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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01967940

Enrollment

Registered

2013-10-23

Start date

2013-10-25

Completion date

2017-07-31

Last updated

2018-11-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV, HIV Infections, Acquired Immunodeficiency Syndrome

Keywords

HIV-1, HIV, Treatment-Experienced

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.

Interventions

DRUGTAF

25 mg tablet administered orally once daily with food

DRUGPlacebo

Tablets to match TAF administered orally once daily with food

DRUGE/C/F/TAF

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

DRUGCurrent failing ARV regimen

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

DRUGATV

300 mg tablet administered orally once daily.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

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

Intervention model description

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

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion 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/

Design outcomes

Primary

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

Measure	Time frame	Description
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	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	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	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 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10	Baseline; Day 10	—
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	—
Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48	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.

Countries

Dominican Republic, Russia, Thailand, Uganda, United States

Participant flow

Recruitment details

Participants were enrolled at study sites in the United States, Uganda, Thailand, Russian Federation, and Dominican Republic. The first participant was screened on 25 October 2013. The last study visit occurred on 31 July 2017.

Pre-assignment details

259 participants were screened.

Participants by arm

Arm	Count
Part 1 Sentinel Cohort TAF TAF 25 mg tablet once daily + their current failing regimen for 10 days	12
Part 1 Randomized Cohort TAF TAF 25 mg tablet once daily + their current failing regimen for 10 days	28
Part 1 Randomized Cohort Placebo Placebo once daily + their current failing regimen for 10 days	15
Total	55

Withdrawals & dropouts

Period	Reason	FG003
Part 2	Adverse Event	1
Part 2	Enrolled in Part 2 and Never Treated	1
Part 2	Unknown Reason	1

Baseline characteristics

Characteristic	Part 1 Sentinel Cohort TAF	Part 1 Randomized Cohort TAF	Part 1 Randomized Cohort Placebo	Total
Age, Continuous	38 years STANDARD_DEVIATION 7.3	40 years STANDARD_DEVIATION 9.1	43 years STANDARD_DEVIATION 8.2	40 years STANDARD_DEVIATION 8.6
CD4 Cell Count	269 cells/µL STANDARD_DEVIATION 207.1	245 cells/µL STANDARD_DEVIATION 244.6	232 cells/µL STANDARD_DEVIATION 162.4	246 cells/µL STANDARD_DEVIATION 213.7
CD4 Percentage	17.4 percentage STANDARD_DEVIATION 10.14	16.5 percentage STANDARD_DEVIATION 11.09	14.3 percentage STANDARD_DEVIATION 8.61	16.1 percentage STANDARD_DEVIATION 10.15
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants	0 Participants	1 Participants	6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants	28 Participants	14 Participants	49 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
HIV-1 RNA	4.18 log10 copies/mL STANDARD_DEVIATION 0.648	4.16 log10 copies/mL STANDARD_DEVIATION 0.544	4.03 log10 copies/mL STANDARD_DEVIATION 0.953	4.13 log10 copies/mL STANDARD_DEVIATION 0.688
HIV-1 RNA Category ≤ 100,000 copies/mL	12 Participants	27 Participants	12 Participants	51 Participants
HIV-1 RNA Category > 100,000 to ≤ 400,000 copies/mL	0 Participants	1 Participants	3 Participants	4 Participants
Race/Ethnicity, Customized Asian	0 Participants	5 Participants	5 Participants	10 Participants
Race/Ethnicity, Customized Black	3 Participants	22 Participants	9 Participants	34 Participants
Race/Ethnicity, Customized Other	5 Participants	0 Participants	1 Participants	6 Participants
Race/Ethnicity, Customized White	4 Participants	1 Participants	0 Participants	5 Participants
Region of Enrollment Dominican Republic	5 participants	0 participants	1 participants	6 participants
Region of Enrollment Russian Federation	2 participants	1 participants	0 participants	3 participants
Region of Enrollment Thailand	0 participants	5 participants	5 participants	10 participants
Region of Enrollment Uganda	0 participants	19 participants	9 participants	28 participants
Region of Enrollment United States	5 participants	3 participants	0 participants	8 participants
Sex: Female, Male Female	3 Participants	16 Participants	4 Participants	23 Participants
Sex: Female, Male Male	9 Participants	12 Participants	11 Participants	32 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 28	0 / 15	0 / 37
other Total, other adverse events	7 / 12	6 / 28	5 / 15	26 / 37
serious Total, serious adverse events	0 / 12	3 / 28	0 / 15	4 / 37

Outcome results

Primary

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

Time frame: Day 10

Population: Part 1 Full Analysis Set: participants who enrolled into Part 1 of the study and received at least one dose of study drug in Part 1.

Arm	Measure	Value (NUMBER)
Part 1 Sentinel Cohort TAF	Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10	58.3 percentage of participants
Part 1 Randomized Cohort TAF	Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10	60.7 percentage of participants
Part 1 Randomized Cohort Placebo	Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10	0 percentage of participants

Comparison: A sample size of 90 participants, randomized in a 2:1 ratio, achieves 89% power to detect a 35% difference in the proportion of participants with HIV-1 RNA decreases from baseline exceeding 0.5 log10 between the TAF and placebo arms at Day 10. Sample size and power computation was based on the assumption that 50% of participants in the TAF arm and 15% of participants in the placebo arm achieved a reduction exceeding 0.5 log10 HIV-1 RNA.p-value: <0.00195% CI: [42.6, 78.8]Fisher Exact

Secondary

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

Time frame: Baseline; Day 10

Population: Part 1 Full Analysis Set

Arm	Measure	Value (MEAN)	Dispersion
Part 1 Sentinel Cohort TAF	Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10	-0.72 log10 copies/mL	Standard Deviation 0.574
Part 1 Randomized Cohort TAF	Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10	-0.70 log10 copies/mL	Standard Deviation 0.628
Part 1 Randomized Cohort Placebo	Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10	-0.04 log10 copies/mL	Standard Deviation 0.233

Secondary