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 Description

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Brief Summary:

Part 1 consists of 2 cohorts, starting with a sentinel cohort, in which approximately 10 participants will be enrolled to receive open-label tenofovir alafenamide (TAF) in addition to their current failing antiretroviral (ARV) regimen. This cohort will then be followed by a randomized, double-blind, cohort of approximately 90 participants 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.

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

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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 9, 2016
Actual Study Completion Date :	July 31, 2017

Arms and Interventions

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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 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 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.	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.

Outcome Measures

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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 Incidence of Laboratory Parameters and Adverse Events at Weeks 24 and 48 [ Time Frame: Up to 48 weeks ]
3. Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
4. Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
5. Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
6. Part 2: Change From Baseline in CD4+ Cell Count (Cells/μL) and Percentage at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
7. Part 2: Pharmacokinetic (PK) Parameter: AUClast of TAF [ Time Frame: Week 4 to Week 12 ]
   AUClast is defined as the concentration of drug from time zero to the last observable concentration
8. Part 2: PK Parameter: Clast of TAF [ Time Frame: Week 4 to Week 12 ]
   Clast is defined as the last observable concentration of drug.
9. Part 2: PK Parameter: Cmax of TAF, Tenofovir (TFV), ATV, and Elvitegravir (EVG) [ Time Frame: Week 4 to Week 12 ]
   Cmax is defined as the maximum concentration of drug.
10. Part 2: PK Parameter: AUCtau of TFV, ATV, and EVG [ Time Frame: Week 4 to Week 12 ]
    AUCtau is defined as concentration of drug over time.
11. Part 2: PK Parameter: Ctau of TFV, ATV, and EVG [ Time Frame: Week 4 to Week 12 ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
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
• Screening or historical genotype report showing either 1 to 3 thymidine-analogue mutations (TAMs) and/or K65R, as well as M184V/I
• 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

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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

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT01967940 History of Changes
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:	September 13, 2017
Last Verified:	August 2017

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; Immunologic Deficiency Syndromes; Acquired Immunodeficiency Syndrome; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immune System Diseases; Slow Virus Diseases; Tenofovir; Emtricitabine; Atazanavir Sulfate

Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Cobicistat; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Anti-HIV Agents; HIV Protease Inhibitors; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors