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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT01363011
First received: May 11, 2011
Last updated: March 29, 2016
Last verified: March 2016
  Purpose
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.

Condition Intervention Phase
Acquired Immunodeficiency Syndrome
HIV Infections
Drug: E/C/F/TDF
Drug: COBI
Drug: ATV
Drug: DRV
Drug: NRTI
Phase 3

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

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) Using the Cockcroft-Gault (CG) Equation at Week 24 (Cohort 1) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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-MDRD at Week 24 (Cohort 2) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in eGFR-CKD-EPI Formula Based on Cystatin C Equation at Week 24 (Cohort 2) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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 eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 1) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline; Week 24 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Actual Glomerular Filtration Rate (aGFR) at Weeks 2, 4, and 24 (Cohort 1) [ Time Frame: Baseline; Weeks 2, 4, and 24 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline; Weeks 2, 4, and 24 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 1) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 2) [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 1) [ Time Frame: Baseline; Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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-CG at Weeks 48 and 96 (Cohort 2) [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 1) [ Time Frame: Baseline; Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 2) [ Time Frame: Baseline; Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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 at Weeks 48 and 96 (Cohort 1) [ Time Frame: Baseline; Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 2) [ Time Frame: Baseline; Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation (Adjusted) at Weeks 48 and 96 (Cohort 1) [ Time Frame: Baseline; Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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 (Adjusted) at Weeks 48 and 96 (Cohort 2) [ Time Frame: Baseline; Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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 1) [ Time Frame: Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 2) [ Time Frame: Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Experienced Adverse Events (Cohort 1) [ Time Frame: Up to 147 weeks plus 30 days ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Experienced Adverse Events (Cohort 2) [ Time Frame: Up to 166 weeks plus 30 days ] [ Designated as safety issue: No ]
    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) [ Time Frame: Up to 147 weeks plus 30 days ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 2) [ Time Frame: Up to 166 weeks plus 30 days ] [ Designated as safety issue: No ]
    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: AUCtau (Cohort 1) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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).

  • Plasma Pharmacokinetics of COBI: AUCtau (Cohort 2) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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: Cmax (Cohort 1) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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 1) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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: Ctau (Cohort 2) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Ctau was analyzed for Cohort 2 (treatment-experienced) and was defined as the observed drug concentration at the end of the dosing interval.

  • Plasma Pharmacokinetics of COBI: Tmax (Cohort 1) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Tmax was analyzed for Cohort 1 (treatment-naive) and was defined as the time of Cmax.

  • Plasma Pharmacokinetics of COBI: Tmax (Cohort 2) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Tmax was analyzed for Cohort 2 (treatment-experienced) and was defined as the time of Cmax.

  • Plasma Pharmacokinetics of COBI: t1/2 (Cohort 1) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    t1/2 was analyzed for Cohort 1 (treatment-naive) and was defined as the estimate of the terminal elimination half-life of the drug.

  • Plasma Pharmacokinetics of COBI: t1/2 (Cohort 2) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    t1/2 was analyzed for Cohort 2 (treatment-experienced) and was defined as the estimate of the terminal elimination half-life of the drug.


Enrollment: 106
Study Start Date: May 2011
Study Completion Date: February 2015
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: E/C/F/TDF (Cohort 1)

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.

Drug: E/C/F/TDF
E/C/F/TDF (150/150/200/300 mg) STR administered orally once daily
Other Name: Stribild®
Experimental: COBI+PI+2 NRTI (Cohort 2)

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.

Drug: COBI
COBI 150 mg tablet administered with food orally once daily
Other Name: Tybost®
Drug: ATV
ATV 300 mg tablet administered orally once daily
Other Name: Reyataz®
Drug: DRV
DRV 800 mg tablet administered orally once daily
Other Name: Prezista®
Drug: NRTI
Participants will receive 2 investigator-selected 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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01363011

  Show 51 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Javier Szwarcberg, MD Gilead Sciences
  More Information

Publications:
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01363011     History of Changes
Other Study ID Numbers: GS-US-236-0118 
Study First Received: May 11, 2011
Results First Received: October 27, 2014
Last Updated: March 29, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
HIV-1
Treatment Naive
Treatment Experienced

Additional relevant MeSH terms:
HIV Infections
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
Renal Insufficiency
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immune System Diseases
Slow Virus Diseases
Kidney Diseases
Urologic Diseases
Tenofovir
Cobicistat
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors

ClinicalTrials.gov processed this record on December 07, 2016