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

HIV Infections Clinical Trial

Official title:

A Phase 3 Open-label Safety Study of Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01363011
• Other study ID #: GS-US-236-0118
• Status: Completed
• Phase: Phase 3
• First received: May 11, 2011
• Last updated: February 25, 2015
• Start date: May 2011
• Est. completion date: February 2015

Study information

• Verified date: February 2015
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study is to characterize the effect of cobicistat-based regimens on parameters of renal function in subjects 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: February 2015
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 EVG, COBI, FTC, TDF, ATV, DRV; or subjects with any known allergies to the excipients of EVG/COBI/FTC/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

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Immunologic Deficiency Syndromes
• Renal Insufficiency

Intervention

Drug:
• Stribild
Stribild® (elvitegravir [EVG] 150 mg/cobicistat [COBI] 150 mg/emtricitabine [FTC] 200 mg/tenofovir disoproxil fumarate [TDF] 300 mg) single-tablet regimen (STR) administered orally once daily.
• COBI
Cobicistat (COBI, /co) 150 mg tablet administered with food orally once daily
• ATV
Atazanavir (ATV) 300 mg tablet administered orally once daily
• DRV
Darunavir (DRV) 800 mg tablet administered orally once daily
• NRTI
Participants will receive 2 investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs), which may include abacavir (ABC), lamivudine (3TC)/zidovudine (ZDV), didanosine (DDI), emtricitabine (FTC), ABC/3TC, 3TC, tenofovir disoproxil fumarate (TDF), or FTC/TDF, administered according to prescribing information.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Dominican Republic,  Germany,  Mexico,  Puerto Rico,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) Using the Cockcroft-Gault (CG) Equation at Week 24 (Cohort 1)	Change from baseline in eGFR-CG equation at Week 24 was analyzed in Cohort 1 (treatment-naive).	Baseline; Week 24	No
Primary	Change From Baseline in eGFR-CG at Week 24 (Cohort 2)	Change from baseline in eGFR-CG equation at Week 24 was analyzed in Cohort 2 (treatment-experienced).	Baseline; Week 24	No
Primary	Change From Baseline in eGFR Using the Modification of Diet in Renal (MDRD) Equation at Week 24 (Cohort 1)	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.	Baseline; Week 24	No
Primary	Change From Baseline in eGFR-MDRD at Week 24 (Cohort 2)	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.	Baseline; Week 24	No
Primary	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)	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.	Baseline; Week 24	No
Primary	Change From Baseline in eGFR-CKD-EPI Formula Based on Cystatin C Equation at Week 24 (Cohort 2)	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.	Baseline; Week 24	No
Primary	Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 1)	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.	Baseline; Week 24	No
Primary	Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 2)	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.	Baseline; Week 24	No
Primary	Change From Baseline in Actual Glomerular Filtration Rate (aGFR) at Weeks 2, 4, and 24 (Cohort 1)	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.	Baseline; Weeks 2, 4, and 24	No
Primary	Change From Baseline in aGFR at Weeks 2, 4, and 24 (Cohort 2)	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.	Baseline; Weeks 2, 4, and 24	No
Primary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 1)	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.	Week 24	No
Primary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 2)	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.	Week 24	No
Secondary	Change From Baseline in eGFR-CG at Week 48 (Cohort 1)	Change from baseline in eGFR-CG at Week 48 was analyzed in Cohort 1 (treatment-naive).	Baseline; Week 48	No
Secondary	Change From Baseline in eGFR-CG at Week 48 (Cohort 2)	Change from baseline in eGFR-CG at Week 48 was analyzed in Cohort 2 (treatment-experienced).	Baseline; Week 48	No
Secondary	Change From Baseline in eGFR-MDRD at Week 48 (Cohort 1)	Change from baseline in eGFR-MDRD at Week 48 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area.	Baseline; Week 48	No
Secondary	Change From Baseline in eGFR-MDRD at Week 48 (Cohort 2)	Change from baseline in eGFR-MDRD at Week 48 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area.	Baseline; Week 48	No
Secondary	Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Week 48 (Cohort 1)	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Week 48 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area.	Baseline; Week 48	No
Secondary	Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Week 48 (Cohort 2)	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Week 48 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area.	Baseline; Week 48	No
Secondary	Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 48 (Cohort 1)	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Week 48 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area.	Baseline; Week 48	No
Secondary	Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 48 (Cohort 2)	Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Week 48 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area.	Baseline; Week 48	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 (Cohort 1)	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed in Cohort 1 (treatment-naive) using the FDA snapshot analysis algorithm.	Week 48	No
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 (Cohort 2)	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed in Cohort 2 (treatment-experienced) using the FDA snapshot analysis algorithm.	Week 48	No
Secondary	Percentage of Participants Who Experienced Adverse Events (Cohort 1)	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.	Up to 48 weeks plus 30 days	No
Secondary	Percentage of Participants Who Experienced Adverse Events (Cohort 2)	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.	Up to 48 weeks plus 30 days	No
Secondary	Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 1)	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.	Up to 48 weeks plus 30 days	No
Secondary	Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 2)	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.	Up to 48 weeks plus 30 days	No
Secondary	Plasma Pharmacokinetics of COBI: AUCtau (Cohort 1)	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).	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.	No
Secondary	Plasma Pharmacokinetics of COBI: AUCtau (Cohort 2)	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).	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.	No
Secondary	Plasma Pharmacokinetics of COBI: Cmax (Cohort 1)	Cmax was analyzed for Cohort 1 (treatment-naive) and was defined as the maximum observed concentration of drug in plasma.	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.	No
Secondary	Plasma Pharmacokinetics of COBI: Cmax (Cohort 2)	Cmax was analyzed for Cohort 2 (treatment-experienced) and was defined as the maximum observed concentration of drug in plasma.	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.	No
Secondary	Plasma Pharmacokinetics of COBI: Ctau (Cohort 1)	Ctau was analyzed for Cohort 1 (treatment-naive) and was defined as the observed drug concentration at the end of the dosing interval.	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.	No
Secondary	Plasma Pharmacokinetics of COBI: Ctau (Cohort 2)	Ctau was analyzed for Cohort 2 (treatment-experienced) and was defined as the observed drug concentration at the end of the dosing interval.	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.	No
Secondary	Plasma Pharmacokinetics of COBI: Tmax (Cohort 1)	Tmax was analyzed for Cohort 1 (treatment-naive) and was defined as the time of Cmax.	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.	No
Secondary	Plasma Pharmacokinetics of COBI: Tmax (Cohort 2)	Tmax was analyzed for Cohort 2 (treatment-experienced) and was defined as the time of Cmax.	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.	No
Secondary	Plasma Pharmacokinetics of COBI: t1/2 (Cohort 1)	t1/2 was analyzed for Cohort 1 (treatment-naive) and was defined as the estimate of the terminal elimination half-life of the drug.	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.	No
Secondary	Plasma Pharmacokinetics of COBI: t1/2 (Cohort 2)	t1/2 was analyzed for Cohort 2 (treatment-experienced) and was defined as the estimate of the terminal elimination half-life of the drug.	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.	No