Open-label Safety Study of E/C/F/TAF (Genvoya®) in HIV-1 Positive Patients With Mild to Moderate Renal Impairment

A Phase 3 Open-label Safety Study of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen in HIV-1 Positive Patients With Mild to Moderate Renal Impairment

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV
• Intervention / Treatment: Drug: E/C/F/TAF

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Holdsworth House Medical Practice
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Clinical Research Infectious Diseases Department- Alfred Hospital
    • Prahran, Victoria, Australia, 3181
      • Prahran Market Clinic
• Dominican Republic
  • Santo Domingo, Dominican Republic, 99999
    • Instituto Dominicano de Estudios Virologicos (IDEV)
• France
  • Lyon, France, 69004
    • Hopital de la Croix Rousse
  • Paris, France, 75651
    • GHPS Service des maladies infectieuses et tropicales pavillon Laveran unité de recherche clinique
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44340
      • Hospital Civil de Guadalajara Dr. Juan I. Menchaca
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• Spain
  • Barcelona, Spain, 8907
    • Hospital Universitari de Bellvitge
  • Barcelona, Spain, 8916
    • Germans Trias i Pujol University Hospital
  • Madrid, Spain, 28046
    • Hospital La Paz
• Thailand
  • Bangkok, Thailand, 10400
    • Faculty of Medicine Ramathibodi Hospital, Mahidol University
  • Bangkok, Thailand, 10330
    • HIV-NAT, Thai Red Cross AIDS Research Centre
  • Bangkok, Thailand, 10700
    • Department of Preventive and Social Medicine, Faculty of Medicine, Siriraj Hospital
  • Khon Kaen, Thailand, 40002
    • Srinagarind Hospital, Khon Kaen University
• United Kingdom
  • Brighton, United Kingdom, BN2 1ES
    • Brighton & Sussex University Hospitals NHS Trust
  • London, United Kingdom, SE5 9RJ
    • Kings College London
  • London, United Kingdom, Sw10 9NH
    • Chelsea and Westminster NHS Foundation Trust Hospital
  • Manchester, United Kingdom, M13 0FH
    • Central Manchester University Hospitals NHS Foundation Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85015
      • Pueblo Family Physicians
    • Phoenix, Arizona, United States, 85006
      • Maricopa Integrated Health System - McDowell Clinic
  • Arkansas
    • Little Rock, Arkansas, United States, 72207
      • Health For Life Clinic Pllc
  • California
    • Beverly Hills, California, United States, 90211
      • Pacific Oaks Medical Group
    • Hayward, California, United States, 94545
      • Kaiser Permanente
    • Long Beach, California, United States, 90813
      • Long Beach Education and Research Consultants
    • Los Angeles, California, United States, 90069
      • Anthony Mills MD, Inc
    • Los Angeles, California, United States, 90036
      • Peter J Ruane, MD, Inc
    • Los Angeles, California, United States, 90028
      • LA Gay & Lesbian Center - Jeffrey Goodman Special Care Clinic
    • Palm Springs, California, United States, 92262
      • Desert Medical Group Inc. dba Desert Oasis Healthcare Medical Group
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Group
    • San Francisco, California, United States, 94109
      • Metropolis Medical
    • San Francisco, California, United States, 94118
      • Kaiser Permanente CTU San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • District of Columbia
    • Washington, District of Columbia, United States, 20009
      • Dupont Circle Physician's Group
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Gary J. Richmond, MD PA
    • Fort Pierce, Florida, United States, 34982
      • Midway Immunology and Research Center
    • Orlando, Florida, United States, 32806
      • Idocf/Valuhealthmd
    • Tampa, Florida, United States, 33602
      • University of South Florida
    • West Palm Beach, Florida, United States, 33401
      • Triple O Research Institute, P.A.
    • Wilton Manors, Florida, United States, 33305
      • Rowan Tree Medical, P.A.
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Infectious Disease Specialists of Atlanta
    • Macon, Georgia, United States, 31210
      • Mercer University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Community Research Initiative of New England
    • Springfield, Massachusetts, United States, 01105
      • The Research Institute
  • Michigan
    • Berkley, Michigan, United States, 48210
      • Be Well Medical Center, P.C.
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • The Kansas City Care Clinic (KC Free Health Clinic)
    • Saint Louis, Missouri, United States, 63139
      • Southampton Healthcare, Inc.
  • New Jersey
    • Neptune, New Jersey, United States, 07754
      • Jersey Shore University Medical Center
    • Newark, New Jersey, United States, 07102
      • Saint Michael's Medical Center
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • Southwest CARE Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Albany, New York, United States, 12208
      • Upstate Infectious Diseases Associates
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital/Division of Infectious Diseases
    • Rochester, New York, United States, 14607
      • Aids Care
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0405
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19104
      • University of PA HIV Clinical Trials Unit
  • Texas
    • Bellaire, Texas, United States, 77401
      • St. Hope Foundation
    • Dallas, Texas, United States, 75246
      • North Texas Infectious Diseases Consultants, PA
    • Harlingen, Texas, United States, 78550
      • Garcias' Family Health Group
    • Houston, Texas, United States, 77004
      • Therapeutic Concepts, PA
    • Houston, Texas, United States, 77098
      • Gordon E. Crofoot MD, PA
  • Washington
    • Seattle, Washington, United States, 98104
      • Peter Shalit, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

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 Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: E/C/F/TAF; E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food; Other Names: Genvoya®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24	eGFR is a measurement of the kidney's ability to filter blood.	Baseline; Week 24
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	eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,cysC method is adjusted for age and sex.	Baseline; Week 24
Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at 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.	Baseline; Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy	aGFR was directly measured using iohexol plasma clearance (CLiohexol).	Baseline; Week 2, 4, or 8; Week 24
Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48	CTX is a biomarker of bone turnover.	Baseline; Weeks 24 and 48
Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48	P1NP is a biomarker of bone turnover.	Baseline; Weeks 24 and 48
Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144	Urine RBP is a renal biomarker which is used to evaluate drug-induced kidney injury.	Baseline; Weeks 24, 48, 96, and 144
Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144	Urine beta-2-microglobulin is a renal biomarker which is used to evaluate drug-induced kidney injury.	Baseline; Weeks 24, 48, 96, and 144
Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities	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.	Baseline up to Week 240 plus 30 days
Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at 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.	Weeks 24, 48, 96, and 144
Pharmacokinetic (PK) Parameter: Cmax of TAF	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.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
PK Parameter: Tmax of TAF	Tmax is defined as the time of Cmax. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
PK Parameter: Clast of TAF	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.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
PK Parameter: Tlast of TAF	Tlast is defined as the time of Clast. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
PK Parameter: λz of TAF	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.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
PK Parameter: AUCtau of TAF	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.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
PK Parameter: t1/2 of TAF	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.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study	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.	Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144	eGFR is a measurement of the kidney's ability to filter blood.	Baseline; Weeks 48, 96, and 144
Change From Baseline in eGFR_CKD-EPI,cysC at 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.	Baseline; Weeks 48, 96, and 144
Change From Baseline in eGFR_CKD-EPI,Creatinine at 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.	Baseline; Weeks 48, 96, and 144

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Pozniak A, Arribas JR, Gathe J, Gupta SK, Post FA, Bloch M, Avihingsanon A, Crofoot G, Benson P, Lichtenstein K, Ramgopal M, Chetchotisakd P, Custodio JM, Abram ME, Wei X, Cheng A, McCallister S, SenGupta D, Fordyce MW; GS-US-292-0112 Study Team. Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal Impairment: 48-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study. J Acquir Immune Defic Syndr. 2016 Apr 15;71(5):530-7. doi: 10.1097/QAI.0000000000000908.
• Post FA, Tebas P, Clarke A, Cotte L, Short WR, Abram ME, Jiang S, Cheng A, Das M, Fordyce MW. Brief Report: Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Adults With Renal Impairment: 96-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study. J Acquir Immune Defic Syndr. 2017 Feb 1;74(2):180-184. doi: 10.1097/QAI.0000000000001186.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2013
• Primary Completion (Actual): July 31, 2014
• Study Completion (Actual): July 18, 2018

Study Registration Dates

• First Submitted: March 22, 2013
• First Submitted That Met QC Criteria: March 22, 2013
• First Posted (Estimate): March 26, 2013

Study Record Updates

• Last Update Posted (Actual): March 2, 2020
• Last Update Submitted That Met QC Criteria: February 18, 2020
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: HIV; Treatment Experienced; Treatment Naive; HIV-1 Infected
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Kidney Diseases; Urologic Diseases; HIV Infections; Renal Insufficiency; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: GS-US-292-0112; 2013-000516-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy.
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No