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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV, HIV Infections

Intervention / Treatment
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* Drug: E/C/F/TAF


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E/C/F/TAF<br>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<br>* E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food<br>* Other names: Genvoya®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, HIV-1 Infected, Treatment Experienced, Treatment Naive