Safety and Efficacy of Cobicistat-boosted Atazanavir Compared to Ritonavir-boosted Atazanavir in Combination With Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naive Adults

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Randomized, Double-Blinded Study of the Safety and Efficacy of GS-9350-boosted Atazanavir (ATV/GS-9350) Compared to Ritonavir-boosted Atazanavir (ATV/r) in Combination With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) in HIV-1 Infected, Antiretroviral Treatment-Naive Adults

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: COBI
* Drug: RTV
* Drug: ATV
* Drug: FTC/TDF
* Drug: COBI placebo
* Drug: RTV placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATV+COBI+FTC/TDF<br>COBI + RTV placebo +ATV+FTC/TDF for 48 weeks | Drug: COBI<br>* Cobicistat (COBI) 150 mg tablet administered orally once daily<br>* Other names: GS-9350;Drug: ATV<br>* Atazanavir (ATV) 300 mg capsule administered orally once daily<br>* Other names: Reyataz®;Drug: FTC/TDF<br>* Emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg fixed-dose combination tablet administered orally once daily<br>* Other names: Truvada®;Drug: RTV placebo<br>* Placebo to match RTV administered orally once daily<br>|
| Active Comparator: ATV+RTV+FTC/TDF<br>RTV + COBI placebo +ATV+FTC/TDF for 48 weeks | Drug: RTV<br>* Ritonavir (RTV) 100 mg soft gelatin capsule administered orally once daily<br>* Other names: Norvir®;Drug: ATV<br>* Atazanavir (ATV) 300 mg capsule administered orally once daily<br>* Other names: Reyataz®;Drug: FTC/TDF<br>* Emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg fixed-dose combination tablet administered orally once daily<br>* Other names: Truvada®;Drug: COBI placebo<br>* Placebo to match COBI administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 48 | 
| 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 48 | 
| Change From Baseline in CD4 Cell Count at Week 24 | The change from baseline in CD4 cell count at Week 24 was analyzed. | Baseline to Week 24 | 
| Change From Baseline in CD4 Cell Count at Week 48 | The change from baseline in CD4 cell count at Week 48 was analyzed. | Baseline to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HIV-1, Antiretroviral Treatment-Naive