ADVANCE Study of DTG + TAF + FTC vs DTG + TDF + FTC and EFV + TDF+FTC in First-line Antiretroviral Therapy

HIV-1 Infection Clinical Trial

— ADVANCE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03122262
• Other study ID #: WRHI060
• Status: Completed
• Phase: Phase 3
• Start date: January 16, 2017
• Est. completion date: July 29, 2022

Study information

• Verified date: February 2023
• Source: University of Witwatersrand, South Africa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1110
• Est. completion date: July 29, 2022
• Est. primary completion date: April 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• Dolutegravir
DTG 50mg Oral Tablet once daily
• Tenofovir Alafenamide
TAF/FTC 25/200mg Oral Tablet once daily
• Truvada

• Atripla

Locations

Country	Name	City	State
South Africa	Charlotte Maxeke Johannesburg Academic Hospital	Johannesburg	Gauteng
South Africa	Shandukani Research Centre	Johannesburg	Gauteng
South Africa	Sunnyside Office Park	Johannesburg	Gauteng
South Africa	Wits RHI Yeoville Clinic	Johannesburg	Gauteng

Sponsors (1)

Lead Sponsor	Collaborator
Professor Francois Venter

Country where clinical trial is conducted

South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Nature and frequency of adverse events	A summary table will be presented, summarised by treatment, SOC and preferred term including the number of patients dosed in treatment group and number and percentage of subjects with AEs.	Week 48, 96, 144, 192
Other	Analysis of PK data in those developing TB	Participants in treatment groups 1 and 2 who develop TB during the study will have DTG trough levels (ng/mL) measured at routine scheduled three visits. Trough levels will also be measured in control subjects (without TB coinfection) in a 3:1 ratio.	Over course of TB treatment in those developing TB, during 3 regular scheduled visits
Other	Analysis of PK data in those becoming pregnant	Participants in treatment groups 1 and 2 who develop TB during the study will have DTG trough levels (ng/mL) measures will be measured in control non-pregnantsubjects in a 3:1 ratio.	Monthly
Other	Virological efficacy in the 12 - 18 year age group	Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48 and 96 in a subgroup analysis of this age-range	Week 48, 96
Primary	Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48	The proportion of participants with undetectable plasma HIV-1 RNA levels at Week 48, will be calculated for each treatment group and summarised.	48 weeks
Secondary	Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48, 96, 144 and 192	Using FDA snapshot algorithm	192 weeks
Secondary	Proportion of patients with plasma HIV-1 RNA levels < 200 copies/mL at Week 192	• Participants with undetectable plasma HIV-1 RNA levels will be defined as those with plasma RNA levels of < 200 copies/mL. Successes/responders will be defined as those participants on each regimen with undetectable plasma HIV-1 RNA levels at Week 192.	192 weeks
Secondary	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)	Time to virologic failure will be modelled by Cox regression.	24 weeks
Secondary	Change from baseline in plasma HIV-1 RNA levels at each visit	Individual patient plasma HIV-1 RNA levels will be summarised and listed by treatment and visit, together with changes from screening/enrolment plasma HIV-1 RNA levels. Observations (linear and log transformed) will also be presented graphically, over time, in the form of line plots.	At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192
Secondary	Change from baseline in plasma CD4 levels at each visit	Individual patient CD4 counts will be summarised and listed by treatment and visit, together with changes from screening/enrolment CD4 values. Observations (linear and log transformed) will also be presented graphically, over time, in the form of line plots.	At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192