Efficacy of Tenofovir Alafenamide Versus Placebo Added to a Failing Regimen Followed by Treatment With Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Atazanavir in HIV-1 Positive, Antiretroviral Treatment-Experienced Adults

A Phase 3, Two-Part Study to Evaluate the Efficacy of Tenofovir Alafenamide Versus Placebo Added to a Failing Regimen Followed by Treatment With Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Atazanavir in HIV-1 Positive, Antiretroviral Treatment-Experienced Adults

The primary objective of this study is to evaluate the efficacy of tenofovir alafenamide (TAF) versus placebo, each administered with the existing, failing antiretroviral (ARV) regimen. There are 2 parts to this study: Part 1 and Part 2.

Part 1 consists of 2 cohorts, starting with a sentinel cohort, in which participants will be enrolled to receive open-label TAF in addition to their current failing ARV regimen. This cohort will then be followed by a randomized, double-blind, cohort to compare the addition of TAF or placebo in HIV-1 positive adults who are failing their current ARV regimen.

In Part 2, all participants who complete Part 1 of the study will discontinue their failing ARV regimen and TAF or placebo for a 14-day washout period. Following the washout period, all participants who received TAF in Part 1 and have a > 0.5 log10 decline in HIV-1 RNA will receive elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen (STR) plus atazanavir (ATV) once daily for 48 weeks. Participants who received TAF who have a ≤ 0.5 log10 decline in HIV-1 RNA will be discontinued from the study and will not be eligible to continue into Part 2 of the study. All participants who received placebo in Part 1 will be eligible to participate in Part 2 regardless of their viral load change. After completion of Part 2, all participants will be eligible to continue to receive E/C/F/TAF plus ATV in the extension phase until E/C/F/TAF becomes commercially available, or until Gilead Sciences terminates development of E/C/F/TAF in the applicable country.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Acquired Immunodeficiency Syndrome; HIV
• Intervention / Treatment: Drug: TAF; Drug: Current failing ARV regimen; Drug: Placebo; Drug: E/C/F/TAF; Drug: ATV

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 3

Contacts and Locations

Study Locations

• Dominican Republic
  • Santo Domingo, Dominican Republic
    • Instituto Dominicano de Estudio Virologicos - IDEV
  • Santo Domingo, Dominican Republic, 10514
    • Salvador B Gautier Hospital - Infectious Diseases Department
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660049
    • Regional state budget health agency Krasnoyarsk Regional Center for Prevention and Control of AIDS
  • Saint Petersburg, Russian Federation, 190020
    • Center For Prevention and Treatment of AIDS and Infectious Diseases, Saint Petersburg
• Thailand
  • Bangkok, Thailand, 10330
    • The HIV Netherlands Australia Thailand Research collaboration (HIV-NAT)
  • Bangkok, Thailand, 10400
    • Ramathibodi Hospital, Mahidol University
  • Bangkok, Thailand, 10700
    • Siriraj Hospital Department of Preventive and Social Medicine, Faculty of Medicine
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University
  • Khon Kaen, Thailand, 40002
    • Khon Kaen University
• Uganda
  • Kampala, Uganda
    • Joint Clinical Research Centre
• United States
  • Florida
    • Fort Pierce, Florida, United States, 34982
      • Midway Immunology and Research Center
    • West Palm Beach, Florida, United States, 33401
      • Triple O Research Institute, P.A.
    • Wilton Manors, Florida, United States, 33305
      • Rowan Tree Medical, P.A.
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
• Currently taking a failing ARV regimen
• Plasma HIV-1 RNA ≥ 500 copies/mL but ≤ 100,000 copies/mL at screening
• Normal ECG
• Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min according to the Cockcroft-Gault formula for creatinine clearance
• Alanine aminotransferase (AST)/aspartate aminotransferase (AST) ≤ 5 × the upper limit of the normal range (ULN)
• Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin
• Adequate hematologic function
• Serum amylase ≤ 5 × ULN

• Females may enter the study if it is confirmed that she is:

  • Not pregnant or nursing
  • Of non-childbearing potential (ie, have had a hysterectomy, both ovaries removed, medically documented ovarian failure, or are postmenopausal women > 54 years of age with cessation [for ≥ 12 months] of previously occurring menses), or

  • Of childbearing potential and agrees to utilize highly effective contraception methods or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following study drug dosing

    • Females who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing.
• Males must agree to utilize a highly effective method of contraception during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from first dose throughout the study period and for 30 days following the last study drug dose.
• Males must agree to refrain from sperm donation from first dose until at least 30 days after the last study drug dose.

Key Exclusion Criteria:

• A new AIDS-defining condition diagnosed within the 30 days prior to screening
• Hepatitis B surface antigen (HBsAg) positive
• Hepatitis C antibody positive (individuals with positive hepatitis C virus (HCV) antibody and without detectable HCV RNA are permitted to enroll)
• History of integrase inhibitor use
• Screening or historical genotype reports shows Q151M or T69ins or more than 3 TAMs.
• Screening or historical genotype report shows resistance to integrase inhibitors
• Individuals experiencing decompensated cirrhosis
• Current alcohol or substance use
• History of malignancy within the past 5 years (prior to screening) or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Individuals with cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Part 1, Day 1 and must not be anticipated to require systemic therapy during the study.
• Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Part 1, Day 1
• Any other clinical condition or prior therapy that would make the individual unsuitable for the study or unable to comply with dosing requirements
• Participation in any other clinical trial (including observational trials) without prior approval from the sponsor is prohibited while participating in this trial
• Receiving ongoing therapy with any disallowed medications, including any drugs not to be used with elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide or known allergies to the excipients of E/C/F/TAF STR

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Sentinel Cohort (TAF); TAF + their current failing ARV regimen for 10 days in Part 1	Drug: TAF; 25 mg tablet administered orally once daily with food; Other Names: Vemlidy®; GS-7340; Drug: Current failing ARV regimen; Participants will continue taking their current ARV regimen as prescribed in Part 1.
Experimental: Part 1 Randomized Cohort (TAF); Following review of safety and efficacy data from the Sentinel Cohort, participants will be randomized to receive TAF + their current failing ARV regimen for 10 days in Part 1.	Drug: TAF; 25 mg tablet administered orally once daily with food; Other Names: Vemlidy®; GS-7340; Drug: Current failing ARV regimen; Participants will continue taking their current ARV regimen as prescribed in Part 1.
Placebo Comparator: Part 1 Randomized Cohort (Placebo); Following review of safety and efficacy data from the Sentinel Cohort, participants will be randomized to receive placebo + their current failing ARV regimen for 10 days in Part 1.	Drug: Current failing ARV regimen; Participants will continue taking their current ARV regimen as prescribed in Part 1.; Drug: Placebo; Tablets to match TAF administered orally once daily with food
Experimental: Part 2 E/C/F/TAF+ATV; Following a 14-day period to confirm eligibility, participants in the Randomized Cohort TAF group with a > 0.5 log10 decline in HIV-1 RNA and all participants completing the Randomized Cohort Placebo group will receive E/C/F/TAF+ATV for 48 weeks in Part 2. After completion of Part 2, all participants will be eligible to continue to receive E/C/F/TAF plus ATV in the extension phase until E/C/F/TAF becomes commercially available, or until Gilead Sciences terminates development of E/C/F/TAF in the applicable country.	Drug: E/C/F/TAF; 150/150/200/10 mg STR administered orally once daily with food; Other Names: Genvoya®; Drug: ATV; 300 mg tablet administered orally once daily.; Other Names: Reyataz®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10	Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.	Week 24
Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10		Baseline; Day 10
Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 24		Up to Week 24
Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 48		Up to Week 48
Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 24		Up to Week 24
Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 48		Up to Week 48
Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.	Week 48
Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24	The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.	Week 24
Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48	The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.	Week 48
Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24		Baseline; Week 24
Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48		Baseline; Week 48
Part 2: Change From Baseline in CD4+ Cell Count at Week 24		Baseline; Week 24
Part 2: Change From Baseline in CD4+ Cell Count at Week 48		Baseline; Week 48
Part 2: Change From Baseline in CD4+ Percentage at Week 24		Baseline; Week 24
Part 2: Change From Baseline in CD4+ Percentage at Week 48		Baseline; Week 48

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2013
• Primary Completion (Actual): May 21, 2015
• Study Completion (Actual): July 31, 2017

Study Registration Dates

• First Submitted: October 18, 2013
• First Submitted That Met QC Criteria: October 18, 2013
• First Posted (Estimate): October 23, 2013

Study Record Updates

• Last Update Posted (Actual): November 16, 2018
• Last Update Submitted That Met QC Criteria: October 19, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: HIV; HIV-1; Treatment-Experienced
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Atazanavir Sulfate; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: GS-US-292-0117; 2013-002830-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and-transparency.
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No