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

• ClinicalTrials.gov Identifier: NCT01967940
• Recruitment Status: Completed
• First Posted: October 23, 2013
• Results First Posted: June 12, 2017
• Last Update Posted: November 16, 2018
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV; HIV Infections; Acquired Immunodeficiency Syndrome	Drug: TAF; Drug: Placebo; Drug: E/C/F/TAF; Drug: Current failing ARV regimen; Drug: ATV	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Part 1 (Sentinel Cohort followed by a Randomized Cohort), 14-day washout period, then Part 2
• Masking: Double (Participant, Investigator)
• Masking Description: Part 1 Sentinel Cohort: Open-label, non-randomized Part 1 Randomized Cohort: Double-blind, randomized Part 2: Open-label, non-randomized
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 25, 2013
• Actual Primary Completion Date: May 21, 2015
• Actual Study Completion Date: July 31, 2017

Arms and Interventions

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: Placebo; Tablets to match TAF administered orally once daily with food; Drug: Current failing ARV regimen; Participants will continue taking their current ARV regimen as prescribed in Part 1.
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 Name: Genvoya®; Drug: ATV; 300 mg tablet administered orally once daily.; Other Name: Reyataz®

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10 [ Time Frame: Baseline; Day 10 ]
2. 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 [ Time Frame: Up to Week 24 ]
3. 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 [ Time Frame: Up to Week 48 ]
4. 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 [ Time Frame: Up to Week 24 ]
5. 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 [ Time Frame: Up to Week 48 ]
6. Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24 [ Time Frame: 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.
7. Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48 [ Time Frame: 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.
8. Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24 [ Time Frame: 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.
9. Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48 [ Time Frame: 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.
10. Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24 [ Time Frame: Baseline; Week 24 ]
11. Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48 [ Time Frame: Baseline; Week 48 ]
12. Part 2: Change From Baseline in CD4+ Cell Count at Week 24 [ Time Frame: Baseline; Week 24 ]
13. Part 2: Change From Baseline in CD4+ Cell Count at Week 48 [ Time Frame: Baseline; Week 48 ]
14. Part 2: Change From Baseline in CD4+ Percentage at Week 24 [ Time Frame: Baseline; Week 24 ]
15. Part 2: Change From Baseline in CD4+ Percentage at Week 48 [ Time Frame: Baseline; Week 48 ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Florida

Midway Immunology and Research center

Fort Pierce, Florida, United States, 34982

Triple O Research Institute, P.A.

West Palm Beach, Florida, United States, 33401

Rowan Tree Medical, P.A.

Wilton Manors, Florida, United States, 33305

United States, North Carolina

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States, 27157

United States, Pennsylvania

Penn Presbyterian Medical Center

Philadelphia, Pennsylvania, United States, 19104

Dominican Republic

Salvador B Gautier Hospital - Infectious Diseases Department

Santo Domingo, Dominican Republic, 10514

Instituto Dominicano de Estudio Virologicos - IDEV

Santo Domingo, Dominican Republic

Russian Federation

Regional state budget health agency Krasnoyarsk Regional Center for Prevention and Control of AIDS

Krasnoyarsk, Russian Federation, 660049

Center For Prevention and Treatment of AIDS and Infectious Diseases, Saint Petersburg

Saint Petersburg, Russian Federation, 190020

Thailand

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT)

Bangkok, Thailand, 10330

Ramathibodi Hospital, Mahidol University

Bangkok, Thailand, 10400

Siriraj Hospital Department of Preventive and Social Medicine, Faculty of Medicine

Bangkok, Thailand, 10700

Chiang Mai University

Chiang Mai, Thailand, 50200

Khon Kaen University

Khon Kaen, Thailand, 40002

Uganda

Joint Clinical Research Centre

Kampala, Uganda

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

More Information

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01967940
• Other Study ID Numbers: GS-US-292-0117; 2013-002830-19 ( EudraCT Number )
• First Posted: October 23, 2013
• Results First Posted: June 12, 2017
• Last Update Posted: November 16, 2018
• Last Verified: July 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.
• URL: http://www.gilead.com/research/disclosure-and-transparency

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gilead Sciences:

HIV-1; HIV; Treatment-Experienced

Additional relevant MeSH terms:

HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immune System Diseases; Slow Virus Diseases; Atazanavir Sulfate; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Protease Inhibitors; Viral Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents