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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV, HIV Infections, Acquired Immunodeficiency Syndrome

Intervention / Treatment
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* Drug: TAF
* Drug: Placebo
* Drug: E/C/F/TAF
* Drug: Current failing ARV regimen
* Drug: ATV


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1 (Sentinel Cohort followed by a Randomized Cohort), 14-day washout period, then Part 2
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Sentinel Cohort (TAF)<br>TAF + their current failing ARV regimen for 10 days in Part 1 | Drug: TAF<br>* 25 mg tablet administered orally once daily with food<br>* Other names: GS-7340;Drug: Current failing ARV regimen<br>* Participants will continue taking their current ARV regimen as prescribed in Part 1.<br>|
| Experimental: Part 1 Randomized Cohort (TAF)<br>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<br>* 25 mg tablet administered orally once daily with food<br>* Other names: GS-7340;Drug: Current failing ARV regimen<br>* Participants will continue taking their current ARV regimen as prescribed in Part 1.<br>|
| Placebo Comparator: Part 1 Randomized Cohort (Placebo)<br>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: Placebo<br>* Tablets to match TAF administered orally once daily with food<br>Drug: Current failing ARV regimen<br>* Participants will continue taking their current ARV regimen as prescribed in Part 1.<br>|
| Experimental: Part 2 E/C/F/TAF+ATV<br>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<br>* 150/150/200/10 mg STR administered orally once daily with food<br>* Other names: Genvoya®;Drug: ATV<br>* 300 mg tablet administered orally once daily.<br>* Other names: Reyataz®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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: 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 | 
| 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 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 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, HIV, Treatment-Experienced