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

• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: May 11, 2011
• First Posted Date: June 1, 2011
• Results First Submitted Date: October 27, 2014
• Results First Posted Date: October 31, 2014
• Last Update Posted Date: May 2, 2016
• Study Start Date: May 2011
• Actual Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 27, 2014)

• 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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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.

• Original Primary Outcome Measures (submitted: May 27, 2011): primary endpoint is the change from baseline to Week 24 in estimated creatinine clearance [ Time Frame: 24 Weeks ]
• Change History: Complete list of historical versions of study NCT01363011 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: March 29, 2016)

• Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 1) [ Time Frame: 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-CG at Weeks 48 and 96 (Cohort 2) [ Time Frame: 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.
• Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 1) [ Time Frame: 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.
• Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 2) [ Time Frame: 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 at Weeks 48 and 96 (Cohort 1) [ Time Frame: 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-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 2) [ Time Frame: 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.
• 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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  t1/2 was analyzed for Cohort 2 (treatment-experienced) and was defined as the estimate of the terminal elimination half-life of the drug.

• Original Secondary Outcome Measures (submitted: May 27, 2011): The proportion of subjects achieving virologic response at Weeks 24 and 48 (HIV-1 RNA < 50 copies/mL) [ Time Frame: 24 & 48 Weeks ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acquired Immunodeficiency Syndrome
• HIV Infections

Intervention

• Drug: E/C/F/TDF
  E/C/F/TDF (150/150/200/300 mg) STR administered orally once daily
  Other Name: Stribild®
• 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.

Study Arms

• 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.

  Intervention: Drug: E/C/F/TDF
• 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.

  Interventions:

  • Drug: COBI
  • Drug: ATV
  • Drug: DRV
  • Drug: NRTI

Publications *

• Fisher M, McDonald C, Moyle G, Martorell C, Ramgopal M, Laplante F, Curley J, Graham H, Tran-Muchowski C, Liu Y, Rhee M, Szwarcberg J. Switching from ritonavir to cobicistat in HIV patients with renal impairment who are virologically suppressed on a protease inhibitor. J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19824. doi: 10.7448/IAS.17.4.19824. eCollection 2014.
• Post FA, Winston J, Andrade-Villanueva JF, Fisher M, Liu Y, Beraud C, Abram ME, Graham H, Rhee MS, Cheng AK, Szwarcberg J; Study 118 Team. Elvitegravir/cobicistat/emtricitabine/tenofovir DF in HIV-infected patients with mild-to-moderate renal impairment. J Acquir Immune Defic Syndr. 2015 Mar 1;68(3):310-3. doi: 10.1097/QAI.0000000000000476.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 27, 2014): 106
• Original Estimated Enrollment (submitted: May 27, 2011): 100
• Actual Study Completion Date: February 2015
• Actual Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Canada, Dominican Republic, Germany, Mexico, Puerto Rico, United Kingdom, United States

Administrative Information

• NCT Number: NCT01363011
• Other Study ID Numbers: GS-US-236-0118
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Gilead Sciences
• Study Sponsor: Gilead Sciences
• Collaborators: Not Provided

Investigators

• Study Director: Javier Szwarcberg, MD; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: March 2016