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

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ClinicalTrials.gov Identifier: NCT03122262
Recruitment Status : Active, not recruiting
First Posted : April 20, 2017
Last Update Posted : February 19, 2019
Sponsor:
Information provided by (Responsible Party):
Willem Daniel Francois Venter, University of Witwatersrand, South Africa

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.

Condition or disease Intervention/treatment Phase
HIV-1 Infection Drug: Dolutegravir Drug: Tenofovir Alafenamide Drug: Truvada Drug: Atripla Phase 3

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 an end of study visit at Week 96 (figure 1). Study medication pill counts will be performed at each follow up visit.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 96-week 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
Actual Study Start Date : January 16, 2017
Estimated Primary Completion Date : April 30, 2019
Estimated Study Completion Date : April 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Active Comparator: Tenofovir Alafenamide
Descovy: Tenofivir alafenamide tablets 25mg daily, Emtricitabine 200mg daily
Drug: Dolutegravir
DTG 50mg Oral Tablet once daily
Other Name: Tivicay

Drug: Tenofovir Alafenamide
TAF/FTC 25/200mg Oral Tablet once daily
Other Name: Descovy

Active Comparator: Dolutegravir
Dolutegravir 50mg daily, Truvada 500mg daily
Drug: Dolutegravir
DTG 50mg Oral Tablet once daily
Other Name: Tivicay

Drug: Truvada
Other Name: TDF/FTC 300/200mg Oral Tablet

Active Comparator: Atripla
Atripla: Efavirenz 600mg daily, Tenofovir Disoproxil Fumarate 300mg daily, Emtricitabine 200mg daily
Drug: Atripla
Other Name: EFV/TDF/FTC 600/200/300mg Oral Tablet




Primary Outcome Measures :
  1. Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48 [ Time Frame: 48 weeks ]
    The proportion of participants with undetectable plasma HIV-1 RNA levels at Week 48, will be calculated for each treatment group and summarised.


Secondary Outcome Measures :
  1. Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48 and 96 [ Time Frame: 96 weeks ]
    Using FDA snapshot algorithm

  2. Proportion of patients with plasma HIV-1 RNA levels < 200 copies/mL at Week 96 [ Time Frame: 96 weeks ]
    • 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 96.

  3. 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 Frame: 24 weeks ]
    Time to virologic failure will be modelled by Cox regression.

  4. Change from baseline in plasma HIV-1 RNA levels at each visit [ Time Frame: At week 12, 24, 36, 60, 72, 84, 96 ]
    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.

  5. Change from baseline in plasma CD4 levels at each visit [ Time Frame: At week 12, 24, 36, 60, 72, 84, 96 ]
    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.


Other Outcome Measures:
  1. Nature and frequency of adverse events [ Time Frame: Week 48 and 96 ]
    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.

  2. Analysis of PK data in those developing TB [ Time Frame: Over course of TB treatment in those developing TB, during 3 regular scheduled visits ]
    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.

  3. Analysis of PK data in those becoming pregnant [ Time Frame: Monthly ]
    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.

  4. Virological efficacy in the 12 - 18 year age group [ Time Frame: Week 48 and 96 ]
    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



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03122262


Locations
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South Africa
Shandukani Research Centre
Johannesburg, Gauteng, South Africa, 2001
Charlotte Maxeke Johannesburg Academic Hospital
Johannesburg, Gauteng, South Africa, 2196
Wits RHI Yeoville Clinic
Johannesburg, Gauteng, South Africa
Sponsors and Collaborators
Willem Daniel Francois Venter
Investigators
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Principal Investigator: Willem Daniel Francois Venter, FCP (SA) Wits Reproductive Health & HIV Institute, University of the Witswatersrand

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Responsible Party: Willem Daniel Francois Venter, Professor, University of Witwatersrand, South Africa
ClinicalTrials.gov Identifier: NCT03122262     History of Changes
Other Study ID Numbers: WRHI060
First Posted: April 20, 2017    Key Record Dates
Last Update Posted: February 19, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Willem Daniel Francois Venter, University of Witwatersrand, South Africa:
Antiretroviral Agents, first-line antiretroviral therapy
dolutegravir
Tenofovir alafenamide

Additional relevant MeSH terms:
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Tenofovir
Dolutegravir
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
HIV Integrase Inhibitors
Integrase Inhibitors