Pharmacokinetics, Safety, and Efficacy of Cobicistat-boosted Atazanavir or Cobicistat-boosted Darunavir in HIV-1 Infected, Treatment-Experienced, Virologically Suppressed Pediatric Subjects

This study is currently recruiting participants.
Verified March 2014 by Gilead Sciences
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT02016924
First received: December 16, 2013
Last updated: March 6, 2014
Last verified: March 2014
  Purpose

This study will evaluate the steady-state pharmacokinetics (PK) and confirm the dose of Cobicistat-boosted Atazanavir (ATV/co) or Cobicistat-boosted Darunavir (DRV/co) in HIV-1 infected antiretroviral treatment-experienced pediatric participants between the ages of 3 months to < 18 years of age.

It will also evaluate the safety, tolerability, and efficacy of ATV/co or DRV/co each co-administered with a background regimen (BR) through 48 weeks and during long-term treatment (total of 5 years).

There will be 2 parts to the study.

  • Part A: A minimum of 54 participants will be enrolled to evaluate the steady state PK and confirm dose of ATV/co and DRV/co. Following screening, enrolled subjects will continue their suppressive regimen of either ATV/r or DRV/r once-daily plus their BR from Day -10 through Day -1. The last dose of ritonavir will be administered on Day -1. All subjects enrolled in Part A will participate in an Intensive PK evaluation of ATV or DRV on Day -1 and COBI and ATV or DRV on Day 10. On Day 1, subjects will initiate once daily cobicistat (COBI) to be taken with their ATV or DRV plus their BR. Following completion of the Intensive PK visit, subjects will continue to receive COBI coadministered with DRV or ATV each with a BR and return for scheduled study visits through 5 years or as specified in Part B.
  • Part B: A minimum of 46 participants will be enrolled to evaluate the safety, tolerability, and efficacy of the ATV/co or DRV/co regimen. For all cohorts in Part B, additional subjects will be screened and initiated sequentially by each age cohort following confirmation of appropriate COBI exposure and PI exposures from the corresponding age cohort in Part A.

Overall, at least 100 subjects in Parts A and B combined are planned to complete 5 years of the COBI containing treatment regimens.


Condition Intervention Phase
Acquired Immune Deficiency Syndrome (AIDS)
HIV Infections
Drug: ATV
Drug: DRV
Drug: Cobicistat
Drug: Background regimen
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2/3, Multicenter, Open-label, Multicohort, Two-Part Study Evaluating Pharmacokinetics (PK), Safety, and Efficacy of Cobicistat-boosted Atazanavir (ATV/co) or Cobicistat-boosted Darunavir (DRV/co), Administered With Background Regimen (BR) in HIV-1 Infected, Treatment-Experienced, Virologically Suppressed Pediatric Subjects

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Plasma pharmacokinetics (PK) parameters of ATV and DRV (as measured by AUCtau) [ Time Frame: Baseline to Day 10 ] [ Designated as safety issue: No ]
    AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).

  • Incidence of treatment-emergent adverse events and laboratory abnormalities [ Time Frame: Baseline to Year 5 plus 30 days ] [ Designated as safety issue: No ]
    Incidence of adverse events and graded laboratory abnormalities will be summarized across the participant population. Graded laboratory abnormalities are those with at least one grade shift from baseline using the Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.


Secondary Outcome Measures:
  • PK parameters of ATV and DRV (as measured by Ctau, Cmax, CL/F. and Vz/F) and Cobicistat (as measured by AUCtau, Cmax, Ctau, CL/F, and Vz/F) [ Time Frame: Baseline to Year 5 ] [ Designated as safety issue: No ]
    • Ctau is defined as the observed drug concentration at the end of the dosing interval
    • Cmax is defined as the maximum concentration of drug
    • AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval)
    • CL/F is the apparent oral clearance following administration of the drug
    • Vz/F is the apparent volume of distribution of the drug

  • Percentage of participants with plasma HIV-1 RNA < 50 copies/mL [ Time Frame: Weeks 12, 24, and 48 ] [ Designated as safety issue: No ]
  • The time to pure virologic failure [ Time Frame: Baseline to Year 5 ] [ Designated as safety issue: No ]
    Pure Virologic failure includes participants who do not achieve confirmed suppression (ie, HIV-1 RNA < 50 copies/mL on 2 consecutive visit) or have confirmed rebound (ie, HIV-1 RNA ≥ 50 copies/mL on 2 consecutive visits or the last available HIV-1 RNA ≥ 50 copies/mL during study followed by premature discontinuation of study) after achieving confirmed suppression.

  • Change in CD4+ cell count and CD4 percentage [ Time Frame: Baseline to Weeks 24 and 48 ] [ Designated as safety issue: No ]
  • Assessment of physical development using Tanner Stages [ Time Frame: Day 1, Weeks 24 and 48, and age of first menses ] [ Designated as safety issue: No ]
    Tanner Stage assessments will be performed for participants ≥ 6 years of age at the time of the visit, at Day 1, Week 24, and Week 48. Once a participant is determined to be Tanner Stage 5, Tanner Stage assessments will no longer be performed. Date of first menses will be documented.

  • Acceptability (assessed by adherence) and palatability of cobicistat [ Time Frame: Baseline to Year 5 ] [ Designated as safety issue: No ]
    Acceptability (assessed by adherence) and palatability of COBI tablets and/or dispersible tablets in each cohort will be summarized.


Estimated Enrollment: 100
Study Start Date: January 2014
Estimated Study Completion Date: August 2021
Estimated Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A, Cohort 1
Participants ages 12 to 17 years old will receive either ATV/co or DRV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: DRV
DRV will be administered once daily (at a dose of 350, 385, 420, 455, 490, 600, 675, or 800 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part A, Cohort 2
Participants ages 6 to 11 years old will receive either ATV/co or DRV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: DRV
DRV will be administered once daily (at a dose of 350, 385, 420, 455, 490, 600, 675, or 800 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part A, Cohort 3
Participants ages 3 to 5 years old will receive either ATV/co or DRV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: DRV
DRV will be administered once daily (at a dose of 350, 385, 420, 455, 490, 600, 675, or 800 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part A, Cohort 4
Participants ages 3 months to 2 years old will receive ATV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 1
Participants ages 12 to 17 years old will receive either ATV/co or DRV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: DRV
DRV will be administered once daily (at a dose of 350, 385, 420, 455, 490, 600, 675, or 800 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 2
Participants ages 6 to 11 years old will receive either ATV/co or DRV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: DRV
DRV will be administered once daily (at a dose of 350, 385, 420, 455, 490, 600, 675, or 800 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 3
Participants ages 3 to 5 years old will receive either ATV/co or DRV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: DRV
DRV will be administered once daily (at a dose of 350, 385, 420, 455, 490, 600, 675, or 800 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 4
Participants ages 3 months to 2 years old will receive ATV/co plus BR.
Drug: ATV
ATV will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (Cohorts 1 and 2), or 20 mg dispersible tablets to form a suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: Background regimen
Background regimen must include 2 nucleoside reverse transcriptase inhibitors (NRTI). The BR may contain additional antiretroviral agents except for the following disallowed agents: saquinavir, indinavir, nelfinavir, double protease inhibitor (PI) regimens, raltegravir, elvitegravir, efavirenz, nevirapine, delaviridine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.

  Eligibility

Ages Eligible for Study:   3 Months to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 infected treatment-experienced males and females aged 3 months to < 18 years at the Day -10 visit (according to requirements of enrolling Cohort)
  • Subjects are able to provide written assent if they have the ability to read and write
  • Parent or legal guardian able to provide written informed consent prior to any screening evaluations and willing to comply with study requirements
  • Body weight at screening greater than 6.25 kg, 10.25 kg, or 15 kg dependent upon age cohort
  • Adequate renal function
  • Adequate hematologic function
  • Hepatic transaminases (AST and ALT) less than or equal to 5 x upper limit of normal (ULN)
  • For subjects on DRV/r, total bilirubin less than or equal to 1.5 mg/dL and normal direct bilirubin. For subjects on ATV/r, total bilirubin less than or equal to 3 mg/dL and normal direct bilirubin.
  • Negative serum pregnancy test
  • Subjects with evidence of suppressed viremia (< 50 copies/mL) at study entry
  • Stable antiretroviral regimen including 2 nucleoside reverse transcriptase inhibitors and either ritonavir-boosted atazanavir or ritonavir-boosted darunavir once or twice daily as per product label for a minimum of 3 months prior to the screening visit. Treatment-experienced pediatric subjects taking DRV/r must have no history of DRV resistance associated mutations.
  • Male and female subjects of childbearing potential must agree to utilize highly effective contraception methods while on study treatment or agree to abstain from heterosexual intercourse throughout the study period and for 30 days following the last dose of study drug
  • Documented negative screening for active pulmonary tuberculosis (TB) per local standard of care within 6 months of a screening visit
  • Must be willing and able to comply with all study requirements
  • No opportunistic infection within 30 days of study entry (at Day -10)

Exclusion Criteria:

  • Subjects with CD4+ cell counts at screening of less than 200 cells/mm^3
  • An AIDS defining condition with onset within 30 days prior to screening
  • Life expectancy of less than 1 year
  • An ongoing serious infection requiring systemic antibiotic therapy at the time of screening.
  • Evidence of active pulmonary or extra-pulmonary tuberculosis disease:

    • Within 3 months of the Screening visit for all subjects 6 months of age or older
    • At anytime for subjects younger than 6 months
  • Anticipated requirement for rifamycin treatment while participating in the study. Note: prophylactic isoniazid therapy for latent TB is allowed.
  • Active hepatitis C virus (HCV) infection. Note: subjects with positive HCV antibody and without detectable HCV RNA are permitted to enroll.
  • Positive Hepatitis B surface antigen or other evidence of active hepatitis B virus (HBV) infection. Note: Subjects with positive HBV surface antibody and no evidence of active HBV infection are permitted to enroll.
  • Subjects with clinically significant abnormal ECGs
  • Anticipated requirement for rifamycin treatment while participating in the study.
  • Active HCV infection
  • Positive Hepatitis B surface antigen or other evidence of active HBV infection Note: Subjects with positive HBV surface antibody and no evidence of active HBV infection are permitted to enroll
  • Have any serious or active medical or psychiatric illness which, in the opinion of the Investigator, would interfere with subject treatment, assessment, or compliance with the protocol.
  • Subjects experiencing decompensated cirrhosis
  • A history of or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma.
  • Pregnant or lactating subjects.
  • Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance.
  • Have history of significant drug sensitivity or drug allergy.
  • Known hypersensitivity to the study drug, the metabolites, or formulation excipients.
  • Have previously participated in an investigational trial involving administration of any investigational agent within 30 days prior to the study dosing.
  • Participation in any other clinical trial without prior approval from sponsor is prohibited while participating in this trial.
  • Subjects receiving ongoing therapy with any medication that is not to be taken with COBI or a component of the BR
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT02016924

Contacts
Contact: Patrick Pakele 650-372-7036 Patrick.pakele@gilead.com

Locations
United States, Florida
University of South Florida College of Medicine Recruiting
Tampa, Florida, United States, 33606
Principal Investigator: Jorge Lujan, MD         
United States, New York
SUNY Upstate Medical University Recruiting
Syracuse, New York, United States, 13210
Principal Investigator: Leonard Weiner, MD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact    901-495-5067      
Principal Investigator: Aditya Gaur, MD         
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Sean Bennett, MD Gilead Sciences
  More Information

No publications provided

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02016924     History of Changes
Other Study ID Numbers: GS-US-216-0128, 2013-001402-28
Study First Received: December 16, 2013
Last Updated: March 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
Pediatrics
Adolescents
HIV
HIV-1
Treatment experienced

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Anti-Retroviral Agents
Atazanavir
Darunavir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents

ClinicalTrials.gov processed this record on April 15, 2014