or a concomitant non-study medication, 
routine management should be performed and documentation of the diagnosis 
provided. 
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9.3.​Toxicity Grade 1-2:  
Subjects who develop a study drug-related Grade 1 or 2 adverse event or laboratory 
abnormalities may continue study medications.   
9.4.​Toxicity grade 3-4:  
For bilirubin, ALT, AST elevation see Section 9.5.  
If the Investigator has compelling evidence that the Grade 3 or 4 AE or toxicity has 
not been caused by IP, dosing may continue (such as high glucose in someone who 
had not performed adequate fasting, or elevated CPK in some participant that 
performed exercises).  
Subjects who develop a Grade 3 AE or toxicity, which the Investigator considers 
related or possibly related to the IP, should have the IP withheld and be rechecked 
each week until the AE returns to Grade 2. Once the AE is Grade ≤ 2, IP may be 
re-started. If the same Grade 3 AE recur within 28 days in the same subject, the IP 
should be permanently discontinued, and the subject withdrawn from study. Subjects 
experiencing Grade 3 AEs requiring permanent discontinuation of IP should be 
followed weekly until resolution of the AE and encouraged to have withdrawal study 
evaluations completed. A Follow-Up visit should be performed 4 weeks after the last 
dose of IP. 
Subjects with lipid abnormalities or other Grade 3 asymptomatic laboratory 
abnormalities should be investigated for all potential non-drug related causes, and if 
this is the case, may continue IP if the Investigator has compelling evidence that the 
toxicity is not related to IP.  
Subjects who develop a Grade 4 AE or toxicity related to the study drug should have 
IP permanently discontinued. However, if there is compelling evidence that the AE is 
not causally related to the IP, dosing may continue. Subjects should be rechecked 
each week until the AE returns to Grade 2. Subjects experiencing Grade 4 AEs 
requiring permanent discontinuation of IP should be followed weekly until resolution 
of the AE and encouraged to complete the withdrawal and follow-up study 
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evaluations as noted above. Subjects with Grade 4 asymptomatic laboratory 
abnormalities should be investigated for all potential non-drug related causes, and 
may continue therapy if the Investigator has compelling evidence that the toxicity is 
not related to IP (including lipid abnormalities) A follow-up visit should be performed 
4 weeks after the last dose of study medication if AEs or laboratory abnormalities are 
ongoing. 
9.5.​Liver Chemistry Stopping and Follow up Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology during administration of study 
drug and the follow-up period. For any participant meeting one of the criteria outlined 
in Table 2 or Table 3, or if the Investigator believes that it is in the best interest of the 
patients, the Investigator must follow the required actions and follow up assessments 
also outlined in these tables. 
o​ Table 2​
Liver Chemistry Stopping 
Criteria - Liver Stopping Event 
ALT absolute 
ALT ≥  8xULN 
ALT increase 
ALT ≥  5xULN but <8xULN persists for ≥ 2 weeks (with bilirubin <2xULN and 
no signs or symptoms of acute hepatitis or hypersensitivity) 
Bilirubin1, 2 
ALT ≥  3xULN and bilirubin ≥  2xULN (>35% direct bilirubin)  
INR2  
ALT ≥  3xULN and International normalized ratio (INR)>1.5, if INR measured 
Cannot Monitor 
ALT ≥ 5xULN but <8xULN and cannot be monitored weekly for >2 weeks 
Symptomatic3 
ALT ≥ 3xULN (if baseline ALT is ≤ULN) with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity 
ALT ≥ 3x baseline (if baseline ALT>ULN) with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
●​
Immediately hold study drugs.  
●​
If a causal relationship between the liver 
event and study drugs cannot be ruled out, 
then study drugs must be permanently 
●​
Viral hepatitis serology, including: 
●​
Hepatitis A immunoglobulin M 
(IgM) antibody; 
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discontinued and the Subject not 
rechallenged due to the risk of a recurrent 
reaction.   
●​
Report the event to FH within 24 hours. 
●​
Events of possible drug-induced liver injury 
with hyperbilirubinemia2 will be reported to FH 
as serious adverse events using the serious 
adverse event case report form. 
●​
Complete the liver event case report form for 
all events meeting liver stopping criteria, and 
submit to FH within one week of first becoming 
aware of the event 
●​
Perform liver event follow up assessments.  
●​
Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING). 
●​
Permanently discontinue study treatment and 
may continue subject in the study for any 
protocol specified follow up assessments. 
MONITORING: 
●​
Make every reasonable attempt to have 
subjects return to clinic within 24 hours for 
repeat liver chemistries (include ALT, aspartate 
aminotransferase, alkaline phosphatase, 
bilirubin) and perform liver event follow up 
assessments at the central laboratory as 
described to the right.  
●​
A specialist or hepatology consultation is 
recommended. 
●​
Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline. 
●​
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. 
Record alcohol use on the liver event 
case report form 
●​
Serum creatinine kinase and lactate 
dehydrogenase. 
●​
Obtain complete blood count with 
differential to assess eosinophilia. 
●​
Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (or gamma 
globulins). 
●​
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver 
disease. Complete Liver Imaging and/or 
Liver Biopsy case report form. 
●​
Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
1.​ Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that subject if ALT ≥ 
3xULN and bilirubin ≥ 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.  
2.​ All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and 
INR>1.5, if INR measured which may indicate severe liver injury must be reported as a 
serious adverse event (excluding studies of hepatic impairment or cirrhosis); INR 
measurement is not required and the threshold value stated will not apply to subjects receiving 
anticoagulants 
3.​ New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to 
hypersensitivity (such as fever, rash or eosinophilia).  Record the appearance or worsening of 
any such clinical symptoms on the adverse event report form. 
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o​ Table 3​
Liver Chemistry Increased 
Monitoring Criteria 
Criteria 
Actions 
ALT ≥ 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for >2 weeks. 
●​
Notify the medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety.  
●​
Subject can continue study treatment   
●​
Subject must return weekly for repeat liver 
chemistries (ALT, aspartate aminotransferase, 
alkaline phosphatase, bilirubin) until resolution, 
stabilization (ALT <5×ULN on 2 consecutive 
evaluations) or return to within baseline   
●​
If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above 
 
9.6.​Hyperglycemia 
Subjects who experience study drug-related glucose elevations of Grade 3 or 4 may 
continue 
study 
medications, 
provided 
that 
appropriate 
management 
of 
hyperglycemia is instituted in a timely manner.  A confirmatory fasting glucose level 
should be obtained within two weeks after the first Grade 3 or 4 glucose elevation.  
Hyperglycemia may be managed with oral hypoglycemic agents or insulin as 
deemed clinically appropriate by the investigator. 
9.7.​CPK Elevation  
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2-4 
weeks to ensure the result is transient or due to exercise and will not require a 
change in study treatment. A history regarding use of drugs known to cause increase 
of CPK (such as statins) physical activity or exercise preceding the CPK evaluation 
should be obtained. Grade 4 elevations in CPK should have a repeat assessment 
after the subject has abstained from exercise for >24 hours. For persistent Grade 4 
CPK elevations that are considered possibly or probably related to the IP, IP should 
be discontinued, and the subject withdrawn from the study. 
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9.8.​Hypertriglyceridemia/Hypercholesterolemia  
Samples for lipid measurements must be obtained in a fasted state. Subjects who 
experience asymptomatic triglyceride or cholesterol elevations may continue to 
receive IP. 
9.9.​Decline in Renal Function 
Treatment with a DTG fixed dose combination containing 3TC or TDF/XTC must be 
discontinued in any Subject developing moderate to severe renal impairment during 
the study, as indicated by creatinine clearance measuring <30 mL/min via calculated 
with Cockroft-Gault method. 
10.​
Reporting 
10.1.​ Observation period for Adverse Event reporting: 
The observation period for adverse events (AE) and serious adverse events (SAE) 
reporting in an individual patient will start at the time of patient screening (after 
Inform Consent is signed) and continue through the Final Visit (4-week 
post-treatment follow-up visit) or up to 4-weeks after the last dose of treatment, 
whichever is later, to document late adverse events or SAE resolution.  
10.2.​ Pregnancy reporting 
Any pregnancy that occurs during study participation must be reported using the 
Pregnancy Report Form to ensure subject safety and the patient must be 
discontinued immediately from study drug. 
Each pregnancy must be reported to the sponsor within one week of learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including 
premature termination) and status of mother and child, which must also be reported 
to the sponsor using the Pregnancy Report Form.  Fundación Huésped Medical 
Monitor will fill the Antiretroviral Pregnancy Registry. Pregnancy complications and 
elective terminations for any reason must be reported as an AE or SAE. 
Spontaneous abortions must be always reported as an SAE. Reporting would 
continue until 6-8 weeks after the estimated delivery date.  
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Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
10.3.​ Events reporting Time Periods for SAEs and pregnancy report  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation 
and will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/ IEC and investigators in accordance with 
all applicable timelines 
Table 4: Timing for reporting by investigator to sponsor, local regulatory 
agencies and ViiV Healthcare 
 
Initial reports 
Follow up information 
Type of event 
Time 
frame 
Documents 
Time 
frame 
Documents 
All SAEs 
24 hours 
SAE data 
collection form 
24 hours 
Follow up SAE data 
collection form 
Pregnancy 
1 week 
Pregnancy 
form 
2 weeks  
Pregnancy Follow up 
form 
All 
events 
meeting 
liver 
chemestry stopping criteria (see 
Section 9.5) 
24 hours 
SAE data 
collection form 
24 hours 
Follow up SAE data 
collection form 
 
For subjects receiving DTG/3TC or DTG liver issues registered on the eCRFs should be 
reported to ViiV Healthcare within 1 week. See section 9.5.   
 
11.​
Data Management 
For this study, subject data will be entered in a REDCap CRF database and 
transmitted electronically to Fundación Huésped. Data will be managed following 
internal FH standard procedures, in order to ensure confidentiality, data protection, 
data integrity and data consistency. 
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11.1.​ Data Analysis and Statistical Considerations 
11.1.1.​
Hypotheses 
This study is designed to assess the antiviral effect of treatment with a DTG+3TC 
regimen at Week 48 among naïve individuals with CD4 ≤200 cells/mm3. No formal 
statistical hypothesis testing will be performed.  
11.1.2.​
Analysis populations 
●​ Intent-to-Treat Exposed (ITT-E) Population: This population will consist of 
all randomized subjects who receive at least one dose of study medication. 
Subjects will be assessed according to their randomized treatment, 
regardless of the treatment they receive. Unless stated otherwise, the 
ITT-E Population will be used for efficacy analyses. 
●​ Per Protocol (PP) Population: This population will consist of subjects in the 
ITT-E Population with the exception of major protocol violators, e.g. 
violations which could affect the assessment of antiviral activity. The PP 
population will be used for sensitivity analyses of the primary efficacy 
measure. 
●​ The Safety Population is defined as all subjects who receive at least one 
dose of study medication. Subjects will be analyzed according to the actual 
treatments received. Unless otherwise stated, the Safety Population will be 
used for safety analyses. 
11.1.3.​
Analysis data sets 
Responses at < 50 c/mL will be calculated according to a snapshot algorithm, as 
established by the FDA. After week 36 any VL > 50 c/mL needs to be confirmed with 
a new VL performed within 4 months of the previous one.  
For assessing virological outcome the windows will be defined as recommended by 
FDA snapshot analysis:  
●​ Week 24, weeks 18-30 (days 127-210) 
●​ Week 48, weeks 42-54 (days 295-378) 
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11.1.4.​
Treatment comparisons 
No formal comparisons will be performed in this study 
11.2.​ Interim Analysis 
The first analysis will be conducted when all subjects complete their week 24 visit. 
The primary analysis will be conducted with all subjects complete their Week 52 visit.  
Blind DSMB analysis will be performed regularly through the study and will inform 
changes in the protocol implementation. First meeting will be scheduled when 
enrolling 50% of the planned participants, and every 4 months thereafter.  
11.3.​ Statistical Plan 
Descriptive statistics will be used to evaluate the primary and secondary outcomes. 
The results will be given as median and interquartile ranges (IQR) or frequencies (%) 
and 95% CI, as appropriate. At each timepoint, longitudinal differences from baseline 
will be assessed using Student's t-test for paired samples in log10 transformed HIV-1 
RNA. A two-tailed P value <0.05 will be considered to be statistically significant. 
Baseline and follow-up characteristics will be compared using the Wilcoxon 
rank-sum test or the chi square/Fisher’s exact test. Changes in CD4 will be 
measured as number of cells gained with treatment at 24 and 48 weeks. For 
resistance, descriptive statistics will be calculated for the presence of INI mutations 
at any point during follow up. All AEs will be evaluated, summarized and described 
as proportion of patients presenting events, and total number of events. AE and 
DAIDS grading will be also used for laboratory test. 
11.3.1.​
Efficacy analyses 
The primary efficacy outcome variable is the proportion of virologic response defined 
as the proportion of patients with viral load count less than 50 copies/mL at week 48 
in an ITT-E analysis using the FDA´s Snapshot algorithm and its 95% confidence 
interval (CI). 
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The following secondary efficacy endpoints will be summarized using descriptive 
statistics: 
●​ Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using 
the Snapshot algorithm; 
●​ Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using 
the Snapshot algorithm in the triple arm; 
●​ Proportion of subjects without virologic or tolerability failure by Weeks 24 
and 48, where failure equals treatment discontinuation (meeting confirmed 
virologic withdrawal criteria, treatment-related AE, safety stopping criteria, 
or lack of efficacy); 
●​ Changes from baseline in CD4+ counts at Week 24 and Week 48. 
The following tertiary efficacy endpoint will be summarized by event type and 
treatment arm using descriptive statistics: 
●​ Change from Baseline in health-related quality of life using EQ-5D-5L at 
Weeks 4, 24, and 48 (or at study Withdrawal) 
11.3.2.​
Safety 
All AEs, SAEs and laboratory abnormalities will be evaluated, summarized and 
described as proportion of patients presenting events, and total number of events. 
AE and DAIDS grading will be also used for laboratory tests. 
Safety will be assessed by the incidence and severity of all adverse events, 
incidence and severity of related AEs, incidence and severity of AEs leading to 
withdrawal and incidence of SAEs.  
In addition, proportion of subjects who permanently discontinued IP due to AEs or 
death, proportion of IRIS, proportion of a new AIDS diagnosis or AIDS related death 
will be summarized.  
All adverse events will be described using the MedDRA classification system. 
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11.4.​ Procedure for Handling Missing, Unused, and Spurious Data 
No imputations or replacement of missing data will be performed. Observations will 
be censored at the time of last follow up.  
11.5.​ Procedures for Reporting Deviations from the Original Statistical 
Plan 
Any deviations will be reported as amendments to the statistical analysis plan. 
12.​
Study Conduct Considerations 
12.1.​ Posting of Information and Results  
The study information from this protocol was published prior to the start of subject 
enrollment in the clinical trial registry clinicaltrial.gov under the publicly available ID 
number NCT04880395. The results summary will be posted to the Clinical Study 
Register no later than eight months after the final primary completion date, the date 
that the final subject was examined or received an intervention for the purposes of 
final collection of data for the primary outcome. In addition, a manuscript will be 
submitted to a peer-reviewed journal for publication no later than 18 months after the 
last subject’s last visit. When manuscript publication in a peer-reviewed journal is not 
feasible, a statement will be added to the register to explain the reason for not 
publishing 
12.2.​ Regulatory and Ethical Considerations, including the Informed 
Consent Process 
A regulatory approval from the IRB is required before initiating the study according 
the ICH GCP and local regulations. 
The study will be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the ethical principles that are outlined in the Declaration of 
Helsinki 2008, including, but not limited to: 
●​ IRB/IEC review and favorable opinion/approval of study protocol and any 
subsequent amendments.  
●​ Subject informed consent.  
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●​ Investigator reporting requirements. 
It is investigator’s responsibility to ensure that each subject is given adequate 
explanation of the aims, methods, anticipated benefits and potential risks of this 
study and voluntarily signs and dates the IRB/IEC-approved informed consent form 
prior to study participation. The investigator must also explain that subjects have the 
right to refuse to participate in the study or to withdraw at any time for any reason, 
without prejudice with respect to future treatment. 
The investigator will document in the subject’s medical record that informed consent 
was obtained prior to the performance of any study related procedure and will retain 
the original consent form with the study records. A copy of the signed and dated 
consent form should be given to the subject.   
12.3.​ Data Handling and Record Keeping 
Electronic Case Report Forms (eCRFs) will be used to store information collected 
during this study. The system will allow to audit of any entry or correction made. 
CRFs will be completed for each subject enrolled in this study with the data extracted 
from source documents. Any necessary corrections in source document will be made 
by drawing a single line through the incorrect entry and the correction will be written 
with the date and signature of the investigator or his/her designee. Data will not be 
obliterated by blacking out, use of correction fluid, or by erasing the original entry. If 
the reason for the correction is not obvious, a brief explanation (e.g., transcription 
error) will accompany the change.  
12.4.​ Quality Control 
In accordance with applicable regulations, GCP, and local procedures, internal 
monitoring unit will train the staff on the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and clinical requirements. An initiation 
site visit will be performed before start.  
Sponsor monitors will ensure that the:  
●​ Data are authentic, accurate and complete.  
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●​ Safety and rights of subjects are being protected. 
●​ Study is conducted in accordance with the currently approved protocol and 
any other study agreements, GCP and all applicable regulatory requirements.  
12.5.​ Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the 
Monitoring Unit will conduct frequent quality assurance assessments of the site 
records. Information collected on CRFs and laboratory results will be verified by the 
quality monitor. More information on this can be found in the monitoring plan. Errors 
and deviations will be documented, summarized and discussed with investigators. 
Trainings will be provided as needed.  
Regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. In the event of an assessment, audit or inspection, the 
investigator (and institution) agrees to grant the advisor(s), auditor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss the conduct of the study, any findings/relevant issues 
and to implement any corrective and/or preventative actions to address any 
findings/issues identified. 
12.6.​ Study and Site Closure  
This study will be considered completed after the last subject completes the last 
study-related clinic visit or assessment. Upon completion or termination of the study, 
the monitor will conduct site closure activities with site staff, in accordance with 
applicable regulations, GCP and local Standard Operating Procedures.  
 
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13.​
References 
 
1​
Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in 
antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 
results from the randomised, double-blind, non-inferiority SAILING study. 
Lancet. 2013;382(9893):700-708. doi:10.1016/S0140-6736(13)61221-0 
2. ​
Walmsley 
SL, 
Antela 
A, 
Clumeck 
N, 
et 
al. 
Dolutegravir 
plus 
abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 
2013;369(19):1807-1818. doi:10.1056/NEJMoa1215541 
3. ​
Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus 
twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection 
(SPRING-2 study): 96 week results from a randomised, double-blind, 
non-inferiority 
trial. 
Lancet 
Infect 
Dis. 
2013;13(11):927-935. 
doi:10.1016/S1473-3099(13)70257-3 
4. ​
Kumar PN, Patel P. Lamivudine for the treatment of HIV. Expert Opin Drug 
Metab Toxicol. 2010;6(1):105-114. doi:10.1517/17425250903490418 
5. ​
Cahn 
P, 
Rolon 
M, 
Figueroa M, Gun A, Patterson P, Sued O. 
Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: 
48 week results of the PADDLE trial. In: 21th International Conference on 
AIDS. ; 2016:Durban, South Africa. 
6. ​
Taiwo BO, Zheng L, Stefanescu A, et al. ACTG A5353: A Pilot Study of 
Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency 
Virus-1 (HIV-1)-infected Participants with HIV-1 RNA <500000 Copies/mL. Clin 
Infect Dis. 2018. doi:10.1093/cid/cix1083 
7. ​
Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus 
dolutegravir 
plus 
tenofovir 
disoproxil 
fumarate 
and 
emtricitabine 
in 
antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): 
week 48 results from two multicentre, double-blind, randomised, non-inferior. 
Lancet. 2019;393(10167):143-155. doi:10.1016/S0140-6736(18)32462-0 
8. ​
Cahn P, Madero JS, Arribas JR, et al. Durable Efficacy of Dolutegravir Plus 
Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 
96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical 
Trials. 
J 
Acquir 
Immune 
Defic 
Syndr. 
2020. 
doi:10.1097/QAI.0000000000002275 
9. ​
van Wyk J, Ajana F, Bisshop F, et al. Efficacy and Safety of Switching to 
Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a 
Tenofovir Alafenamide–Based 3- or 4-Drug Regimen for Maintenance of 
Virologic Suppression in Adults Living With Human Immunodeficiency Virus 
Type 1: Phase 3, Randomized, Noninferiority TANGO Study. Clin Infect Dis. 
2020. doi:10.1093/cid/ciz1243 
10. ​ DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. 
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and 
Adolescents. December. 2019. 
11. ​
European AIDS Clinical Society. European AIDS Clinical Society (EACS) 
Guidelines. Version 10. 2019. 
12. ​ Vitoria M, Hill A, Ford N, et al. The transition to dolutegravir and other new 
53 
 


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antiretrovirals in low- and middle-income countries – what are the issues? 
AIDS. May 2018:1. doi:10.1097/QAD.0000000000001845 
13. ​ Vitoria M, Ford N, Clayden P, Pozniak AL, Hill AM. When could new 
antiretrovirals be recommended for national treatment programmes in 
low-income 
and 
middle-income 
countries. 
Curr 
Opin 
HIV 
AIDS. 
2017;12(4):414-422. doi:10.1097/COH.0000000000000380 
14. ​ Komninakis S V, Mota ML, Hunter JR, Diaz RS. Late Presentation HIV/AIDS Is 
Still a Challenge in Brazil and Worldwide. AIDS Res Hum Retroviruses. 
2018;34(2):129-131. doi:10.1089/AID.2015.0379 
15. ​ Ministerio de Salud y Desarrollo Social. Boletín sobre tuberculosis en la 
Argentina. 2019. 
16. ​ Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus 
raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results 
from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 
2013;381(9868):735-743. doi:10.1016/S0140-6736(12)61853-4 
 
 
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Appendices 
 
14.​
Appendix 1. Protocol Synopsis 
 
Protocol Title: 
DOLCE: Dolutegravir-Lamivudine naïve HIV-Infected Patients with ≤ 
200 CD4/mm3 
Protocol Number: 
FH-57 
Study Objectives: 
To assess the antiviral activity at week 48 of DTG+3TC among naïve 
HIV patients with a CD4 count ≤ 200 cells /mm3. 
Primary endpoint: 
Proportion of patients with viral load < 50 copies/mL at week 48 using 
the ITT-exposed analysis (FDA snapshot) for the intent-to-treat 
exposed (ITT-E) population 
Secondary Objectives: 
●​
To 
assess 
the 
antiviral 
activity 
of 
DTG+3TC 
and 
DTG+TDF/XTC at week 24  
●​
To evaluate the safety and tolerability of DTG+3TC and 
DTG+TDF/XTC over time 
●​
To 
assess 
the 
antiviral 
activity 
of 
DTG+3TC 
and 
DTG+TDF/XTC at week 48 in patients with baseline viral 
load >100,000 c/mL  
●​
To evaluate immunological activity (CD4+ lymphocyte [CD4 
counts]) at Week 24 and Week 48 
●​
To assess the development of HIV-1 resistance in patients 
with virologic failure or viral rebound treated with DTG+3TC 
or DTG+TDF/XTC 
●​
To 
evaluate 
the 
incidence 
of 
disease 
progression 
(HIV-associated conditions, AIDS and death) of DTG + 3TC 
and DTG + TDF/XTC over time 
Secondary endpoints:  
 
●​
Proportion 
of 
patients 
treated 
with 
DTG+3TC 
and 
DTG+TDF/XTC with HIV-1 levels of less than 50 copies/mL 
at week 24 
●​
Frequency, type and severity of adverse events and 
laboratory abnormalities and proportion of patients who 
discontinue DTG+3TC or DTG+TDF/XTC due to adverse 
events or death 
●​
Proportion of patients with baseline HIV-1 RNA >100,000 
c/mL that achieve virological suppression at week 48 weeks,  
●​
Changes in CD4 count, CD8 count and CD4/CD8 ratio 
between baseline and 48 weeks 
●​
Number and type of resistance mutations in case of virologic 
failure (defined as a confirmed viral above 200 copies/mL 
after week 24 copies/mL or viral rebound at any timepoint)  
●​
Incidence of IRIS and disease progression (HIV associated 
conditions, AIDS and death). 
Tertiary objectives:  
 
●​
TDF/XTCTo explore change in health-related quality-of-life 
for subjects treated with DTG plus 3TC and DTG + TDF/XTC 
 
Tertiary endpoints:  
 
●​
Change from Baseline in health-related quality of life using 
EQ-5D-5L and PHQ9 at Weeks 24, and 48 
 
Patient Population: 
HIV-1-infected subjects aged >18 years who are naïve to 
antiretroviral therapy with ≤200 CD4 cell/mm3 
Study Design: 
Prospective, Phase IV, randomized, multicenter, parallel group study 
design  
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Regimens: 
Dolutegravir 50 mg /lamivudine 300 mg QD FDC  
Dolutegravir 50 mg QD plus tenofovir 300 mg/emtricitabine 200mg or 
plus tenofovir 300 mg/ lamivudine 300 mg. 
Duration: 
48 weeks 
Sample size: 
230 subjects  
 
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15.​
Appendix 2. CDC Classification System for HIV-1 Infections 
(1993) 
Reference - 1993 revised classification system for HIV infection and expanded 
surveillance case definition for AIDS among adolescents and adults. MMWR 
1992;41 (No. RR-17):1-19. 
Clinical Categories 
The clinical categories of HIV infection are defined as follows: 
Category A 
Category A consists of one or more of the conditions listed below in an adolescent or 
adult (>13 years) with documented HIV infection. Conditions listed in Categories B 
and C must not have occurred. 
●​ Asymptomatic HIV infection 
●​ Persistent generalized lymphadenopathy 
●​ Acute (primary) HIV infection with accompanying illness or history of acute 
HIV 
Category B (Symptomatic non-AIDS conditions) 
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult 
that are not included among conditions listed in clinical Category C and that meet at 
least one of the following criteria: a) the conditions are attributed to HIV infection or 
are indicative of a defect in cell-mediated immunity; or b) the conditions are 
considered by physicians to have a clinical course or to require management that is 
complicated by HIV infection. Examples of conditions in clinical Category B include, 
but are not limited to: 
●​ Bacillary angiomatosis 
●​ Candidiasis, oropharyngeal (thrush) 
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●​ Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to 
therapy 
●​ Cervical dysplasia (moderate or severe)/cervical carcinoma in situ 
●​ Constitutional symptoms, such as fever (38.5C) or diarrhea lasting >1 
month 
●​ Hairy leukoplakia, oral 
●​ Herpes zoster (shingles), involving at least two distinct episodes or more than 
one dermatome 
●​ Idiopathic thrombocytopenic purpura 
●​ Listeriosis 
●​ Pelvic inflammatory disease, particularly if complicated by tubo-ovarian 
abscess 
●​ Peripheral neuropathy 
For classification purposes, Category B conditions take precedence over those in 
Category A. For example, someone previously treated for oral or persistent vaginal 
candidiasis (and who has not developed a Category C disease) but who is now 
asymptomatic should be classified in clinical Category B. 
Category C (AIDS indicator conditions as defined by diagnostic or presumptive 
measures). 
Category C includes the clinical conditions listed in the AIDS surveillance case 
definition. For classification purposes, once a Category C condition has occurred, the 
person will remain in Category C. 
Conditions in Category C include: 
●​ Candidiasis of bronchi, trachea, or lungs 
●​ Candidiasis, esophageal 
●​ Cervical cancer, invasive 
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●​ Coccidioidomycosis, disseminated or extrapulmonary 
●​ Cryptococcosis, extrapulmonary 
●​ Cryptosporidiosis, chronic intestinal (>1 month’s duration) 
●​ Cytomegalovirus disease (other than liver, spleen, or nodes) 
●​ Cytomegalovirus retinitis (with loss of vision) 
●​ Encephalopathy, HIV-related 
●​ Herpes simplex: chronic ulcer(s) (>1 month’s duration);or bronchitis, 
pneumonitis, or esophagitis 
●​ 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 
M. 
kansasii, 
disseminated 
or 
extrapulmonary 
●​ Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary) 
●​ Mycobacterium, other species or unidentified species, disseminated or 
Extrapulmonary 
●​ Pneumocystis carinii pneumonia 
●​ Pneumonia, recurrent 
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●​ Progressive multifocal leukoencephalopathy 
●​ Salmonella septicemia, recurrent 
●​ Toxoplasmosis of brain 
●​ Wasting syndrome due to HIV 
●​ Non-CDC, HIV-associated conditions 
 
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16.​
Appendix 3: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
The list does not apply to FRP with same sex partners or for subjects who are and 
will continue to be abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
1. Contraceptive subdermal implant 
2. Intrauterine device or intrauterine system 
3. Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]) 
4. Injectable progestogen [Hatcher, 2011] 
5. Contraceptive vaginal ring [Hatcher, 2011] 
6. Percutaneous contraceptive patches [Hatcher, 2011] 
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination, and/or semen 
analysis, or medical history interview provided by her or her partner. 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of 
contraception.  
Reference 
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 20th edition. Atlanta, 
Georgia: Ardent Media, Inc., 2011: 50. Table 3-2. 
 
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17.​
Appendix 4: Essential Elements of Informed Consent 
 
A signed consent must be obtained prior to any study-specific activities, the process 
needs to be documented in the medical chart, and a signed copy needs to be 
provided to the participant. The investigators should contact their local IRB regarding 
specific requirements. The ICF must include at least the following items:  
●​ Explanation of the research, purpose, expected duration of participation, and 
description of procedures.   
●​ A description of any reasonably foreseeable risks, inconveniences or 
discomforts to the patients and, if applicable, to an embryo, fetus or nursing 
infant. 
●​ A description of any benefits to the patient or to others which may reasonably 
be expected from the research.  According to Argentinean Regulation, no 
compensation is to be provided, but description of the reimbursement of 
transport and foods should be stated.  
●​ A disclosure of appropriate alternative procedures or courses of treatment, if 
any, that might be advantageous to the patient, and where to obtain them.  
●​ A statement that participation is voluntary, that refusal to participate will 
involve no penalty or loss of benefits to which the patient is otherwise entitled, 
and that the patient may discontinue participation at any time without penalty 
or loss of benefits to which the patient is otherwise entitled. 
●​ That the investigator and the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), will be granted direct access to the subject’s original 
medical records for verification of clinical trial procedures and/or data, without 
violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations and that, by signing a written informed 
consent form, the subject or the subject’s legally acceptable representative is 
authorizing such access. 
●​ That records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
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available.  If the results of the study are published, the subject’s identity will 
remain confidential. 
●​ To whom answers to pertinent questions about the research and research 
patients’ rights, should be directed. 
●​ A statement of the agreement to participate (e.g., “I agree to participate ...”) 
with signature and date for the participant (or legally authorized 
representative) and for the person who explained the nature of the study to 
the patient (investigator or investigator’s representative). 
●​ A statement of anticipated circumstances or reasons under which the patient’s 
participation may be terminated by the investigator without regard to patient’s 
consent. 
●​ A statement that significant new findings developed during the course of the 
research which may relate to the patient’s willingness to continue participation 
will be provided to the patient (or the patient’s legally acceptable 
representative) in a timely manner. 
 
 
 
 
 
 
 
 
 
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18.​
Appendix 5: Adherence questionnaires  
 
 
 
 
 
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Follow-up ACTG adherence Questionnaire 
 
 
                                                                                                                         
Subject # __ __ __ __ __ __ __                       Visit Date __ __  /  __ __ __  /  __ __   
  
Subject Initials __ __ __                                   Week # __ __   
 
 
This questionnaire asks about study medications that you took recently.  Many people find it hard to always 
remember their pills.  For example, 
 
●​
Some people get busy and forget to carry their pills with them. 
●​
Some people find it hard to take their pills according to special instructions, such as to    increase 
the amount of medication you are taking if you have a herpes flare. 
●​
Some people decide to skip pills to avoid side effects or to just not be taking 
pills that day. 
 
We need to understand how people with HIV are really doing with their pills. Please tell us what you are 
actually doing. Don’t worry about telling us if you don’t take all your pills. 
We need to know what is really happening, not what you think we “want to hear.” 
 
 
1. How many doses of your study medication did you miss… 
 
Yesterday?​
​
​
​
​
​
  dose(s) 
 
The day before yesterday (2 days ago)?​
​
​
  dose(s) 
 
3 days ago?​
​
​
​
​
​
  dose(s) 
​
 
4 days ago?​
​
​
​
​
​
  dose(s) 
 
If you did not miss any doses, write a zero (0) in the space provided. 
 
 
2. This study medication needs to be taken 2 times a day.  How closely did you follow this specific schedule over 
the last four days? 
 
​
Never​
​
Some of​             About half​
Most of​              All of 
​
​
the time             ​ of the time​
the time ​​
the time 
☐​
 ​
☐​
             ☐​
​
☐​
​
☐​
​
 
​
0​
​
1​
            ​ 2​
​
3​
​
4 
 
 
 
3. Did study staff give you special instructions to take extra medication because of a herpes flare in the last four 
days? 
 
Yes​
​
No 
☐​
 ​
☐​
 
1​
2​
 
 
If Yes, how often did you follow those special instructions over the last four days? 
 
​
Never​
​
Some of​​
About half​
Most of​ All of 
​
​
the time​ of the time​
the time​ the time 
☐​
 ​
☐​
​
☐​
​
☐​
​
☐​
​
 
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​
0​
​
1​
​
2​
​
3​
​
4 
 
4. Some people find that they forget to take their pills on the weekend days. Did you miss any of your study 
medications last weekend - last Saturday or Sunday? 
 
Yes​
​
No 
☐​
 ​
☐​
 
1​
​
2​
 
 
5. Some people find that they forget to take their pills on the weekend days.   How often did you miss any of your 
study medications on a weekend during the past 3 months? 
 
​
Never​
​
Some of​About half​
Most of​ ​
All of 
​
​
the time​ ​
of the time​
the time​ ​
the time 
☐​
 ​
☐​
​
☐​
​
☐​
​
☐​
​
 
​
0​
​
1​
​
2​
​
3​
​
4 
 
6. When was the last time you missed any of your medications?   (Check one box) 
 
Within the​
1-2 weeks​
2-4 weeks​
1-3 months​
More than 3​
Never 
past week​
ago​
​
ago​
​
ago​
​
months ago 
☐​
 ​
☐​
​
☐​
​
☐​
​
☐​
​
☐ 
​
5​
​
4​
​
3​
 
 
 
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19.​
Appendix 6: Quality of Life questionnaires 
 
The form can be accessed at 
 
http://www.med.umich.edu/pdf/weight-management/EQ-5D-HealthQ.pdf 
 
 
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20.​
Appendix 7: Mental Health Questionnaire  
 
 
 
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21.​
Appendix 8: DTG+3TC Risk Assessment 
Dolutegravir/Lamivudine 
​
Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
 
Investigational Product: dolutegravir/Lamivudine 
Refer to Investigator Brochure and/or approved Local Prescribing Information for additional 
information 
Hypersensitivity 
and rash 
 
Hypersensitivity reactions have been 
observed uncommonly with DTG. Rash, 
generally mild to moderate in intensity, 
was commonly reported in DTG Phase 
IIb/III clinical trials. No episodes of 
severe rash, such as Stevens-Johnson 
Syndrome, toxic epidermal necrolysis 
and erythema multiforme, were 
reported in these clinical trials.  
 
 
Subjects with history or presence 
of allergy/sensitivity to any of the 
study drugs or their components 
are excluded  
Specific toxicity management 
guidance is provided for 
hypersensitivity reactions and rash  
The subject informed consent 
form includes information on this 
risk and the actions subjects 
should take in the event of a 
hypersensitivity reaction or 
associated signs and symptoms. 
Drug induced 
liver injury and 
other clinically 
significant liver 
chemistry 
elevations 
Non-clinical data suggested a possible, 
albeit low, risk for hepatobiliary toxicity 
with DTG. Drug-related hepatitis is 
considered an uncommon risk for 
antiretroviral therapy containing DTG 
regardless of dose or treatment 
population. For subjects with hepatitis B 
virus and/or hepatitis C virus 
co-infection, improvements in 
immunosuppression because of human 
immunodeficiency virus (HIV) virologic 
and immunologic responses to 
DTG-containing antiretroviral therapy, 
along with inadequate therapy for 
hepatitis B virus co-infected subjects, 
likely contributed to significant 
elevations in liver chemistries. 
 
There have been rare post-marketing 
reports of acute hepatic failure in 
association with DTG-containing 
regimens. 
 
Subjects meeting any of the 
following criteria during the 
screening period are excluded 
from participating  
●​ Alanine aminotransferase (ALT) 
≥5 times the upper limit of 
normal (ULN) or ALT ≥3xULN 
and bilirubin ≥1.5xULN (with 
>35% direct bilirubin) 
●​ Unstable liver disease, cirrhosis 
and/or known biliary 
abnormalities (except for 
hyperbilirubinemia or jaundice 
due to Gilbert's syndrome or 
asymptomatic gallstones) 
●​ Subjects with hepatitis B 
infection or an anticipated 
need for hepatitis C virus 
therapy are excluded 
Specific/detailed liver stopping 
criteria and toxicity management 
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Current treatment guidelines do not 
recommend monotherapy with 3TC for 
patients with HBV infection, which is 
what subjects randomized to DTG plus 
3TC, would effectively be receiving. 
Emergence of HBV variants associated 
with resistance to 3TC has been 
reported in HIV-1-infected patients who 
have received 3TC-containing 
antiretroviral regimens in the presence 
of concurrent infection with HBV. 
Additionally, discontinuation of 3TC in 
HBV co-infected subjects can result in 
severe exacerbations of hepatitis B. 
 
For subjects co-infected with hepatitis C 
virus and HIV, treatment guidelines 
recommend that the hepatitis C virus 
infection is treated first before starting 
treatment for the HIV. Additionally, 
interferon and/or ribavirin toxicity 
maybe frequent and difficult to 
differentiate from adverse reactions to 
investigational product. 
 
 
guidance are provided for 
suspected drug induced liver 
injury or other clinically significant 
liver chemistry elevations  
Neural Tube 
Defects 
In a birth outcome surveillance study in 
Botswana, a numerically higher rate of 
neural tube defects was identified with 
exposure to dolutegravir compared to 
non-dolutegravir-containing 
antiretroviral regimens at the time of 
conception, however, the difference 
was not statistically significant. Seven 
cases of neural tube defects were 
reported in 3,591 deliveries (0.19%) to 
mothers taking dolutegravir-containing 
regimens at the time of conception, 
compared with 21 cases in 19,361 
deliveries (0.11%) to mothers taking 
non-dolutegravir-containing regimens at 
the time of conception (Prevalence 
Difference 0.09%; 95% CI -0.03, 0.30) 
[Zash 2020].   
Reproductive toxicology studies have 
not shown any relevant findings. DTG 
has been shown to cross the placenta. 
Pregnancy testing should be 
performed before initiation 
of DTG therapy in all women of 
child bearing potential (negative 
pregnancy test at screening and 
randomization).  
 
Women who are pregnant or who 
plan to become pregnant, are 
excluded.  
 
All women of reproductive 
potential should use effective 
contraception (Appendix 3). 
 
The subject informed consent 
form provides information about 
this potential risk. 
 
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Data available from other sources 
including the Antiretroviral Pregnancy 
Registry (APR), other cohorts and 
clinical trials are insufficient to confirm 
or refute this potential risk.   
 
 
74