Open-label Safety Study of E/C/F/TAF (Genvoya®) in HIV-1 Positive Patients With Mild to Moderate Renal Impairment
- Conditions
- HIVHIV Infections
- Interventions
- Drug: E/C/F/TAF
- Registration Number
- NCT01818596
- Lead Sponsor
- Gilead Sciences
- Brief Summary
The primary objective of this study is to evaluate the effect of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) tablet on renal parameters at Week 24 in treatment-naive and treatment-experienced HIV-positive, adults with mild to moderate renal impairment.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 252
Cohort 1 (treatment-experienced switch)
- Must not have a history of known resistance to elvitegravir (EVG), tenofovir disoproxil fumarate (TDF), or emtricitabine (FTC)
- Plasma HIV-1 RNA concentrations (at least two measurements) at undetectable levels (according to the local assay being used) in the 6 months preceding the screening visit and have HIV-1 RNA < 50 copies/mL at screening
- Estimated glomerular filtration rate (GFR) 30-69 mL/min according to the Cockcroft-Gault formula for creatinine clearance, using actual weight
- May be currently enrolled in Gilead studies GS-US-236-0102, GS-US-236-0103, and GS-US-216-0114, but will be eligible to enroll only after the Week 144 visit for that study is complete; or currently receiving Stribild® (STB) or atazanavir (ATV)/cobicistat (COBI) + Truvada (TVD) in Gilead studies GS-US-236-0104 or GS-US-216-0105, but will be eligible to enroll only after the Week 48 visit for that study is complete.
Cohort 2 (treatment-naive)
- Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening
- Screening genotype report provided by Gilead Sciences must show sensitivity to EVG, FTC, and TDF
- No prior use of any approved or investigational antiretroviral drug for any length of time, except the use for pre-exposure prophylaxis (PrEP), or post-exposure prophylaxis (PEP), up to 6 months prior to screening
- Estimated GFR 30-69 mL/min according to the Cockcroft Gault formula for creatinine clearance, using actual weight
All Cohorts:
All individuals must meet all of the following inclusion criteria to be eligible for participation in this study:
- The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
- CD4+ count of ≥ 50 cells/μL
- Stable renal function: serum creatinine measurements to be taken at least once (within three months of screening)
- Cause of underlying chronic kidney disease (eg hypertension, diabetes) stable, without change in medical management, for 3 months prior to baseline
- Normal electrocardiogram (ECG)
- Hepatic transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN)
- Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin
- Adequate hematologic function
- Serum amylase ≤ 5 x ULN
- Females of childbearing potential must agree to utilize highly effective contraception methods (two separate forms of contraception, one of which must be an effective barrier method, or be non-heterosexually active, practice sexual abstinence) from screening throughout the duration of study treatment and for 30 days following the last dose of study drug
- Females who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing
- Males must agree to utilize a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of investigational medicinal product. A highly effective method of contraception is defined as two separate forms of contraception, one of which must be an effective barrier method, or males must be non-heterosexually active, or practice sexual abstinence
Key
- A new AIDS-defining condition (excluding CD4 cell count and percentage criteria) diagnosed within the 30 days prior to screening,with the exception of the first two bullet points
- Hepatitis C virus (HCV) antibody positive. Individuals who are HCV positive, but have a documented negative HCV RNA, are eligible
- Hepatitis B surface antigen (HBVsAg) positive
- Individuals receiving drug treatment for Hepatitis C, or individuals who are anticipated to receive treatment for Hepatitis C during the course of the study
- Individuals experiencing decompensated cirrhosis (eg, ascites, encephalopathy, etc.)
- Females who are breastfeeding
- Positive serum pregnancy test
- Have an implanted defibrillator or pacemaker
- Current alcohol or substance use judged by the Investigator to potentially interfere with study compliance
- A history of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma
- Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline
- Individuals on hemodialysis, other forms of renal replacement therapy, or on treatment for underlying kidney diseases (including prednisolone and dexamethasone)
- Individuals receiving ongoing therapy with any medications not to be used with EVG, COBI, FTC, or TAF or individuals with any known allergies to the excipients of E/C/F/TAF
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description E/C/F/TAF E/C/F/TAF Participants will receive E/C/F/TAF for 144 weeks. Following Week 144, in countries where E/C/F/TAF is not available (except for the United Kingdom), participants will be given the option to continue in the study and receive E/C/F/TAF for another 48 weeks, or until the product becomes available through an access program, or until Gilead Sciences elects to discontinue the study in that country, whichever comes first.
- Primary Outcome Measures
Name Time Method Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 Baseline; Week 24 eGFR is a measurement of the kidney's ability to filter blood.
Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24 Baseline; Week 24 eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,cysC method is adjusted for age and sex.
Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24 Baseline; Week 24 eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,creatinine method is adjusted for age, race, and sex.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy Baseline; Week 2, 4, or 8; Week 24 aGFR was directly measured using iohexol plasma clearance (CLiohexol).
Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities Baseline up to Week 240 plus 30 days Adverse events (AEs) and graded laboratory abnormalities occurring during the E/C/F/TAF treatment period were summarized across the participant population. A participant was counted once if they had a qualifying event.
PK Parameter: Clast of TAF Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose Clast is defined as the last observable concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
PK Parameter: Tlast of TAF Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose Tlast is defined as the time of Clast. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 Baseline; Weeks 48, 96, and 144 eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,cysC method is adjusted for age and sex.
Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48 Baseline; Weeks 24 and 48 CTX is a biomarker of bone turnover.
Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 Weeks 24, 48, 96, and 144 The percentage of participants achieving HIV-1 RNA \< 50 Copies/mL at Weeks 24, 48, 96, and 144 was analyzed using the snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48 Baseline; Weeks 24 and 48 P1NP is a biomarker of bone turnover.
Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 Baseline; Weeks 24, 48, 96, and 144 Urine RBP is a renal biomarker which is used to evaluate drug-induced kidney injury.
PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose TFV-DP is an active phosphorylated metabolite of tenofovir alafenamide. AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 Baseline; Weeks 24, 48, 96, and 144 Urine beta-2-microglobulin is a renal biomarker which is used to evaluate drug-induced kidney injury.
Pharmacokinetic (PK) Parameter: Cmax of TAF Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose Cmax is defined as the maximum concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
PK Parameter: Tmax of TAF Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose Tmax is defined as the time of Cmax. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
PK Parameter: t1/2 of TAF Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
PK Parameter: λz of TAF Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose λz is defined as the terminal elimination rate constant. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
PK Parameter: AUCtau of TAF Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 Baseline; Weeks 48, 96, and 144 eGFR is a measurement of the kidney's ability to filter blood.
Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 Baseline; Weeks 48, 96, and 144 eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,creatinine method is adjusted for age, race, and sex.
Trial Locations
- Locations (70)
Peter J Ruane, MD, Inc
🇺🇸Los Angeles, California, United States
Mercer University
🇺🇸Macon, Georgia, United States
Anthony Mills MD, Inc
🇺🇸Los Angeles, California, United States
University of PA HIV Clinical Trials Unit
🇺🇸Philadelphia, Pennsylvania, United States
Gary J. Richmond, MD PA
🇺🇸Fort Lauderdale, Florida, United States
Triple O Research Institute, P.A.
🇺🇸West Palm Beach, Florida, United States
Infectious Disease Specialists of Atlanta
🇺🇸Decatur, Georgia, United States
Community Research Initiative of New England
🇺🇸Boston, Massachusetts, United States
Peter Shalit, MD
🇺🇸Seattle, Washington, United States
Kaiser Permanente CTU San Francisco
🇺🇸San Francisco, California, United States
Indiana University School of Medicine
🇺🇸Indianapolis, Indiana, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Gordon E. Crofoot MD, PA
🇺🇸Houston, Texas, United States
Hennepin County Medical Center
🇺🇸Minneapolis, Minnesota, United States
Saint Michael's Medical Center
🇺🇸Newark, New Jersey, United States
HIV-NAT, Thai Red Cross AIDS Research Centre
🇹🇭Bangkok, Thailand
Faculty of Medicine Ramathibodi Hospital, Mahidol University
🇹🇭Bangkok, Thailand
MetroHealth Medical Center
🇺🇸Cleveland, Ohio, United States
Jacobi Medical Center
🇺🇸Bronx, New York, United States
Hospital Civil de Guadalajara Dr. Juan I. Menchaca
🇲🇽Guadalajara, Jalisco, Mexico
Department of Preventive and Social Medicine, Faculty of Medicine, Siriraj Hospital
🇹🇭Bangkok, Thailand
Jersey Shore University Medical Center
🇺🇸Neptune, New Jersey, United States
Maricopa Integrated Health System - McDowell Clinic
🇺🇸Phoenix, Arizona, United States
Pueblo Family Physicians
🇺🇸Phoenix, Arizona, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Long Beach Education and Research Consultants
🇺🇸Long Beach, California, United States
Pacific Oaks Medical Group
🇺🇸Beverly Hills, California, United States
Dupont Circle Physician's Group
🇺🇸Washington, District of Columbia, United States
Southampton Healthcare, Inc.
🇺🇸Saint Louis, Missouri, United States
The Kansas City Care Clinic (KC Free Health Clinic)
🇺🇸Kansas City, Missouri, United States
LA Gay & Lesbian Center - Jeffrey Goodman Special Care Clinic
🇺🇸Los Angeles, California, United States
Desert Medical Group Inc. dba Desert Oasis Healthcare Medical Group
🇺🇸Palm Springs, California, United States
Metropolis Medical
🇺🇸San Francisco, California, United States
Rowan Tree Medical, P.A.
🇺🇸Wilton Manors, Florida, United States
Be Well Medical Center, P.C.
🇺🇸Berkley, Michigan, United States
Therapeutic Concepts, PA
🇺🇸Houston, Texas, United States
Aids Care
🇺🇸Rochester, New York, United States
Instituto Dominicano de Estudios Virologicos (IDEV)
🇩🇴Santo Domingo, Dominican Republic
Hospital Universitari de Bellvitge
🇪🇸Barcelona, Spain
Kings College London
🇬🇧London, United Kingdom
Chelsea and Westminster NHS Foundation Trust Hospital
🇬🇧London, United Kingdom
Central Manchester University Hospitals NHS foundation Trust
🇬🇧Manchester, United Kingdom
Germans Trias i Pujol University Hospital
🇪🇸Barcelona, Spain
Hospital La Paz
🇪🇸Madrid, Spain
Health for Life Clinic PLLC
🇺🇸Little Rock, Arkansas, United States
Kaiser Permanente
🇺🇸Hayward, California, United States
National Jewish Health
🇺🇸Denver, Colorado, United States
Midway Immunology and Research Center
🇺🇸Fort Pierce, Florida, United States
The Research Institute
🇺🇸Springfield, Massachusetts, United States
Upstate Infectious Diseases Associates
🇺🇸Albany, New York, United States
North Shore University Hospital/Division of Infectious Diseases
🇺🇸Manhasset, New York, United States
Albany Medical College
🇺🇸Albany, New York, United States
Southwest CARE Center
🇺🇸Santa Fe, New Mexico, United States
Garcias' Family Health Group
🇺🇸Harlingen, Texas, United States
North Texas Infectious Diseases Consultants, PA
🇺🇸Dallas, Texas, United States
St. Hope Foundation
🇺🇸Bellaire, Texas, United States
Clinical Research Infectious Diseases Department- Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Holdsworth House Medical Practice
🇦🇺Darlinghurst, New South Wales, Australia
Hopital de la Croix Rousse
🇫🇷Lyon, France
Prahran Market Clinic
🇦🇺Prahran, Victoria, Australia
GHPS Service des maladies infectieuses et tropicales pavillon Laveran unité de recherche clinique
🇫🇷Paris, France
Brighton & Sussex University Hospitals NHS Trust
🇬🇧Brighton, United Kingdom
Srinagarind Hospital, Khon Kaen University
🇹🇭Khon Kaen, Thailand
University of Colorado
🇺🇸Aurora, Colorado, United States
Idocf/Valuhealthmd
🇺🇸Orlando, Florida, United States
University of South Florida
🇺🇸Tampa, Florida, United States
Kaiser Permanente Medical Group
🇺🇸Sacramento, California, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
University Medical Center Utrecht
🇳🇱Utrecht, Netherlands