HIV, HIV Infections
Conditions
Keywords
Treatment Naive, HIV 1 Infected
Brief summary
The objective of this study is to evaluate the safety and efficacy of a regimen containing cobicistat-boosted atazanavir (ATV+COBI) plus emtricitabine/tenofovir disoproxil fumarate (Truvada®; FTC/TDF) fixed-dose combination (FDC) versus ritonavir-boosted atazanavir (ATV+RTV) plus FTC/TDF FDC in HIV-1 infected, antiretroviral treatment-naive adults. Participants will be randomized in a 1:1 ratio. Randomization will be stratified by HIV-1 RNA level (≤ 100,000 copies/mL or \> 100,000 copies/mL) at screening.
Interventions
DRUGCOBI
Cobicistat (COBI) 150 mg tablet administered orally once daily
DRUGRTV
Ritonavir (RTV) 100 mg tablet administered orally once daily
DRUGATV
Atazanavir (ATV) 300 mg capsule administered orally once daily
DRUGFTC/TDF
Emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg fixed-dose combination tablet administered orally once daily
DRUGCOBI placebo
Placebo to match COBI administered orally once daily
DRUGRTV placebo
Placebo to match RTV administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures * Plasma HIV-1 RNA levels ≥ 5,000 copies/mL at screening * No prior use of any approved or investigational antiretroviral drug for any length of time * Screening genotype report must show sensitivity to FTC, TDF and ATV * Normal ECG * Adequate renal function (eGFR calculated using the Cockcroft-Gault equation ≥ 70 mL/min) * Hepatic transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Adequate hematologic function * Serum amylase ≤ 5 x ULN * Males and females of childbearing potential must agree to utilize highly effective contraception methods from screening throughout the duration of study treatment and for 30 days following the last dose of study drug. * Age ≥ 18 years * Life expectancy ≥ 1 year
Exclusion criteria
* A new AIDS-defining condition diagnosed within the 30 days prior to screening * Receiving drug treatment for Hepatitis C, or anticipated to receive treatment for Hepatitis C * Subjects experiencing decompensated cirrhosis * Females who are breastfeeding * Positive serum pregnancy test (female of childbearing potential) * Have an implanted defibrillator or pacemaker * Have an ECG PR interval ≥ 220 msec * Current alcohol or substance use judged by the Investigator to potentially interfere with subject study compliance. * A history of malignancy within the past 5 years 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 baseline. * Medications contraindicated for use with COBI, emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), atazanavir (ATV), ritonavir (RTV) or subjects with any known allergies to the excipients of COBI tablets, Truvada tablets, atazanavir capsules or ritonavir tablets. * Participation in any other clinical trial without prior approval from the sponsor is prohibited while participating in this trial. * Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with the dosing requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL 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 prespecified time point within an allowed window of time, along with study drug discontinuation status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 144 | Week 144 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 144 was analyzed using the snapshot algorithm. |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 192 | Week 192 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 192 was analyzed using the snapshot algorithm. |
| Change From Baseline in CD4 Cell Count at Week 48 | Baseline to Week 48 | — |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 | Week 96 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm. |
| Change From Baseline in CD4 Cell Count at Week 144 | Baseline to Week 144 | — |
| Change From Baseline in CD4 Cell Count at Week 192 | Baseline to Week 192 | — |
| Change From Baseline in CD4 Cell Count at Week 96 | Baseline to Week 96 | — |
Countries
Australia, Austria, Belgium, Brazil, Canada, Denmark, Dominican Republic, France, Germany, Italy, Mexico, Netherlands, Portugal, Puerto Rico, Spain, Switzerland, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in a total of 144 study sites in Asia, Australia, Europe, and South and North America. The last study visit occurred on 17 April 2015.
Pre-assignment details
867 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| ATV+COBI+FTC/TDF COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily | 344 |
| ATV+RTV+FTC/TDF RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily | 348 |
| Total | 692 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 26 | 19 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Investigator's Discretion | 12 | 10 |
| Overall Study | Joined Another Gilead-sponsored Study | 186 | 195 |
| Overall Study | Lack of Efficacy | 3 | 0 |
| Overall Study | Lost to Follow-up | 20 | 17 |
| Overall Study | Participant Noncompliance | 5 | 7 |
| Overall Study | Pregnancy | 0 | 3 |
| Overall Study | Randomized but Not Treated | 5 | 1 |
| Overall Study | Withdrew Consent | 21 | 15 |
Baseline characteristics
| Characteristic | Total | ATV+RTV+FTC/TDF | ATV+COBI+FTC/TDF |
|---|---|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 9.7 | 38 years STANDARD_DEVIATION 9.6 | 37 years STANDARD_DEVIATION 9.8 |
| CD4 Cell Count Category 201 to ≤ 350 cells/μL | 240 participants | 126 participants | 114 participants |
| CD4 Cell Count Category 351 to ≤ 500 cells/μL | 240 participants | 117 participants | 123 participants |
| CD4 Cell Count Category > 500 cells/μL | 95 participants | 48 participants | 47 participants |
| CD4 Cell Count Category ≤ 50 cells/μL | 23 participants | 12 participants | 11 participants 3.2 |
| CD4 Cell Count Category 51 to ≤ 200 cells/μL | 94 participants | 45 participants | 49 participants |
| Cluster of differentiation (CD4) Cell Count | 352 cells/µL STANDARD_DEVIATION 172.9 | 351 cells/µL STANDARD_DEVIATION 175.5 | 353 cells/µL STANDARD_DEVIATION 170.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 189 Participants | 92 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 498 Participants | 253 Participants | 245 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 2 Participants |
| Hepatitis B Surface Antigen Status Negative | 667 participants | 339 participants | 328 participants |
| Hepatitis B Surface Antigen Status Positive | 25 participants | 9 participants | 16 participants |
| Hepatitis C Antibody Status Indeterminate | 1 participants | 1 participants | 0 participants |
| Hepatitis C Antibody Status Negative | 654 participants | 331 participants | 323 participants |
| Hepatitis C Antibody Status Positive | 37 participants | 16 participants | 21 participants |
| HIV-1 RNA | 4.83 log10 copies/mL STANDARD_DEVIATION 0.589 | 4.84 log10 copies/mL STANDARD_DEVIATION 0.594 | 4.81 log10 copies/mL STANDARD_DEVIATION 0.585 |
| HIV-1 RNA Category ≤ 100,000 copies/mL | 417 participants | 205 participants | 212 participants |
| HIV-1 RNA Category > 100,000 copies/mL | 275 participants | 143 participants | 132 participants |
| HIV Disease Status AIDS | 52 participants | 24 participants | 28 participants |
| HIV Disease Status Asymptomatic | 577 participants | 292 participants | 285 participants |
| HIV Disease Status Symptomatic HIV Infections | 63 participants | 32 participants | 31 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 81 participants | 37 participants | 44 participants |
| Race/Ethnicity, Customized Black or African Heritage | 128 participants | 63 participants | 65 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Permitted | 5 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized Other | 60 participants | 27 participants | 33 participants |
| Race/Ethnicity, Customized White | 413 participants | 215 participants | 198 participants |
| Region of Enrollment Australia | 15 participants | 8 participants | 7 participants |
| Region of Enrollment Austria | 18 participants | 5 participants | 13 participants |
| Region of Enrollment Belgium | 18 participants | 11 participants | 7 participants |
| Region of Enrollment Brazil | 35 participants | 17 participants | 18 participants |
| Region of Enrollment Canada | 44 participants | 18 participants | 26 participants |
| Region of Enrollment Denmark | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Dominican Republic | 58 participants | 31 participants | 27 participants |
| Region of Enrollment France | 31 participants | 19 participants | 12 participants |
| Region of Enrollment Germany | 38 participants | 21 participants | 17 participants |
| Region of Enrollment Italy | 21 participants | 15 participants | 6 participants |
| Region of Enrollment Mexico | 35 participants | 17 participants | 18 participants |
| Region of Enrollment Netherlands | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Portugal | 14 participants | 5 participants | 9 participants |
| Region of Enrollment Spain | 7 participants | 4 participants | 3 participants |
| Region of Enrollment Switzerland | 15 participants | 12 participants | 3 participants |
| Region of Enrollment Thailand | 66 participants | 31 participants | 35 participants |
| Region of Enrollment United Kingdom | 32 participants | 18 participants | 14 participants |
| Region of Enrollment United States | 248 participants | 114 participants | 134 participants |
| Sex: Female, Male Female | 118 Participants | 61 Participants | 57 Participants |
| Sex: Female, Male Male | 574 Participants | 287 Participants | 287 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 311 / 344 | 312 / 348 |
| serious Total, serious adverse events | 64 / 344 | 50 / 348 |
Outcome results
Primary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL 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 prespecified time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Week 48
Population: Intent-to-Treat (ITT) Analysis Set: participants who were randomized and received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATV+COBI+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 85.2 percentage of participants |
| ATV+RTV+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 87.4 percentage of participants |
Comparison: 700 planned subjects had 95% power to evaluate noninferiority assuming a response rate of 79.5% for both arms and a noninferiority margin of 12%.95.2% CI: [-7.4, 3]
Secondary
Change From Baseline in CD4 Cell Count at Week 144
Time frame: Baseline to Week 144
Population: Participants in the ITT Analysis Set with available change data at Week 144 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ATV+COBI+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 144 | 310 cells/μL | Standard Deviation 188 |
| ATV+RTV+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 144 | 332 cells/μL | Standard Deviation 199.8 |
p-value: 0.1895% CI: [-54, 10]ANOVA
Secondary
Change From Baseline in CD4 Cell Count at Week 192
Time frame: Baseline to Week 192
Population: Participants in the ITT Analysis Set with available change data at Week 192 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ATV+COBI+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 192 | 350 cells/μL | Standard Deviation 191.3 |
| ATV+RTV+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 192 | 343 cells/μL | Standard Deviation 190.7 |
p-value: 0.8495% CI: [-55, 67]ANOVA
Secondary
Change From Baseline in CD4 Cell Count at Week 48
Time frame: Baseline to Week 48
Population: Participants in the ITT Analysis Set with available change data at Week 48 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ATV+COBI+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 48 | 213 cells/μL | Standard Deviation 151 |
| ATV+RTV+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 48 | 219 cells/μL | Standard Deviation 150.4 |
p-value: 0.6795% CI: [-28, 18]ANOVA
Secondary
Change From Baseline in CD4 Cell Count at Week 96
Time frame: Baseline to Week 96
Population: Participants in the ITT Analysis Set with available change data at Week 96 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ATV+COBI+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 96 | 277 cells/μL | Standard Deviation 176.8 |
| ATV+RTV+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 96 | 287 cells/μL | Standard Deviation 181.5 |
p-value: 0.5195% CI: [-38, 19]ANOVA
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 144
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 144 was analyzed using the snapshot algorithm.
Time frame: Week 144
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATV+COBI+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 144 | 72.1 percentage of participants |
| ATV+RTV+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 144 | 74.1 percentage of participants |
95% CI: [-8.7, 4.5]
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 192
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 192 was analyzed using the snapshot algorithm.
Time frame: Week 192
Population: Week 192 Modified ITT Analysis Set: includes participants in the ITT analysis set excluding those who either (1) transferred to other Gilead-sponsored studies after completing their Week 144 visit and before the lower limit of the Week 192 analysis window, or (2) prematurely discontinued study drug prior to the Week 144 visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATV+COBI+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 192 | 71.6 percentage of participants |
| ATV+RTV+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 192 | 79.7 percentage of participants |
95% CI: [-22.2, 6.3]
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm.
Time frame: Week 96
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATV+COBI+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 | 77.9 percentage of participants |
| ATV+RTV+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 | 79.3 percentage of participants |
95% CI: [-7.6, 4.7]