Clinical trial NCT03122262: ADVANCE Study of DTG + TAF + FTC vs DTG + TDF + FTC and EFV + TDF+FTC in First-line Antiretroviral Therapy
Official title: WRHI 060 (ADVANCE): A Randomised, Phase 3 Non-inferiority Study of DTG + TAF + FTC Compared With DTG + TDF + FTC and EFV + TDF + FTC in Patients Infected With HIV-1 Starting First-line Antiretroviral Therapy - Extension to 192 Weeks
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infection
Keywords: Antiretroviral Agents, first-line antiretroviral therapy
dolutegravir
Tenofovir alafenamide
Lead sponsor: University of Witwatersrand, South Africa
Sponsor class: OTHER
First posted: 2017-04-20
Enrollment: 1110
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a non-inferiority (10% non-inferiority margin), study to assess the efficacy and safety of dolutegravir, DTG (50 mg once daily \[QD\]) administered in combination with tenofovir alafenamide fumarate, TAF (25 mg QD) and emtricitabine, FTC (200 mg QD) compared to DTG (50 mg QD) administered in combination with tenofovir disoproxil fumarate, TDF (300 mg QD) and FTC (200 mg QD) and compared to efavirenz, EFV (600 mg QD) administered in combination with TDF (300 mg QD) and FTC (200 mg QD) through 96 weeks in patients with HIV-1 starting first-line ART.

Detailed description: This is an open label randomised, non-inferiority (10% non-inferiority margin), phase 3 study to assess the efficacy and safety of DTG (50 mg once daily \[QD\]) administered in combination with TAF (25 mg QD) and FTC (200 mg QD) compared to DTG (50 mg QD) administered in combination with TDF (300 mg QD) and FTC (200 mg QD) and compared to EFV (600 mg QD) administered in combination with TDF (300 mg QD) and FTC (200 mg QD) through 96 weeks in patients with HIV-1 starting first-line ART.

Approximately 1110 male and female patients infected with HIV-1 who are eligible for first-line ART will be randomly assigned in a 1:1:1 ratio (approximately 370 patients per treatment group) to Treatment Group 1 (DTG + TAF + FTC) or Treatment Group 2 (DTG + TDF + FTC) or Treatment Group 3 (EFV + TDF + FTC). To ensure adequate representation of adolescents (12 - 18 years) in any treatment group, randomisation will be stratified according to age greater or less than 18 years. The study includes screening and baseline visits, 8 study visits from Week 4 to Week 84, and a preliminary end of study visit at Week 96.

The study will then take patients on Treatment Group 1 (DTG + TAF + FTC) or Treatment Group 2 (DTG + TDF + FTC) or Treatment Group 3 (EFV + TDF + FTC), who have completed 96 weeks successfully, and follow them to 192 weeks, with visits every 24 weeks after enrolment to 192 weeks. Study medication pill counts will be performed at each follow-up visit.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 12 years and ≥ 40 kg
2. Documented laboratory diagnosis of infection with HIV-1 (positive enzyme-linked immunosorbent assay HIV-1 antibody test) at screening
3. Plasma HIV-1 RNA (VL) ≥ 500 copies/mL
4. All pre-existing medical or laboratory abnormalities must be deemed to be stable by the investigator prior to study enrolment
5. Calculated creatinine clearance (CrCl) \> 60 mL/min (Cockcroft-Gault formula) in \> 18 years old OR \> 80 mL/min (modified Cockcroft-Gault) in ≤ 18 years old
6. Ability to comprehend the full nature and purpose of the study, in the opinion of the investigator, and to comply with the requirements of the entire study.

To enrol in extension post-96 weeks:

Each patient must meet all of the following criteria to be enrolled in this study:

1. Previously enrolled on the ADVANCE study, and followed to week 96 (including those on post-trial access)
2. Ability to comprehend the full nature and purpose of the study, including the extended timeline, in the opinion of the investigator, and to comply with the requirements of the entire study.

Exclusion Criteria:

1. Previously received more than 30 days of treatment with any form of antiretroviral therapy (ART) or
2. Received any antiretrovirals within the last 6 months
3. Women who are pregnant at the time of the screening or baseline visit
4. Active tuberculosis and/or are on antituberculous therapy at the time of the baseline visit
5. Taking and cannot discontinue prohibited concomitant medications listed in 7.3 at least 2 weeks prior to the baseline visit and for the duration of the study period
6. Clinically unstable, in the investigator's opinion
7. Current history of drug or alcohol abuse that, in the opinion of the investigator, may be an impediment to patient adherence to the protocol
8. Patients who participated in a study with an investigational drug within 60 days of screening or who are currently receiving treatment with any other investigational drug or device may be ineligible to participate. This is an investigator decision
9. Have a strong likelihood of relocating far enough to make access to the study site difficult
10. History or presence of allergy to the study drugs or their components
11. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); Child-Pugh C.

To enrol in extension post-96 weeks:

Patients meeting the following criteria will be excluded from the study:

1. HbA1c, lipids and blood pressures that are not responding to treatment, in the opinion of the investigator and in consultation with the principal investigator, justifying substitution of DTG or TAF
2. Clinically unstable, in the opinion of the investigator
3. Have a strong likelihood of relocating far enough to make access to the study site difficult.

Primary outcomes:
measure: Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48
timeFrame: 48 weeks
Secondary outcomes:
measure: Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48, 96, 144 and 192
timeFrame: 192 weeks
measure: Proportion of patients with plasma HIV-1 RNA levels < 200 copies/mL at Week 192
timeFrame: 192 weeks
measure: Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥ 1000 copies/mL at week 12 - 24 or ≥ 200 copies/mL at or after week 24)
timeFrame: 24 weeks
measure: Change from baseline in plasma HIV-1 RNA levels at each visit
timeFrame: At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192
measure: Change from baseline in plasma CD4 levels at each visit
timeFrame: At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192
Other outcomes:
measure: Nature and frequency of adverse events
timeFrame: Week 48, 96, 144, 192
measure: Analysis of PK data in those developing TB
timeFrame: Over course of TB treatment in those developing TB, during 3 regular scheduled visits
measure: Analysis of PK data in those becoming pregnant
timeFrame: Monthly
measure: Virological efficacy in the 12 - 18 year age group
timeFrame: Week 48, 96
Locations:
city: Johannesburg
country: South Africa
facility: Shandukani Research Centre
state: Gauteng
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Academic Hospital
state: Gauteng
city: Johannesburg
country: South Africa
facility: Sunnyside Office Park
state: Gauteng
city: Johannesburg
country: South Africa
facility: Wits RHI Yeoville Clinic
state: Gauteng
Study officials:
affiliation: Wits Reproductive Health & HIV Institute, University of the Witswatersrand
name: Willem Daniel Francois Venter, FCP (SA)
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cindi Z, Maartens G, Bradford Y, Venter WDF, Sokhela S, Chandiwana NC, Haas DW, Sinxadi P. Genetic Associations with Weight Gain among South Africans who Initiated Dolutegravir-Containing and Tenofovir-Containing Regimens. J Acquir Immune Defic Syndr. 2021 Jul 1;87(3):1002-1009. doi: 10.1097/QAI.0000000000002661.
citation: Siedner MJ, Moorhouse MA, Simmons B, de Oliveira T, Lessells R, Giandhari J, Kemp SA, Chimukangara B, Akpomiemie G, Serenata CM, Venter WDF, Hill A, Gupta RK. Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase. Nat Commun. 2020 Dec 1;11(1):5922. doi: 10.1038/s41467-020-19801-x.
citation: Venter WDF, Sokhela S, Simmons B, Moorhouse M, Fairlie L, Mashabane N, Serenata C, Akpomiemie G, Masenya M, Qavi A, Chandiwana N, McCann K, Norris S, Chersich M, Maartens G, Lalla-Edward S, Vos A, Clayden P, Abrams E, Arulappan N, Hill A. Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV. 2020 Oct;7(10):e666-e676. doi: 10.1016/S2352-3018(20)30241-1.
citation: Venter WDF, Moorhouse M, Sokhela S, Fairlie L, Mashabane N, Masenya M, Serenata C, Akpomiemie G, Qavi A, Chandiwana N, Norris S, Chersich M, Clayden P, Abrams E, Arulappan N, Vos A, McCann K, Simmons B, Hill A. Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV. N Engl J Med. 2019 Aug 29;381(9):803-815. doi: 10.1056/NEJMoa1902824. Epub 2019 Jul 24.