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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

Primary Purpose

HIV, HIV Infections, Acquired Immunodeficiency Syndrome

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

TAF

Placebo

E/C/F/TAF

Current failing ARV regimen

ATV

About this trial

This is an interventional treatment trial for HIV focused on measuring HIV-1, HIV, Treatment-Experienced

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Midway Immunology and Research center
Triple O Research Institute, P.A.
Rowan Tree Medical, P.A.
Wake Forest University Health Sciences
Penn Presbyterian Medical Center
Salvador B Gautier Hospital - Infectious Diseases Department
Instituto Dominicano de Estudio Virologicos - IDEV
Regional state budget health agency Krasnoyarsk Regional Center for Prevention and Control of AIDS
Center For Prevention and Treatment of AIDS and Infectious Diseases, Saint Petersburg
The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT)
Ramathibodi Hospital, Mahidol University
Siriraj Hospital Department of Preventive and Social Medicine, Faculty of Medicine
Chiang Mai University
Khon Kaen University
Joint Clinical Research Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Arm Label

Part 1 Sentinel Cohort (TAF)

Part 1 Randomized Cohort (TAF)

Part 1 Randomized Cohort (Placebo)

Part 2 E/C/F/TAF+ATV

Arm Description

TAF + their current failing ARV regimen for 10 days in Part 1

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at 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

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

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.

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.

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.

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.

Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24

Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48

Part 2: Change From Baseline in CD4+ Cell Count at Week 24

Part 2: Change From Baseline in CD4+ Cell Count at Week 48

Part 2: Change From Baseline in CD4+ Percentage at Week 24

Part 2: Change From Baseline in CD4+ Percentage at Week 48

Full Information

NCT ID

NCT01967940

First Posted

October 18, 2013

Last Updated

October 19, 2018

Sponsor

Gilead Sciences

1. Study Identification

Unique Protocol Identification Number

NCT01967940

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2018

Overall Recruitment Status

Completed

Study Start Date

October 25, 2013 (Actual)

Primary Completion Date

May 21, 2015 (Actual)

Study Completion Date

July 31, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Gilead Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV, HIV Infections, Acquired Immunodeficiency Syndrome

Keywords

HIV-1, HIV, Treatment-Experienced

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Model Description

Part 1 (Sentinel Cohort followed by a Randomized Cohort), 14-day washout period, then Part 2

Masking

ParticipantInvestigator

Masking Description

Part 1 Sentinel Cohort: Open-label, non-randomized Part 1 Randomized Cohort: Double-blind, randomized Part 2: Open-label, non-randomized

Allocation

Randomized

Enrollment

55 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1 Sentinel Cohort (TAF)

Arm Type

Experimental

Arm Description

TAF + their current failing ARV regimen for 10 days in Part 1

Arm Title

Part 1 Randomized Cohort (TAF)

Arm Type

Experimental

Arm Description

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.

Arm Title

Part 1 Randomized Cohort (Placebo)

Arm Type

Placebo Comparator

Arm Description

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.

Arm Title

Part 2 E/C/F/TAF+ATV

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

TAF

Other Intervention Name(s)

Vemlidy®, GS-7340

Intervention Description

25 mg tablet administered orally once daily with food

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Tablets to match TAF administered orally once daily with food

Intervention Type

Drug

Intervention Name(s)

E/C/F/TAF

Other Intervention Name(s)

Genvoya®

Intervention Description

150/150/200/10 mg STR administered orally once daily with food

Intervention Type

Drug

Intervention Name(s)

Current failing ARV regimen

Intervention Description

Participants will continue taking their current ARV regimen as prescribed in Part 1.

Intervention Type

Drug

Intervention Name(s)

ATV

Other Intervention Name(s)

Reyataz®

Intervention Description

300 mg tablet administered orally once daily.

Primary Outcome Measure Information:

Title

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 Measure Information:

Title

Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10

Time Frame

Baseline; Day 10

Title

Time Frame

Up to Week 24

Title

Time Frame

Up to Week 48

Title

Time Frame

Up to Week 24

Title

Time Frame

Up to Week 48

Title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

Description

Time Frame

Week 24

Title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

Description

Time Frame

Week 48

Title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

Description

Time Frame

Week 24

Title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

Description

Time Frame

Week 48

Title

Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24

Time Frame

Baseline; Week 24

Title

Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48

Time Frame

Baseline; Week 48

Title

Part 2: Change From Baseline in CD4+ Cell Count at Week 24

Time Frame

Baseline; Week 24

Title

Part 2: Change From Baseline in CD4+ Cell Count at Week 48

Time Frame

Baseline; Week 48

Title

Part 2: Change From Baseline in CD4+ Percentage at Week 24

Time Frame

Baseline; Week 24

Title

Part 2: Change From Baseline in CD4+ Percentage at Week 48

Time Frame

Baseline; Week 48

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gilead Study Director

Organizational Affiliation

Gilead Sciences

Official's Role

Study Director

Facility Information:

Facility Name

Midway Immunology and Research center

City

Fort Pierce

State/Province

Florida

ZIP/Postal Code

34982

Country

United States

Facility Name

Triple O Research Institute, P.A.

City

West Palm Beach

State/Province

Florida

ZIP/Postal Code

33401

Country

United States

Facility Name

Rowan Tree Medical, P.A.

City

Wilton Manors

State/Province

Florida

ZIP/Postal Code

33305

Country

United States

Facility Name

Wake Forest University Health Sciences

City

Winston-Salem

State/Province

North Carolina

ZIP/Postal Code

27157

Country

United States

Facility Name

Penn Presbyterian Medical Center

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Salvador B Gautier Hospital - Infectious Diseases Department

City

Santo Domingo

ZIP/Postal Code

10514

Country

Dominican Republic

Facility Name

Instituto Dominicano de Estudio Virologicos - IDEV

City

Santo Domingo

Country

Dominican Republic

Facility Name

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

City

Krasnoyarsk

ZIP/Postal Code

660049

Country

Russian Federation

Facility Name

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

City

Saint Petersburg

ZIP/Postal Code

190020

Country

Russian Federation

Facility Name

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

City

Bangkok

ZIP/Postal Code

10330

Country

Thailand

Facility Name

Ramathibodi Hospital, Mahidol University

City

Bangkok

ZIP/Postal Code

10400

Country

Thailand

Facility Name

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

City

Bangkok

ZIP/Postal Code

10700

Country

Thailand

Facility Name

Chiang Mai University

City

Chiang Mai

ZIP/Postal Code

50200

Country

Thailand

Facility Name

Khon Kaen University

City

Khon Kaen

ZIP/Postal Code

40002

Country

Thailand

Facility Name

Joint Clinical Research Centre

City

Kampala

Country

Uganda

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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 URL

http://www.gilead.com/research/disclosure-and-transparency

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