HIV-1 Infection
Conditions
Keywords
HIV, HIV-1 Positive, Virologically-suppressed
Brief summary
This study will evaluate the efficacy of switching from emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) fixed dose combination (FDC) to emtricitabine/tenofovir alafenamide (F/TAF) FDC in HIV-1 positive participants who are virologically suppressed on regimens containing FTC/TDF. This study will consist of a 96 week double-blind treatment period. After Week 96, all participants will continue on blinded study drug treatment and attend visits every 12 weeks until treatment assignments are unblinded. All participants will return for an unblinding visit and will be given the option to receive open-label F/TAF and attend visits every 12 weeks until F/TAF is commercially available, or the sponsor terminates the F/TAF clinical development program.
Interventions
DRUGFTC/TDF
200/300 mg FDC tablets administered orally once daily
DRUGF/TAF
Tablets administered orally once daily
DRUGAllowed third antiretroviral agent
An allowed third antiretroviral agent of the participant's pre-existing regimen may include one of the following: ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted lopinavir (LPV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV; Sustiva®), rilpivirine (RPV; Edurant®), nevirapine (NVP;Viramune®), raltegravir (RAL; Isentress®), dolutegravir (DTG;Tivicay®), and maraviroc (MVC; Selzentry®).
DRUGFTC/TDF Placebo
Tablets administered orally once daily
DRUGF/TAF Placebo
Tablets administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 receiving antiretroviral regimen containing FTC/TDF in combination with one third agent for ≥ 6 consecutive months prior to screening. * Plasma HIV-1 RNA levels \< 50 copies/mL for at least 6 months preceding the screening visit (measured at least twice using the same assay) and not experienced two consecutive HIV-1 RNA above detectable levels after achieving a confirmed (two consecutive) HIV-1 RNA below detectable levels on the current regimen in the past year. * Plasma HIV-1 RNA should be \< 50 copies/mL at the screening visit. * Normal electrocardiogram (ECG) * Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min according to the Cockcroft-Gault formula for creatinine clearance * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × the upper limit of the normal range (ULN) * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin (individuals with documented Gilbert's syndrome or with Atazanavir-associated hyperbilirubinemia may have total bilirubin up to 5 x ULN) * Adequate hematologic function * Serum amylase ≤ 5 × ULN * Females of childbearing potential must agree to utilize highly effective contraception methods or be non-heterosexually active, or practice abstinence from screening throughout the duration of the study treatment and for 30 days following the last dose of the study drug. * Females who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian hormonal failure must have a serum follicle stimulating hormone (FSH) level at screening within the post-menopausal range based on the Central Laboratory reference range. * 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. Key
Exclusion criteria
* A new AIDS-defining condition diagnosed within the 30 days prior to screening * Hepatitis C virus (HCV) antibody positive and HCV RNA detectable * Individuals experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.) * Individuals receiving ongoing treatment with bisphosphonate to treat bone disease (eg, osteoporosis) * Females who are breastfeeding * Positive serum pregnancy test * Have an implanted defibrillator or pacemaker * Current alcohol or substance use judged by the investigator to potentially interfere with study compliance * A 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. * Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 Visit * Individuals receiving ongoing therapy with any of the medications not to be used with FTC, TAF, TDF or other antiretroviral third agents. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis | Week 48 | The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | Baseline; Week 48 | Hip BMD was assessed by dual energy x-ray absorptiometry (DXA) scan. |
| Percentage Change From Baseline in Spine BMD at Week 48 | Baseline; Week 48 | Spine BMD was assessed by DXA scan. |
| Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis | Week 48 | The percentage of participants achieving HIV-1 RNA \< 20 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
| Change From Baseline in CD4+ Cell Count at Week 48 | Baseline; Week 48 | — |
| Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 96 as Defined by the FDA Snapshot Analysis | Week 96 | The percentage of participants achieving HIV-1 RNA \< 20 copies/mL at Week 96 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 96 as Defined by the FDA Snapshot Analysis | Week 96 | The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
| Percentage Change From Baseline in Hip BMD at Week 96 | Baseline; Week 96 | Hip BMD was assessed by DXA scan. |
| Percentage Change From Baseline in Spine BMD at Week 96 | Baseline; Week 96 | Spine BMD was assessed by DXA scan. |
| Change From Baseline in CD4+ Cell Count at Week 96 | Baseline; Week 96 | — |
Countries
Belgium, Canada, France, Italy, Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America and Europe. The first participant was screened on 06 May 2014. The last study visit occurred on 1 March 2019.
Pre-assignment details
780 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| F/TAF + 3rd Agent Double-Blind Phase: F/TAF (200/25 mg or 200/10 mg) tablet + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) placebo tablet + third agent administered orally once daily for at least 96 weeks. | 333 |
| FTC/TDF + 3rd Agent Double-Blind Phase: FTC/TDF 200/300 mg tablet + F/TAF placebo tablet + third agent administered orally once daily for at least 96 weeks. | 330 |
| Total | 663 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Phase | Adverse Event | 5 | 0 |
| Double-Blind Phase | Death | 1 | 1 |
| Double-Blind Phase | Lost to Follow-up | 7 | 4 |
| Double-Blind Phase | Non-Compliance with Study Drug | 3 | 1 |
| Double-Blind Phase | Physician Decision | 2 | 5 |
| Double-Blind Phase | Protocol Violation | 0 | 3 |
| Double-Blind Phase | Randomized but Never Treated | 1 | 4 |
| Double-Blind Phase | Withdrawal by Subject | 19 | 16 |
| Open-Label Phase | Lost to Follow-up | 1 | 0 |
| Open-Label Phase | Physician Decision | 8 | 8 |
| Open-Label Phase | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | FTC/TDF + 3rd Agent | F/TAF + 3rd Agent | Total |
|---|---|---|---|
| Age, Continuous | 48 Years STANDARD_DEVIATION 9.7 | 47 Years STANDARD_DEVIATION 9.9 | 48 Years STANDARD_DEVIATION 9.8 |
| Baseline Third Agent Atazanavir boosted with ritonavir (ATV/r) | 50 participants | 53 participants | 103 participants |
| Baseline Third Agent Darunavir boosted with ritonavir (DRV/r) | 82 participants | 84 participants | 166 participants |
| Baseline Third Agent Dolutegravir (DTG) | 23 participants | 26 participants | 49 participants |
| Baseline Third Agent Efavirenz (EFV) | 6 participants | 8 participants | 14 participants |
| Baseline Third Agent Lopinavir boosted with ritonavir (LPV/r) | 18 participants | 18 participants | 36 participants |
| Baseline Third Agent Maraviroc (MVC) | 6 participants | 1 participants | 7 participants |
| Baseline Third Agent Nevirapine (NVP) | 66 participants | 74 participants | 140 participants |
| Baseline Third Agent Raltegravir (RAL) | 73 participants | 66 participants | 139 participants |
| Baseline Third Agent Rilpivirine (RPV) | 6 participants | 3 participants | 9 participants |
| CD4 Cell Count | 667 cells/µL STANDARD_DEVIATION 272.3 | 691 cells/µL STANDARD_DEVIATION 272.6 | 679 cells/µL STANDARD_DEVIATION 272.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 78 Participants | 48 Participants | 126 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 252 Participants | 285 Participants | 537 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HIV-1 RNA Categories < 50 copies/mL | 326 participants | 329 participants | 655 participants |
| HIV-1 RNA Categories >= 50 copies/mL | 4 participants | 4 participants | 8 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 6 participants | 6 participants |
| Race/Ethnicity, Customized Black | 67 participants | 69 participants | 136 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Not Permitted | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Other | 7 participants | 9 participants | 16 participants |
| Race/Ethnicity, Customized White | 253 participants | 244 participants | 497 participants |
| Region of Enrollment Belgium | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Canada | 9 participants | 5 participants | 14 participants |
| Region of Enrollment France | 21 participants | 18 participants | 39 participants |
| Region of Enrollment Italy | 6 participants | 2 participants | 8 participants |
| Region of Enrollment United Kingdom | 17 participants | 23 participants | 40 participants |
| Region of Enrollment United States | 274 participants | 282 participants | 556 participants |
| Sex: Female, Male Female | 54 Participants | 48 Participants | 102 Participants |
| Sex: Female, Male Male | 276 Participants | 285 Participants | 561 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 | 2 / 333 | 1 / 330 | 0 / 33 | 0 / 31 |
| other Total, other adverse events | 242 / 333 | 226 / 330 | 12 / 33 | 13 / 31 |
| serious Total, serious adverse events | 29 / 333 | 31 / 330 | 2 / 33 | 3 / 31 |
Outcome results
Primary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis
The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Week 48
Population: The Full Analysis Set included all participants who were randomized into the study and received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| F/TAF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis | 94.3 percentage of participants |
| FTC/TDF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis | 93.0 percentage of participants |
p-value: 0.595.002% CI: [-2.5, 5.1]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in CD4+ Cell Count at Week 48
Time frame: Baseline; Week 48
Population: Participants in the Full Analysis Set with on-treatment data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| F/TAF + 3rd Agent | Change From Baseline in CD4+ Cell Count at Week 48 | 20 cells/μL | Standard Deviation 161.8 |
| FTC/TDF + 3rd Agent | Change From Baseline in CD4+ Cell Count at Week 48 | 21 cells/μL | Standard Deviation 152.7 |
Secondary
Change From Baseline in CD4+ Cell Count at Week 96
Time frame: Baseline; Week 96
Population: Participants in the Full Analysis Set with on-treatment data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| F/TAF + 3rd Agent | Change From Baseline in CD4+ Cell Count at Week 96 | 50 cells/μL | Standard Deviation 198.7 |
| FTC/TDF + 3rd Agent | Change From Baseline in CD4+ Cell Count at Week 96 | 46 cells/μL | Standard Deviation 169.4 |
Secondary
Percentage Change From Baseline in Hip BMD at Week 96
Hip BMD was assessed by DXA scan.
Time frame: Baseline; Week 96
Population: Participants in the Hip DXA Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| F/TAF + 3rd Agent | Percentage Change From Baseline in Hip BMD at Week 96 | 1.856 percentage change | Standard Deviation 3.2195 |
| FTC/TDF + 3rd Agent | Percentage Change From Baseline in Hip BMD at Week 96 | -0.289 percentage change | Standard Deviation 2.9912 |
Secondary
Percentage Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48
Hip BMD was assessed by dual energy x-ray absorptiometry (DXA) scan.
Time frame: Baseline; Week 48
Population: Participants in the Hip DXA Analysis Set (participants who were randomized and received at least one dose of study drug and had nonmissing baseline hip BMD data) with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| F/TAF + 3rd Agent | Percentage Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | 1.236 percentage change | Standard Deviation 2.6602 |
| FTC/TDF + 3rd Agent | Percentage Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | -0.071 percentage change | Standard Deviation 2.3316 |
Secondary
Percentage Change From Baseline in Spine BMD at Week 48
Spine BMD was assessed by DXA scan.
Time frame: Baseline; Week 48
Population: Participants in the Spine DXA Analysis Set (participants who were randomized and received at least one dose of study drug and had nonmissing baseline spine BMD data) with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| F/TAF + 3rd Agent | Percentage Change From Baseline in Spine BMD at Week 48 | 1.662 percentage change | Standard Deviation 3.1279 |
| FTC/TDF + 3rd Agent | Percentage Change From Baseline in Spine BMD at Week 48 | -0.109 percentage change | Standard Deviation 3.3476 |
Secondary
Percentage Change From Baseline in Spine BMD at Week 96
Spine BMD was assessed by DXA scan.
Time frame: Baseline; Week 96
Population: Participants in the Spine DXA Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| F/TAF + 3rd Agent | Percentage Change From Baseline in Spine BMD at Week 96 | 2.159 percentage change | Standard Deviation 3.8374 |
| FTC/TDF + 3rd Agent | Percentage Change From Baseline in Spine BMD at Week 96 | -0.109 percentage change | Standard Deviation 3.6738 |
Secondary
Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis
The percentage of participants achieving HIV-1 RNA \< 20 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Week 48
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| F/TAF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis | 91.6 percentage of participants |
| FTC/TDF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 as Defined by the FDA Snapshot Analysis | 90.9 percentage of participants |
Secondary
Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 96 as Defined by the FDA Snapshot Analysis
The percentage of participants achieving HIV-1 RNA \< 20 copies/mL at Week 96 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Week 96
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| F/TAF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 96 as Defined by the FDA Snapshot Analysis | 83.5 percentage of participants |
| FTC/TDF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 96 as Defined by the FDA Snapshot Analysis | 86.1 percentage of participants |
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 96 as Defined by the FDA Snapshot Analysis
The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm, which defines a participant's virologic response using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Week 96
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| F/TAF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 96 as Defined by the FDA Snapshot Analysis | 88.6 percentage of participants |
| FTC/TDF + 3rd Agent | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 96 as Defined by the FDA Snapshot Analysis | 89.1 percentage of participants |