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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 106
- 试验地点
- 51
- 主要终点
- Change From Baseline in eGFR-CKD-EPI Formula Based on Cystatin C Equation at Week 24 (Cohort 2)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: E/C/F/TDF (Drug)
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.
干预措施: COBI (Drug)
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.
干预措施: ATV (Drug)
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.
干预措施: DRV (Drug)
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.
干预措施: NRTI (Drug)
结局指标
主要结局
Change From Baseline in eGFR-CKD-EPI Formula Based on Cystatin C Equation at Week 24 (Cohort 2)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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.
次要结局
- Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 2)(Baseline; Week 48)
- Percentage of Participants Who Experienced Adverse Events (Cohort 1)(Up to 147 weeks plus 30 days)
- 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-MDRD 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) at Weeks 48 and 96 (Cohort 1)(Baseline; Weeks 48 and 96)
- Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 2)(Baseline; Weeks 48 and 96)
- Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 1)(Weeks 48 and 96)
- 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.)
- 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.)
- 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.)
- Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 1)(Baseline; Weeks 48 and 96)
- Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 1)(Baseline; Weeks 48 and 96)
- Percentage of Participants Who Experienced Adverse Events (Cohort 2)(Up to 166 weeks plus 30 days)
- Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 1)(Up to 147 weeks plus 30 days)
- 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.)
- 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.)
- 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)
- Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 2)(Weeks 48 and 96)
- 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.)
- Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 2)(Up to 166 weeks plus 30 days)
- 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.)
- 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.)
- 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.)
- 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.)