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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03122262
Recruitment Status : Active, not recruiting
First Posted : April 20, 2017
Last Update Posted : June 9, 2020
Sponsor:
Information provided by (Responsible Party):
Willem Daniel Francois Venter, University of Witwatersrand, South Africa

Tracking Information
First Submitted Date  ICMJE October 11, 2016
First Posted Date  ICMJE April 20, 2017
Last Update Posted Date June 9, 2020
Actual Study Start Date  ICMJE January 16, 2017
Estimated Primary Completion Date April 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 16, 2017)
Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48 [ Time Frame: 48 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2020)
  • Proportion of patients with undetectable plasma HIV-1 RNA levels (< 50 copies/mL) at Week 48, 96, 144 and 192 [ Time Frame: 192 weeks ]
    Using FDA snapshot algorithm
  • Proportion of patients with plasma HIV-1 RNA levels < 200 copies/mL at Week 192 [ Time Frame: 192 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 192.
  • 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.
  • Change from baseline in plasma HIV-1 RNA levels at each visit [ Time Frame: At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192 ]
    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.
  • Change from baseline in plasma CD4 levels at each visit [ Time Frame: At week 12, 24, 36, 60, 72, 84, 96, 120, 144, 168, 192 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 16, 2017)
  • 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
  • Proportion of patients with plasma HIV-1 RNA levels < 200 copies/mL at Week 96 [ Time Frame: 96 weeks ]
  • 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 ]
  • Change from baseline in plasma HIV-1 RNA levels at each visit [ Time Frame: At week 12, 24, 36, 60, 72, 84, 96 ]
  • Change from baseline in plasma CD4 levels at each visit [ Time Frame: At week 12, 24, 36, 60, 72, 84, 96 ]
Current Other Pre-specified Outcome Measures
 (submitted: June 5, 2020)
  • Nature and frequency of adverse events [ Time Frame: Week 48, 96, 144, 192 ]
    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.
  • 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.
  • 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.
  • Virological efficacy in the 12 - 18 year age group [ Time Frame: Week 48, 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
Original Other Pre-specified Outcome Measures
 (submitted: April 16, 2017)
  • Nature and frequency of adverse events [ Time Frame: Week 48 and 96 ]
  • 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.
  • 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.
  • Virological efficacy in the 12 - 18 year age group [ Time Frame: Over 96 weeks ]
    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
 
Descriptive Information
Brief Title  ICMJE ADVANCE Study of DTG + TAF + FTC vs DTG + TDF + FTC and EFV + TDF+FTC in First-line Antiretroviral Therapy
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV-1 Infection
Intervention  ICMJE
  • 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
  • Drug: Truvada
    Other Name: TDF/FTC 300/200mg Oral Tablet
  • Drug: Atripla
    Other Name: EFV/TDF/FTC 600/200/300mg Oral Tablet
Study Arms  ICMJE
  • Active Comparator: Tenofovir Alafenamide
    Descovy: Tenofivir alafenamide tablets 25mg daily, Emtricitabine 200mg daily
    Interventions:
    • Drug: Dolutegravir
    • Drug: Tenofovir Alafenamide
  • Active Comparator: Dolutegravir
    Dolutegravir 50mg daily, Truvada 500mg daily
    Interventions:
    • Drug: Dolutegravir
    • Drug: Truvada
  • Active Comparator: Atripla
    Atripla: Efavirenz 600mg daily, Tenofovir Disoproxil Fumarate 300mg daily, Emtricitabine 200mg daily
    Intervention: Drug: Atripla
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: April 16, 2017)
1110
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 30, 2022
Estimated Primary Completion Date April 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03122262
Other Study ID Numbers  ICMJE WRHI060
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Willem Daniel Francois Venter, University of Witwatersrand, South Africa
Study Sponsor  ICMJE Willem Daniel Francois Venter
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Willem Daniel Francois Venter, FCP (SA) Wits Reproductive Health & HIV Institute, University of the Witswatersrand
PRS Account University of Witwatersrand, South Africa
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP