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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01818596
• Other study ID #: GS-US-292-0112
• Secondary ID: 2013-000516-25
• Status: Completed
• Phase: Phase 3
• Start date: March 27, 2013
• Est. completion date: July 18, 2018

Study information

• Verified date: June 2019
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 252
• Est. completion date: July 18, 2018
• Est. primary completion date: July 31, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV
• HIV Infections
• Renal Insufficiency

Intervention

Drug:
• E/C/F/TAF
E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food

Locations

Country	Name	City	State
Australia	Holdsworth House Medical Practice	Darlinghurst	New South Wales
Australia	Clinical Research Infectious Diseases Department- Alfred Hospital	Melbourne	Victoria
Australia	Prahran Market Clinic	Prahran	Victoria
Dominican Republic	Instituto Dominicano de Estudios Virologicos (IDEV)	Santo Domingo
France	Hopital de la Croix Rousse	Lyon
France	GHPS Service des maladies infectieuses et tropicales pavillon Laveran unité de recherche clinique	Paris
Mexico	Hospital Civil de Guadalajara Dr. Juan I. Menchaca	Guadalajara	Jalisco
Netherlands	University Medical Center Utrecht	Utrecht
Spain	Germans Trias i Pujol University Hospital	Barcelona
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	Hospital La Paz	Madrid
Thailand	Department of Preventive and Social Medicine, Faculty of Medicine, Siriraj Hospital	Bangkok
Thailand	Faculty of Medicine Ramathibodi Hospital, Mahidol University	Bangkok
Thailand	HIV-NAT, Thai Red Cross AIDS Research Centre	Bangkok
Thailand	Srinagarind Hospital, Khon Kaen University	Khon Kaen
United Kingdom	Brighton & Sussex University Hospitals NHS Trust	Brighton
United Kingdom	Chelsea and Westminster NHS Foundation Trust Hospital	London
United Kingdom	Kings College London	London
United Kingdom	Central Manchester University Hospitals NHS foundation Trust	Manchester
United States	Albany Medical College	Albany	New York
United States	Upstate Infectious Diseases Associates	Albany	New York
United States	University of Colorado	Aurora	Colorado
United States	St. Hope Foundation	Bellaire	Texas
United States	Be Well Medical Center, P.C.	Berkley	Michigan
United States	Pacific Oaks Medical Group	Beverly Hills	California
United States	Community Research Initiative of New England	Boston	Massachusetts
United States	Jacobi Medical Center	Bronx	New York
United States	Montefiore Medical Center	Bronx	New York
United States	University of Cincinnati	Cincinnati	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	North Texas Infectious Diseases Consultants, PA	Dallas	Texas
United States	Infectious Disease Specialists of Atlanta	Decatur	Georgia
United States	National Jewish Health	Denver	Colorado
United States	Henry Ford Health System	Detroit	Michigan
United States	Gary J. Richmond, MD PA	Fort Lauderdale	Florida
United States	Midway Immunology and Research Center	Fort Pierce	Florida
United States	Garcias' Family Health Group	Harlingen	Texas
United States	Kaiser Permanente	Hayward	California
United States	Gordon E. Crofoot MD, PA	Houston	Texas
United States	Therapeutic Concepts, PA	Houston	Texas
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	The Kansas City Care Clinic (KC Free Health Clinic)	Kansas City	Missouri
United States	Health for Life Clinic PLLC	Little Rock	Arkansas
United States	Long Beach Education and Research Consultants	Long Beach	California
United States	Anthony Mills MD, Inc	Los Angeles	California
United States	LA Gay & Lesbian Center - Jeffrey Goodman Special Care Clinic	Los Angeles	California
United States	Peter J Ruane, MD, Inc	Los Angeles	California
United States	Mercer University	Macon	Georgia
United States	North Shore University Hospital/Division of Infectious Diseases	Manhasset	New York
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Jersey Shore University Medical Center	Neptune	New Jersey
United States	Saint Michael's Medical Center	Newark	New Jersey
United States	Idocf/Valuhealthmd	Orlando	Florida
United States	Desert Medical Group Inc. dba Desert Oasis Healthcare Medical Group	Palm Springs	California
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of PA HIV Clinical Trials Unit	Philadelphia	Pennsylvania
United States	Maricopa Integrated Health System - McDowell Clinic	Phoenix	Arizona
United States	Pueblo Family Physicians	Phoenix	Arizona
United States	Aids Care	Rochester	New York
United States	Kaiser Permanente Medical Group	Sacramento	California
United States	Southampton Healthcare, Inc.	Saint Louis	Missouri
United States	Kaiser Permanente CTU San Francisco	San Francisco	California
United States	Metropolis Medical	San Francisco	California
United States	Southwest CARE Center	Santa Fe	New Mexico
United States	Peter Shalit, MD	Seattle	Washington
United States	The Research Institute	Springfield	Massachusetts
United States	University of South Florida	Tampa	Florida
United States	Dupont Circle Physician's Group	Washington	District of Columbia
United States	Triple O Research Institute, P.A.	West Palm Beach	Florida
United States	Rowan Tree Medical, P.A.	Wilton Manors	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Australia,  Dominican Republic,  France,  Mexico,  Netherlands,  Spain,  Thailand,  United Kingdom, 

References & Publications (2)

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 — View Citation

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. Switchin — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	PK Parameter: ?z of TAF	?z 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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