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. (see Contacts and Locations)
Verified October 2014 by Gilead Sciences
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT02016924
First received: December 16, 2013
Last updated: October 14, 2014
Last verified: October 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 80 participants will be enrolled sequentially by age cohort to evaluate the steady state PK and confirm dose of ATV/co and DRV/co. Following screening, enrolled participants will continue their suppressive regimen of either ATV/r or DRV/r once-daily plus their BR from Day -10 through Day -1. All participants 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, participants will discontinue ritonavir and initiate once daily cobicistat (COBI) to be taken with their ATV or DRV plus their BR. Following completion of the intensive PK visit, participants 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 20 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 participants 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 participants 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: BR
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) at Day 10 [ 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 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, and every 12 weeks after Week 48 for up to 5 years ] [ 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 from baseline in log10 HIV-1 RNA (copies/mL) [ Time Frame: Baseline to Weeks 24 and 48, and every 12 weeks after Week 48 for up to 5 years ] [ Designated as safety issue: No ]
  • Change from baseline in CD4+ cell count (cells/µL) [ Time Frame: Baseline to Weeks 24 and 48, and every 12 weeks after Week 48 for up to 5 years ] [ Designated as safety issue: No ]
  • 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 cobicistat tablets and/or dispersible tablets in each cohort will be summarized.

  • Change from baseline in CD4 percentage [ Time Frame: Baseline to Weeks 24 and 48, and every 12 weeks after Week 48 for up to 5 years ] [ Designated as safety issue: No ]
  • Change from baseline in CD4 percentage in participants < 5 years old [ Time Frame: Baseline to Weeks 24 and 48, and every 12 weeks after Week 48 for up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 100
Study Start Date: January 2014
Estimated Study Completion Date: August 2033
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 cobicistat with either ATV or DRV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: DRV
Darunavir (DRV) will be administered once daily (at a dose of 600, 675, and 800 mg depending on weight) according to manufacturer's instructions.
Other Name: Prezista®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part A, Cohort 2
Participants ages 6 to 11 years old will receive cobicistat with either ATV or DRV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: DRV
Darunavir (DRV) will be administered once daily (at a dose of 600, 675, and 800 mg depending on weight) according to manufacturer's instructions.
Other Name: Prezista®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part A, Cohort 3
Participants ages 3 to 5 years old will receive cobicistat with either ATV or DRV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: DRV
Darunavir (DRV) will be administered once daily (at a dose of 600, 675, and 800 mg depending on weight) according to manufacturer's instructions.
Other Name: Prezista®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part A, Cohort 4
Participants ages 3 months to 2 years old will receive cobicistat with ATV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 1
Participants ages 12 to 17 years old will receive cobicistat with either ATV or DRV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: DRV
Darunavir (DRV) will be administered once daily (at a dose of 600, 675, and 800 mg depending on weight) according to manufacturer's instructions.
Other Name: Prezista®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 2
Participants ages 6 to 11 years old will receive cobicistat with either ATV or DRV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: DRV
Darunavir (DRV) will be administered once daily (at a dose of 600, 675, and 800 mg depending on weight) according to manufacturer's instructions.
Other Name: Prezista®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 3
Participants ages 3 to 5 years old will receive cobicistat with either ATV or DRV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: DRV
Darunavir (DRV) will be administered once daily (at a dose of 600, 675, and 800 mg depending on weight) according to manufacturer's instructions.
Other Name: Prezista®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, maraviroc, etravirine, rilpivirine, dolutegravir, and investigational antiretroviral agents.
Experimental: Part B, Cohort 4
Participants ages 3 months to 2 years old will receive cobicistat with ATV plus BR.
Drug: ATV
Atazanavir (ATV) will be administered once daily (at a dose of 150, 200, or 300 mg depending on weight) according to manufacturer's instructions.
Other Name: Reyataz®
Drug: Cobicistat
Cobicistat 150 mg will be administered as two 75 mg tablets (cohorts 1 and 2), or 20 mg dispersible tablets as an oral suspension (cohorts 3 and 4).
Other Names:
  • COBI
  • GS-9350
Drug: BR
Background regimen (BR) 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, delavirdine, 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)
  • 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 individuals on DRV/r, total bilirubin less than or equal to 1.5 mg/dL and normal direct bilirubin. For individuals on ATV/r, total bilirubin less than or equal to 3 mg/dL and normal direct bilirubin.
  • Negative serum pregnancy test
  • Individuals 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 individuals taking DRV/r must have no history of DRV resistance associated mutations.
  • Males and females 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:

  • Individuals 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 individuals 6 months of age or older
    • At anytime for individuals 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: individuals 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: individuals with positive HBV surface antibody and no evidence of active HBV infection are permitted to enroll.
  • Individuals with clinically significant abnormal ECGs
  • Have any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with treatment, assessment, or compliance with the protocol.
  • Individuals 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 females.
  • Current alcohol or substance abuse judged by the investigator to potentially interfere with 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.
  • Individuals receiving ongoing therapy with any medication that is not to be taken with COBI or a component of the BR
  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: NCT02016924

Contacts
Contact: Gilead Study Team GSUS2160128@gilead.com

Locations
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Elizabeth McFarland, MD         
United States, Florida
University of South Florida Clinic at Children's Medical Services Recruiting
Tampa, Florida, United States, 33620
Principal Investigator: Carina Rodriguez, MD         
United States, Georgia
Grady Health System Recruiting
Atlanta, Georgia, United States, 30308
Principal Investigator: Rana Chakraborty, MD         
United States, Massachusetts
Boston Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Principal Investigator: Ellen R Cooper, MD         
United States, New York
Bellevue Hospital Recruiting
New York, New York, United States, 10016
Principal Investigator: William Borkowsky, MD         
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
Principal Investigator: Aditya Gaur, MD         
United States, Texas
University of Texas Health Science Center of Houston Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Gloria Heresi, MD         
Thailand
The HIV NAT Research Collaboration Recruiting
Pathumwan, Bangkok, Thailand
Principal Investigator: Torsak Bunupuradah         
Srinagarind Hospital Khon Kaen University Recruiting
Amphur Muang, Khon Kaen, Thailand
Principal Investigator: Pope Kosalaraksa         
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Martin Rhee, 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: October 14, 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
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Atazanavir
Darunavir
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
HIV Protease Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014