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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: COBI; Drug: ATV; Drug: FTC/TDF; Drug: RTV placebo; Drug: COBI placebo; Drug: RTV

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Southwest Center For Hiv/Aids
  • Arkansas
    • Little Rock, Arkansas, United States, 72207
      • Health for Life Clinic, PLLC
  • California
    • Beverly Hills, California, United States, 90804
      • AIDS Healthcare Foundation-Research Center
    • Long Beach, California, United States, 90813
      • The Living Hope Foundation
    • Los Angeles, California, United States, 90036
      • Peter J. Ruane, MD, Inc.
    • Newport Beach, California, United States, 92663
      • Orange Coast Medical Group
    • San Diego, California, United States, 92103
      • David J. Shamblaw, MD Inc.
    • San Francisco, California, United States, 94115
      • Metropolis Medical
  • Colorado
    • Denver, Colorado, United States, 80220
      • Denver Infectious Disease Consultants, PLLC
  • District of Columbia
    • Washington, District of Columbia, United States, 20009
      • Whitman Walker Clinic
    • Washington, District of Columbia, United States, 20009
      • Dupont Circle Physicians Group
    • Washington, District of Columbia, United States, 20036
      • Capital Medical Associates PC
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Gary Richmond, MD, PA, Inc.
    • Miami Beach, Florida, United States, 33139
      • Wohlfeiler, Piperato and Associates, LLC
    • Orlando, Florida, United States, 32806
      • ValuehealthMD, LLC
    • Tampa, Florida, United States, 33614
      • St. Joseph's Comprehensive Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • AIDS Research Consortium of Atlanta
    • Decatur, Georgia, United States, 30033
      • Infectious Disease Specialists of Atlanta (IDSA)
  • Illinois
    • Chicago, Illinois, United States, 60657
      • Northstar Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Chase Brexton Health Services, Inc.
  • Michigan
    • Berkley, Michigan, United States, 48072
      • Be Well Medical Center
  • Missouri
    • St. Louis, Missouri, United States, 63139
      • Southampton Healthcare, Inc.
    • St. Louis, Missouri, United States, 63108
      • Central West Healthcare
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • Saint Michael's Medical Center
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • Southwest C.A.R.E. Center
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Rosedale Infectious Diseases
  • Texas
    • Dallas, Texas, United States, 75215
      • AIDS Arms/ Peabody Health Center
    • Dallas, Texas, United States, 75204
      • Nicholaos Bellos, MD, PA
    • Houston, Texas, United States, 77098
      • Gordon E. Crofoot, MD, PA
    • Houston, Texas, United States, 77478
      • Therapeutic Concepts, P.A.
  • Washington
    • Seattle, Washington, United States, 98103
      • TribalMed

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Chair: Marshall Fordyce, MD, Gilead Sciences

Publications and helpful links

General Publications

• Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, Mathias AA, Chuck SL, Kearney BP, Warren DR; GS-US-216-0105 Study Team. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection. AIDS. 2011 Sep 24;25(15):1881-6. doi: 10.1097/QAD.0b013e32834b4d48.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: April 30, 2009
• First Submitted That Met QC Criteria: May 1, 2009
• First Posted (Estimate): May 4, 2009

Study Record Updates

• Last Update Posted (Estimate): February 15, 2016
• Last Update Submitted That Met QC Criteria: January 15, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: HIV; HIV-1; Antiretroviral Treatment-Naive
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Cobicistat; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Atazanavir Sulfate
• Other Study ID Numbers: GS-US-216-0105