Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment

Phase 3

Completed

Conditions: Acquired Immunodeficiency Syndrome
HIV Infections

Interventions: Drug: E/C/F/TDF
Drug: COBI
Drug: ATV
Drug: DRV
Drug: NRTI

Registration Number: NCT01363011

Lead Sponsor: Gilead Sciences

Brief Summary: This study is to characterize the effect of cobicistat-based regimens on parameters of renal function in participants with HIV infection and who have mild to moderate renal impairment, and to assess the safety and tolerability of the regimens in order to generate appropriate dosing recommendations.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 106

Inclusion Criteria

Cohort 1 (treatment-naive)

Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening
Screening genotype report must show sensitivity to FTC and TDF
No prior use of any approved or investigational antiretroviral drug for any length of time

Cohort 2 (treatment-experienced, pharmacoenhancer switch)

Subjects must be receiving ATV 300 mg/ritonavir (RTV) 100 mg plus 2 NRTIs OR DRV 800 mg/RTV 100 mg plus 2 NRTIs for at least 6 months prior to screening
Plasma HIV-1 RNA concentrations at undetectable levels in the 6 months preceding the screening visit and have HIV-1 RNA < 50 copies/mL at screening
Subjects experiencing intolerance to RTV (as determined by the investigator)

Both groups

The ability to understand and sign a written informed consent form
Normal ECG
Mild to moderate renal function
Stable renal function
Hepatic transaminases (AST and ALT) ≤ 5 x the upper limit of the normal range (ULN)
Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin (subjects with documented Gilbert's Syndrome or hyperbilirubinemia due to atazanavir therapy may have total bilirubin up to 5 x ULN)
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

Exclusion Criteria

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)
Implanted defibrillator or pacemaker
Current alcohol or substance use judged by the investigator to potentially interfere with subject study compliance
History of malignancy within the past 5 years or ongoing malignancy 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
Receiving ongoing therapy with any of medications contraindicated for use with elvitegravir (EVG), COBI, FTC, TDF, ATV, DRV; or subjects with any known allergies to the excipients of E/C/F/TDF STR, COBI tablets, ATV capsules or DRV tablets or contraindicated for the 2 NRTIs as part of the PI/co regimen
Participation in any other clinical trial without prior approval
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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
COBI+PI+2 NRTI (Cohort 2)	ATV	Participants who have received prior ARV treatment and who are virologically suppressed at baseline will continue their treatment regimen, switching the regimen's pharmacoenhancer component from ritonavir to cobicistat (COBI), and continuing their existing protease inhibitor (PI; either atazanavir (ATV) or darunavir (DRV)) plus 2 nucleoside reverse transcriptase inhibitor (NRTI) regimen for up to 96 weeks. Following Week 96, participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.
COBI+PI+2 NRTI (Cohort 2)	DRV	Participants who have received prior ARV treatment and who are virologically suppressed at baseline will continue their treatment regimen, switching the regimen's pharmacoenhancer component from ritonavir to cobicistat (COBI), and continuing their existing protease inhibitor (PI; either atazanavir (ATV) or darunavir (DRV)) plus 2 nucleoside reverse transcriptase inhibitor (NRTI) regimen for up to 96 weeks. Following Week 96, participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.
COBI+PI+2 NRTI (Cohort 2)	NRTI	Participants who have received prior ARV treatment and who are virologically suppressed at baseline will continue their treatment regimen, switching the regimen's pharmacoenhancer component from ritonavir to cobicistat (COBI), and continuing their existing protease inhibitor (PI; either atazanavir (ATV) or darunavir (DRV)) plus 2 nucleoside reverse transcriptase inhibitor (NRTI) regimen for up to 96 weeks. Following Week 96, participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.
E/C/F/TDF (Cohort 1)	E/C/F/TDF	Participants who have not received prior antiretroviral (ARV) treatment and who are virologically unsuppressed at baseline will initiate treatment with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) single-tablet regimen (STR) for up to 96 weeks. Following Week 96, participants continued their treatment until all participants discontinued from the study or commercial approval of E/C/F/TDF was received in the applicable country.
COBI+PI+2 NRTI (Cohort 2)	COBI	Participants who have received prior ARV treatment and who are virologically suppressed at baseline will continue their treatment regimen, switching the regimen's pharmacoenhancer component from ritonavir to cobicistat (COBI), and continuing their existing protease inhibitor (PI; either atazanavir (ATV) or darunavir (DRV)) plus 2 nucleoside reverse transcriptase inhibitor (NRTI) regimen for up to 96 weeks. Following Week 96, participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in eGFR-CKD-EPI Formula Based on Cystatin C Equation at Week 24 (Cohort 2)	Baseline; Week 24	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m\^2 body surface area.
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) Using the Cockcroft-Gault (CG) Equation at Week 24 (Cohort 1)	Baseline; Week 24	Change from baseline in eGFR-CG equation at Week 24 was analyzed in Cohort 1 (treatment-naive).
Change From Baseline in eGFR-CG at Week 24 (Cohort 2)	Baseline; Week 24	Change from baseline in eGFR-CG equation at Week 24 was analyzed in Cohort 2 (treatment-experienced).
Change From Baseline in eGFR Using the Modification of Diet in Renal (MDRD) Equation at Week 24 (Cohort 1)	Baseline; Week 24	Change from baseline in eGFR-MDRD equation at Week 24 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m\^2 body surface area.
Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 1)	Baseline; Week 24	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m\^2 body surface area.
Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 2)	Baseline; Week 24	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m\^2 body surface area.
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 2)	Week 24	The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 24 was analyzed in Cohort 2 (treatment-experienced) using the FDA snapshot analysis algorithm.
Change From Baseline in eGFR-MDRD at Week 24 (Cohort 2)	Baseline; Week 24	Change from baseline in eGFR-MDRD equation at Week 24 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m\^2 body surface area.
Change From Baseline in eGFR Using the Chronic Kidney Disease, Epidemiology Collaboration (CKD-EPI) Formula Based on Cystatin C Equation at Week 24 (Cohort 1)	Baseline; Week 24	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m\^2 body surface area.
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 1)	Week 24	The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 24 was analyzed in Cohort 1 (treatment-naive) using the FDA snapshot analysis algorithm.
Change From Baseline in Actual Glomerular Filtration Rate (aGFR) at Weeks 2, 4, and 24 (Cohort 1)	Baseline; Weeks 2, 4, and 24	Change from baseline in aGFR at Weeks 2, 4, and 24 was analyzed in Cohort 1 (treatment-naive). aGFR was calculated using iohexol plasma clearance.
Change From Baseline in aGFR at Weeks 2, 4, and 24 (Cohort 2)	Baseline; Weeks 2, 4, and 24	Change from baseline in aGFR at Weeks 2, 4, and 24 was analyzed in Cohort 2 (treatment-experienced). aGFR was calculated using iohexol plasma clearance.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 2)	Baseline; Week 48	Change from baseline in eGFR-CG at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Percentage of Participants Who Experienced Adverse Events (Cohort 1)	Up to 147 weeks plus 30 days	Adverse events (AEs) occurring from baseline up to 30 days following the last dose of study drug were summarized for Cohort 1 (treatment-naive). A participant was counted once if they had a qualifying event.
Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 1)	Baseline; Weeks 48 and 96	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m\^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 2)	Baseline; Weeks 48 and 96	Change from baseline in eGFR-MDRD at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m\^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation (Adjusted) at Weeks 48 and 96 (Cohort 1)	Baseline; Weeks 48 and 96	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m\^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 2)	Baseline; Weeks 48 and 96	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m\^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 1)	Weeks 48 and 96	The percentage of participants with HIV-1 RNA \< 50 copies/mL at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive) using the FDA snapshot analysis algorithm.
Plasma Pharmacokinetics of COBI: Cmax (Cohort 1)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	Cmax was analyzed for Cohort 1 (treatment-naive) and was defined as the maximum observed concentration of drug in plasma.
Plasma Pharmacokinetics of COBI: Cmax (Cohort 2)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	Cmax was analyzed for Cohort 2 (treatment-experienced) and was defined as the maximum observed concentration of drug in plasma.
Plasma Pharmacokinetics of COBI: Ctau (Cohort 2)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	Ctau was analyzed for Cohort 2 (treatment-experienced) and was defined as the observed drug concentration at the end of the dosing interval.
Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 1)	Baseline; Weeks 48 and 96	Change from baseline in eGFR-CG at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 1)	Baseline; Weeks 48 and 96	Change from baseline in eGFR-MDRD at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m\^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Percentage of Participants Who Experienced Adverse Events (Cohort 2)	Up to 166 weeks plus 30 days	Adverse events (AEs) occurring from baseline up to 30 days following the last dose of study drug were summarized for Cohort 2 (treatment-experienced). A participant was counted once if they had a qualifying event.
Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 1)	Up to 147 weeks plus 30 days	Laboratory abnormalities were summarized for Cohort 1 (treatment-naive) and were defined as values that increased at least one toxicity grade from baseline at any time postbaseline up to and including the date of last dose of study drug plus 30 days. A participant was counted once if they had a qualifying event.
Plasma Pharmacokinetics of COBI: Tmax (Cohort 1)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	Tmax was analyzed for Cohort 1 (treatment-naive) and was defined as the time of Cmax.
Plasma Pharmacokinetics of COBI: Tmax (Cohort 2)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	Tmax was analyzed for Cohort 2 (treatment-experienced) and was defined as the time of Cmax.
Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation (Adjusted) at Weeks 48 and 96 (Cohort 2)	Baseline; Weeks 48 and 96	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m\^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 2)	Weeks 48 and 96	The percentage of participants with HIV-1 RNA \< 50 copies/mL at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced) using the FDA snapshot analysis algorithm.
Plasma Pharmacokinetics of COBI: AUCtau (Cohort 1)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	AUCtau was analyzed for Cohort 1 (treatment-naive) and was defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).
Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 2)	Up to 166 weeks plus 30 days	Laboratory abnormalities were summarized for Cohort 2 (treatment-experienced) and were defined as values that increased at least one toxicity grade from baseline at any time postbaseline up to and including the date of last dose of study drug plus 30 days. A participant was counted once if they had a qualifying event.
Plasma Pharmacokinetics of COBI: t1/2 (Cohort 2)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	t1/2 was analyzed for Cohort 2 (treatment-experienced) and was defined as the estimate of the terminal elimination half-life of the drug.
Plasma Pharmacokinetics of COBI: AUCtau (Cohort 2)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	AUCtau was analyzed for Cohort 2 (treatment-experienced) and was defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).
Plasma Pharmacokinetics of COBI: Ctau (Cohort 1)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	Ctau was analyzed for Cohort 1 (treatment-naive) and was defined as the observed drug concentration at the end of the dosing interval.
Plasma Pharmacokinetics of COBI: t1/2 (Cohort 1)	Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.	t1/2 was analyzed for Cohort 1 (treatment-naive) and was defined as the estimate of the terminal elimination half-life of the drug.

Trial Locations

Locations (51): Chelsea Village Medical
🇺🇸
New York, New York, United States
Anthony Mills, MD, Inc.
🇺🇸
Los Angeles, California, United States
Homerton University Hospital
🇬🇧
London, United Kingdom
Center for HIV and Hepatogastroenterology
🇩🇪
Düsseldorf, Germany
Mount Sinai Downtown Comprehensive Health Program
🇺🇸
New York, New York, United States
Southwest Infectious Disease Clinical Research, Inc.
🇺🇸
Addison, Texas, United States
Peter J. Ruane, M.D., Inc.
🇺🇸
Los Angeles, California, United States
Carolinas Medical Center
🇺🇸
Charlotte, North Carolina, United States
Central West Clinical Research, Inc.
🇺🇸
St.Louis, Missouri, United States
East Bay AIDS Center
🇺🇸
Oakland, California, United States
AIDS Care
🇺🇸
Rochester, New York, United States
Clinique Medicale du Quartier Latin
🇨🇦
Montreal, Canada
AHF Research Center
🇺🇸
Beverly Hills, California, United States
Midway Immunology and Research Center
🇺🇸
Fort Pierce, Florida, United States
St Stephen's AIDS Trust
🇬🇧
London, United Kingdom
Holdsworth House Medical Practice
🇦🇺
Sydney, Australia
Brighton and Sussex University Hospitals NHS Trust
🇬🇧
Brighton, United Kingdom
Northstar Medical Center
🇺🇸
Chicago, Illinois, United States
Tarrant County Infectious Disease Associates
🇺🇸
Fort Worth, Texas, United States
The Research Institute
🇺🇸
Springfield, Massachusetts, United States
Medical Faculty Associates
🇺🇸
Washington, District of Columbia, United States
Infectious Diseases Unit - The Alfred Hospital
🇦🇺
Melbourne, Australia
Barts & the London NHS Trust
🇬🇧
London, United Kingdom
Taylor Square Private Clinic
🇦🇺
Darlinghurst, Australia
Kaiser Permanente
🇺🇸
Los Angeles, California, United States
Orange Coast Medical Group
🇺🇸
Newport Beach, California, United States
Therafirst Medical Center
🇺🇸
Fort Lauderdale, Florida, United States
Broward Health
🇺🇸
Fort Lauderdale, Florida, United States
Gary J. Richmond.M.D.,P.A.
🇺🇸
Fort Lauderdale, Florida, United States
Infectious Disease Specialists of Atlanta
🇺🇸
Decatur, Georgia, United States
Mercer University/ Mercer Medicine Clinical Research
🇺🇸
Macon, Georgia, United States
Therapeutic Concepts, PA
🇺🇸
Houston, Texas, United States
Sunnybrook Health Sciences Center
🇨🇦
Toronto, Ontario, Canada
Metropolis Medical
🇺🇸
San Francisco, California, United States
National Jewish Health
🇺🇸
Denver, Colorado, United States
IDOCF/ValueHealthMD, LLC
🇺🇸
Orlando, Florida, United States
Landeskrankenhaus Graz West
🇦🇹
Graz, Austria
University of California, Davis
🇺🇸
Sacramento, California, United States
Yale University School of Medicine AIDS Program
🇺🇸
New Haven, Connecticut, United States
Spectrum Medical Group
🇺🇸
Phoenix, Arizona, United States
Whitman Walker Clinic
🇺🇸
Washington, District of Columbia, United States
HOPE Clinical Research
🇵🇷
San Juan, Puerto Rico
Instituto Dominicano de Estudio Virologicos
🇩🇴
Santo Domingo, Dominican Republic
Clinical Research Puerto Rico
🇵🇷
San Juan, Puerto Rico
Orlando Immunology Center
🇺🇸
Orlando, Florida, United States
ID Care
🇺🇸
Hillsborough, New Jersey, United States
Hospital Civil de Guadalajara "Fray Antonio Alcalde"
🇲🇽
Guadalajara, Mexico
Otto Wagner Spital
🇦🇹
Wien, Austria
North Shore University Hospital
🇺🇸
Manhasset, New York, United States
Health for Life Clinic
🇺🇸
Little Rock, Arkansas, United States
Guy's King's and St. Thomas' School of Medicine
🇬🇧
London, United Kingdom