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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT01818596
First received: March 22, 2013
Last updated: March 3, 2014
Last verified: March 2014
  Purpose

This open-label, multicenter, multi-cohort study is to assess the safety, tolerability, and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen (STR) 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 STR 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 Intervention Phase
HIV
HIV Infections
Drug: E/C/F/TAF
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Change from baseline in the estimated glomerular filtration rate (eGFR) at Week 24 [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]

    eGFR, a measure of blood filtration by the kidney, will be assessed by the following methods:

    • eGFR calculated by the Cockcroft-Gault (CG) formula (eGFR-CG)
    • eGFR calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method based on Cystatin C (mg/L) and adjusted for age and sex
    • eGFR calculated by the CKD-EPI method based on serum creatinine and adjusted for age, sex, and race


Secondary Outcome Measures:
  • Change from baseline in the eGFR at Week 48 and 96 [ Time Frame: Baseline to Weeks 48 and 96 ] [ Designated as safety issue: No ]

    eGFR will be assessed by the following methods:

    • eGFR-CG based on serum creatinine
    • eGFR-CKD-EPI based on Cystatin C (mg/L) and adjusted for age and sex
    • eGFR-CKD-EPI based on serum creatinine and adjusted for age, sex, and race

  • Plasma PD (true GFR) of E/C/F/TAF for participants enrolled in the PK/PD sub-study [ Time Frame: Weeks 2, 4, 8, and 24 ] [ Designated as safety issue: No ]
    True GFR will be directly measured using iohexol plasma clearance (CLiohexol)

  • Change from baseline in bone and renal biomarkers at Weeks 24, 48, and 96 [ Time Frame: Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]

    Bone biomarkers will be monitored by evaluating dual-energy X-ray absorptiometry (DEXA) scans of the spine and hip, and will include:

    • C-type collagen sequence (CTX)
    • Procollagen type 1 N-terminal propeptide (P1NP)

    Renal biomarkers will include:

    • Retinol binding protein
    • beta-2-microglobulin

  • Incidence of adverse events and graded laboratory abnormalities [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
  • Proportion of participants achieving virologic response at Weeks 24, 48, and 96 [ Time Frame: Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
    Virologic response is defined as HIV-1 RNA < 50 copies/mL using the FDA-defined snapshot analysis algorithm

  • Plasma PK of E/C/F/TAF including Cmax, Tmax, Clast, Tlast, Ctau, λz, AUCtau, and t1/2 for participants enrolled in the PK/PD sub-study [ Time Frame: Weeks 2, 4, and 8 ] [ Designated as safety issue: No ]
    • Cmax is defined as the maximum concentration of drug
    • Tmax is defined as the time of Cmax
    • Clast is defined as the last observable concentration of drug
    • Tlast is defined as the time of Clast
    • Ctau is defined as the observed drug concentration at the end of the dosing interval
    • λz is defined as the terminal elimination rate constant
    • AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval)
    • t1/2 is defined as the estimate of the terminal elimination half-life of the drug

  • TFV-DP concentration in peripheral blood mononuclear cell (PBMC) for participants enrolled in PK/PD sub-study [ Time Frame: Weeks 2, 4, and 8 ] [ Designated as safety issue: No ]

Enrollment: 245
Study Start Date: March 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: E/C/F/TAF
Participants will receive E/C/F/TAF for 96 weeks.
Drug: E/C/F/TAF
Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg (E/C/F/TAF) single-tablet regimen (STR) administered orally once daily with food

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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 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 is complete.

Cohort 2 (Treatment-naïve)

  • 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 PrEP (pre-exposure prophylaxis), or PEP (post-exposure prophylaxis), 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

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 (e.g., 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 STR
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01818596

  Show 122 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Marshall Fordyce, MD Gilead Sciences
  More Information

No publications provided

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01818596     History of Changes
Other Study ID Numbers: GS-US-292-0112, 2013-000516-25
Study First Received: March 22, 2013
Last Updated: March 3, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
HIV
Treatment Naive
HIV 1 Infected

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Renal Insufficiency
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Kidney Diseases
Urologic Diseases
Tenofovir
Emtricitabine
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on August 01, 2014