HIV-1 Infection
Conditions
Keywords
HIV, HIV-1, Antiretroviral Treatment-Naive
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) versus ritonavir-boosted atazanavir (ATV+RTV) plus FTC/TDF in HIV-1 infected, antiretroviral treatment-naive adults. Participants will be randomized in a 2:1 ratio. Randomization will be stratified by HIV-1 RNA level (≤ 100,000 copies/mL or \> 100,000 copies/mL) at screening. After Week 48, participants will continue to take their blinded study drug and attend visits every 12 weeks until treatment assignments are unblinded, at which point all participants will return for an unblinding visit and be given the option to participate in an open-label rollover extension and receive ATV+COBI+FTC/TDF until COBI tablets become commercially available, or until Gilead Sciences elects to terminate the study.
Interventions
DRUGCOBI
Cobicistat (COBI) 150 mg tablet administered orally once daily
DRUGRTV
Ritonavir (RTV) 100 mg soft gelatin capsule 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, Caregiver, Investigator)
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 * Plasma HIV-1 RNA levels ≥ 5,000 copies/mL * No prior use of any approved or experimental anti-HIV drug * Normal ECG (or if abnormal, determined by the investigator to be not clinically significant) * Adequate renal function (estimated glomerular filtration rate ≥ 80 mL/min according to the Cockcroft-Gault formula) * Hepatic transaminases ≤ 2.5 × upper limit of normal * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Adequate hematologic function (absolute neutrophil count ≥ 1000/mm\^3; platelets ≥ 50,000/mm\^3; hemoglobin ≥ 8.5 g/dL) * Cluster of differentiation 4 (CD4) cell count \> 50 cells/µL * Serum amylase ≤ 1.5 × ULN (subjects with serum amylase \>1.5 × ULN remained eligible if serum lipase is ≤ 1.5 × ULN) * Normal thyroid-stimulating hormone * Negative serum pregnancy test (females of childbearing potential only) * 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 drugs * Age ≥ 18 years * Life expectancy ≥ 1 year
Exclusion criteria
* New AIDS-defining condition diagnosed within the 30 days prior to screening * Documented drug resistance to nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), or primary PI resistance mutation(s) * Hepatitis B surface antigen positive * Hepatitis C antibody positive * Participants experiencing cirrhosis * Participants experiencing ascites * Participants experiencing encephalopathy * Females who are breastfeeding * Positive serum pregnancy test (female of childbearing potential) * Vaccinated within 90 days of study dosing * History or family history of Long QT Syndrome or have a family history of sudden cardiac death or unexplained death in an otherwise healthy individual under the age of 30 years * Presence or history of cardiovascular disease, cardiomyopathy, and/or cardiac conduction abnormalities * Prolonged QTcF (QT interval corrected for heart rate using Fridericia's formula) interval at screening (eg, a prolongation of the QTcF interval of greater than 450 msec for males and greater than 470 msec for females) * PR interval greater than or equal to 200 msec or less than or equal to 120 msec on ECG at screening * QRS greater than or equal to 120 msec on ECG at screening * Implanted defibrillator or pacemaker * Subjects receiving ongoing therapy with any disallowed medications * Current alcohol or substance use judged to potentially interfere with subject study compliance * History of or ongoing malignancy (including untreated carcinoma in-situ) other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, noninvasive cutaneous squamous carcinoma * Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline * Participation in any other clinical trial without prior approval * Medications contraindicated for use with ATV, RTV, FTC, or TDF * Any known allergies to the excipients of ATV capsules, RTV capsules, COBI tablets or FTC/TDF tablets * Any other clinical condition or prior therapy that 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 24 | Week 24 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 24 was analyzed using the missing = failure method, where participants with missing data were considered to have failed to achieve the endpoint. |
Secondary
| 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 missing = failure method. |
| Change From Baseline in HIV-1 RNA at Week 24 | Baseline to Week 24 | The change from baseline in log\_10 HIV-1 RNA at Week 24 was analyzed. |
| Change From Baseline in HIV-1 RNA at Week 48 | Baseline to Week 48 | The change from baseline in log\_10 HIV-1 RNA at Week 48 was analyzed. |
| Change From Baseline in CD4 Cell Count at Week 24 | Baseline to Week 24 | The change from baseline in CD4 cell count at Week 24 was analyzed. |
| Change From Baseline in CD4 Cell Count at Week 48 | Baseline to Week 48 | The change from baseline in CD4 cell count at Week 48 was analyzed. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled and treated in 32 study centers in the United States. The first participant was screened on 04 May 2009, and the last study visit occurred on 15 January 2015.
Pre-assignment details
137 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| ATV+COBI+FTC/TDF Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily | 50 |
| ATV+RTV+FTC/TDF Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily | 29 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-Label Extension Phase | Adverse Event | 4 | 2 |
| Open-Label Extension Phase | Investigator's Discretion | 1 | 0 |
| Open-Label Extension Phase | Lack of Efficacy | 1 | 0 |
| Open-Label Extension Phase | Lost to Follow-up | 3 | 1 |
| Open-Label Extension Phase | Withdrew Consent | 3 | 1 |
| Randomized Phase | Adverse Event | 2 | 2 |
| Randomized Phase | Investigator's Discretion | 1 | 0 |
| Randomized Phase | Lost to Follow-up | 1 | 3 |
| Randomized Phase | Randomized but not treated | 6 | 0 |
| Randomized Phase | Withdrew Consent | 1 | 0 |
Baseline characteristics
| Characteristic | ATV+COBI+FTC/TDF | ATV+RTV+FTC/TDF | Total |
|---|---|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 9.6 | 34 years STANDARD_DEVIATION 10.1 | 36 years STANDARD_DEVIATION 9.8 |
| CD4 Cell Count Category 201 to ≤ 350 cells/μL | 16 participants | 7 participants | 23 participants |
| CD4 Cell Count Category 351 to ≤ 500 cells/μL | 17 participants | 11 participants | 28 participants |
| CD4 Cell Count Category > 500 cells/μL | 7 participants | 4 participants | 11 participants |
| CD4 Cell Count Category ≤ 50 cells/μL | 1 participants | 1 participants | 2 participants |
| CD4 Cell Count Category 51 to ≤ 200 cells/μL | 9 participants | 6 participants | 15 participants |
| Chronic Hepatitis B Infection Status Negative | 50 participants | 29 participants | 79 participants |
| Chronic Hepatitis B Infection Status Positive | 0 participants | 0 participants | 0 participants |
| Chronic Hepatitis C Infection Status Negative | 50 participants | 29 participants | 79 participants |
| Chronic Hepatitis C Infection Status Positive | 0 participants | 0 participants | 0 participants |
| Cluster of differentiation (CD4) Cell Count | 365 cells/uL STANDARD_DEVIATION 201.3 | 343 cells/uL STANDARD_DEVIATION 178.1 | 357 cells/uL STANDARD_DEVIATION 192.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 24 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HIV-1 RNA | 4.56 log_10 copies/mL STANDARD_DEVIATION 0.657 | 4.69 log_10 copies/mL STANDARD_DEVIATION 0.53 | 4.61 log_10 copies/mL STANDARD_DEVIATION 0.614 |
| HIV-1 RNA Category ≤ 100,000 copies/mL | 38 participants | 18 participants | 56 participants |
| HIV-1 RNA Category > 100,000 copies/mL | 12 participants | 11 participants | 23 participants |
| HIV Disease Status AIDS | 8 participants | 3 participants | 11 participants |
| HIV Disease Status Asymptomatic | 41 participants | 25 participants | 66 participants |
| HIV Disease Status Symptomatic HIV Infections | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Black | 18 participants | 9 participants | 27 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 31 participants | 16 participants | 47 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 47 Participants | 25 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 50 | 23 / 29 | 54 / 69 |
| serious Total, serious adverse events | 2 / 50 | 2 / 29 | 13 / 69 |
Outcome results
Primary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 24 was analyzed using the missing = failure method, where participants with missing data were considered to have failed to achieve the endpoint.
Time frame: Week 24
Population: 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 24 | 84.0 percentage of participants |
| ATV+RTV+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 | 89.7 percentage of participants |
Comparison: A total planned sample size of 75 subjects had 26% power to evaluate noninferiority with respect to the response rate of HIV-1 RNA \< 50 copies/mL at Week 24 if a response rate of 84% for both arms and a noninferiority margin of 0.12 were assumed.95% CI: [-24.6, 9.9]
Secondary
Change From Baseline in CD4 Cell Count at Week 24
The change from baseline in CD4 cell count at Week 24 was analyzed.
Time frame: Baseline to Week 24
Population: Participants in the ITT Analysis Set with available change data at Week 24 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ATV+COBI+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 24 | 200 cells/μL | Standard Deviation 164.6 |
| ATV+RTV+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 24 | 202 cells/μL | Standard Deviation 115.1 |
p-value: 0.7895% CI: [-63, 84]ANOVA
Secondary
Change From Baseline in CD4 Cell Count at Week 48
The change from baseline in CD4 cell count at Week 48 was analyzed.
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 | 243 cells/μL | Standard Deviation 186.5 |
| ATV+RTV+FTC/TDF | Change From Baseline in CD4 Cell Count at Week 48 | 213 cells/μL | Standard Deviation 168.2 |
p-value: 0.2995% CI: [-41, 134]ANOVA
Secondary
Change From Baseline in HIV-1 RNA at Week 24
The change from baseline in log\_10 HIV-1 RNA at Week 24 was analyzed.
Time frame: Baseline to Week 24
Population: Participants in the ITT Analysis Set with available change data at Week 24 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ATV+COBI+FTC/TDF | Change From Baseline in HIV-1 RNA at Week 24 | -2.80 log_10 copies/mL | Standard Deviation 0.619 |
| ATV+RTV+FTC/TDF | Change From Baseline in HIV-1 RNA at Week 24 | -2.97 log_10 copies/mL | Standard Deviation 0.707 |
p-value: 0.8795% CI: [-0.25, 0.22]ANOVA
Secondary
Change From Baseline in HIV-1 RNA at Week 48
The change from baseline in log\_10 HIV-1 RNA at Week 48 was analyzed.
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 HIV-1 RNA at Week 48 | -2.79 log_10 copies/mL | Standard Deviation 0.678 |
| ATV+RTV+FTC/TDF | Change From Baseline in HIV-1 RNA at Week 48 | -2.96 log_10 copies/mL | Standard Deviation 0.765 |
p-value: 0.8295% CI: [-0.3, 0.23]ANOVA
Secondary
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 missing = failure method.
Time frame: Week 48
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATV+COBI+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 82.0 percentage of participants |
| ATV+RTV+FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 89.7 percentage of participants |
95% CI: [-25.9, 9.4]