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

Study Description

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Brief Summary:

This open-label, multicenter, multi-cohort study is to assess the safety, tolerability, and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya®; E/C/F/TAF) fixed-dose combination (FDC) tablet in treatment-naive and treatment-experienced HIV-positive, adult participants with mild to moderate renal impairment.

The primary objective of this study is to evaluate the effect of E/C/F/TAF on renal parameters at Week 24. The proportion of subjects achieving virologic response of HIV-1 RNA < 50 copies/mL will also be assessed.

At sites able to conduct the appropriate testing, approximately 30 participants will be enrolled into an intensive pharmacokinetic/pharmacodynamic (PK/PD) substudy to evaluate the PK/PD parameters of the individual components of E/C/F/TAF as well as tenofovir diphosphate (TFV-DP).

Condition or disease	Intervention/treatment	Phase
HIV; HIV Infections	Drug: E/C/F/TAF	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	252 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Actual Study Start Date :	April 19, 2013
Actual Primary Completion Date :	July 31, 2014
Actual Study Completion Date :	July 18, 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: E/C/F/TAF; Participants will receive E/C/F/TAF for 144 weeks.	Drug: E/C/F/TAF; E/C/F/TAF FDC tablet administered orally once daily with food; Other Name: Genvoya®

Outcome Measures

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Primary Outcome Measures :

1. Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 [ Time Frame: Baseline; Week 24 ]
   eGFR is a measurement of the kidney's ability to filter blood.
2. 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 [ Time Frame: 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.
3. Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24 [ Time Frame: 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 :

1. Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy [ Time Frame: Baseline; Week 2, 4, or 8; Week 24 ]
   aGFR was directly measured using iohexol plasma clearance (CLiohexol).
2. Percent Change From Baseline in C-type Collagen Sequence (CTX) at Week 24 [ Time Frame: Baseline; Week 24 ]
   CTX is a biomarker of bone turnover.
3. Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Week 24 [ Time Frame: Baseline; Week 24 ]
   P1NP is a biomarker of bone turnover.
4. Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Week 24 [ Time Frame: Baseline; Week 24 ]
   Urine RBP is a renal biomarker which is used to detect drug-induced kidney injury.
5. Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Week 24 [ Time Frame: Baseline; Week 24 ]
   Urine beta-2-microglobulin is a renal biomarker which is used to detect drug-induced kidney injury.
6. Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities [ Time Frame: Baseline to Week 24 Data Cut (average 42 weeks) ]

   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.

   Data were collected for all participants through the Week 24 visit; additional data are included for participants who had passed the Week 24 visit.

7. Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 24 [ Time Frame: Week 24 ]
   The percentage of participants achieving HIV-1 RNA < 50 Copies/mL at Week 24 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.
8. Pharmacokinetic (PK) Parameter: Cmax of TAF [ Time Frame: 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.
9. PK Parameter: Tmax of TAF [ Time Frame: 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.
10. PK Parameter: Clast of TAF [ Time Frame: 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.
11. PK Parameter: Tlast of TAF [ Time Frame: 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.
12. PK Parameter: λz of TAF [ Time Frame: 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.
13. PK Parameter: AUCtau of TAF [ Time Frame: 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.
14. PK Parameter: t1/2 of TAF [ Time Frame: 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.
15. PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study [ Time Frame: 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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 subjects 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
• Female subjects 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
• Male subjects 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 male subjects must be non-heterosexually active, or practice sexual abstinence
• Age ≥ 18 years

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. Subjects who are HCV positive, but have a documented negative HCV RNA, are eligible
• Hepatitis B surface antigen (HBVsAg) positive
• Subjects receiving drug treatment for Hepatitis C, or subjects who are anticipated to receive treatment for Hepatitis C during the course of the study
• Subjects 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 subject 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
• Subjects on hemodialysis, other forms of renal replacement therapy, or on treatment for underlying kidney diseases (including prednisolone and dexamethasone)
• Subjects receiving ongoing therapy with any medications not to be used with EVG, COBI, FTC, or TAF or subjects with any known allergies to the excipients of E/C/F/TAF

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

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  Show 117 Study Locations

Sponsors and Collaborators

Gilead Sciences

Investigators

Study Director:	Gilead Study Director	Gilead Sciences

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT01818596 History of Changes
Other Study ID Numbers:	GS-US-292-0112; 2013-000516-25 ( EudraCT Number )
First Posted:	March 26, 2013
Results First Posted:	February 18, 2016
Last Update Posted:	November 16, 2018
Last Verified:	August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and-transparency.
Supporting Materials:	Study Protocol; Statistical Analysis Plan (SAP)
Time Frame:	18 months after study completion
Access Criteria:	A secured external environment with username, password, and RSA code.
URL:	http://www.gilead.com/research/disclosure-and-transparency

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Gilead Sciences:

HIV; HIV-1 Infected; Treatment Experienced; Treatment Naive

Additional relevant MeSH terms:

HIV Infections; Renal Insufficiency; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases	Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Kidney Diseases; Urologic Diseases