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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 December 2016 by Gilead Sciences
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT02016924
First received: December 16, 2013
Last updated: December 1, 2016
Last verified: December 2016
  Purpose

The primary objectives of this study are to 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, virologically suppressed, pediatric participants between the ages of 3 months to < 18 years of age.

This study 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 the 5 year long-term treatment.

There will be 2 parts to the study.

  • Part A: 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. On Day 1, participants will discontinue ritonavir and initiate once daily cobicistat (COBI) to be taken with their ATV or DRV plus their BR. All participants enrolled in Part A will participate in an intensive PK evaluation of COBI and ATV or DRV on Day 10. 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.
  • Part B: 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, 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.

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:
  • Pharmacokinetic (PK) Parameter: AUCtau of ATV and DRV [ Time Frame: Predose and up to 12 hours postdose on Day 10 ] [ Designated as safety issue: No ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

  • Incidence of Treatment-Emergent Adverse Events and Laboratory Abnormalities [ Time Frame: Up to 6 years 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 Parameter: Ctau of ATV, DRV, and Cobicistat [ Time Frame: Predose and up to 12 hours postdose on Day 10 ] [ Designated as safety issue: No ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

  • PK Parameter: Cmax of ATV, DRV, and Cobicistat [ Time Frame: Predose and up to 12 hours postdose on Day 10 ] [ Designated as safety issue: No ]
    Cmax is defined as the maximum observed concentration of drug.

  • PK Parameter: CL/F of ATV, DRV, and Cobicistat [ Time Frame: Predose and up to 12 hours postdose on Day 10 ] [ Designated as safety issue: No ]
    CL/F is defined as the apparent oral clearance following administration of the drug.

  • PK Parameter: AUCtau of Cobicistat [ Time Frame: Predose and up to 12 hours postdose on Day 10 ] [ Designated as safety issue: No ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

  • PK Parameter: Vz/F of Cobicistat [ Time Frame: Predose and up to 12 hours postdose on Day 10 ] [ Designated as safety issue: No ]
    Vz/F is defined as the apparent volume of distribution of the drug.

  • Percentage of Participants with Plasma HIV-1 RNA < 50 Copies/mL at Week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
  • Percentage of Participants with Plasma HIV-1 RNA < 50 Copies/mL at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Percentage of Participants with Plasma HIV-1 RNA < 50 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  • Percentage of Participants with Plasma HIV-1 RNA < 50 Copies/mL Every 12 Weeks After Week 48 [ Time Frame: Every 12 weeks after Week 48 ] [ Designated as safety issue: No ]
  • Time to Pure Virologic Failure [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
    Pure virologic failure includes participants who 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)

  • Change from Baseline in log10 HIV-1 RNA (Copies/mL) at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Change from Baseline in log10 HIV-1 RNA (Copies/mL) at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  • Change from Baseline in log10 HIV-1 RNA (Copies/mL) Every 12 Weeks After Week 48 [ Time Frame: Every 12 weeks after Week 48 ] [ Designated as safety issue: No ]
  • Change from Baseline in CD4+ Cell Count (Cells/µL) at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Change from Baseline in CD4+ Cell Count (Cells/µL) at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  • Change from Baseline in CD4+ Cell Count (Cells/µL) Every 12 Weeks After Week 48 [ Time Frame: Every 12 weeks after Week 48 ] [ Designated as safety issue: No ]
  • Change from Baseline in CD4 Percentage at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Change from Baseline in CD4 Percentage at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  • Change from Baseline in CD4 Percentage Every 12 Weeks After Week 48 [ Time Frame: Every 12 weeks after Week 48 ] [ Designated as safety issue: No ]
  • Acceptability and Palatability of Cobicistat [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
    Acceptability and palatability of cobicistat tablets and/or dispersible tablets in each cohort will be summarized.


Estimated Enrollment: 100
Study Start Date: January 2014
Estimated Study Completion Date: December 2024
Estimated Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A, Cohort 1
Participants ages 12 to <18 years old will receive cobicistat 150 mg (2 x 75 mg or 1 x 150 mg) with either ATV or DRV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: DRV
Tablets or liquid oral suspension administered once daily according to dosing recommendations per product monograph
Other Name: Prezista®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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 <12 years old will receive cobicistat 150 mg (2 x 75 mg or 1 x 150 mg if ≥ 25 kg) or cobicistat 90 mg (if ≥ 15 kg and < 25 kg) with either ATV or DRV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: DRV
Tablets or liquid oral suspension administered once daily according to dosing recommendations per product monograph
Other Name: Prezista®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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 <6 years old will receive cobicistat (dose to be determined) with either ATV or DRV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: DRV
Tablets or liquid oral suspension administered once daily according to dosing recommendations per product monograph
Other Name: Prezista®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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 <3 years old will receive cobicistat (dose to be determined) with ATV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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 <18 years old will receive cobicistat 150 mg (2 x 75 mg or 1 x 150 mg) with either ATV or DRV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: DRV
Tablets or liquid oral suspension administered once daily according to dosing recommendations per product monograph
Other Name: Prezista®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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 <12 years old will receive cobicistat 150 mg (2 x 75 mg or 1 x 150 mg if ≥ 25 kg) or cobicistat 90 mg (if ≥ 15 kg and < 25 kg) with either ATV or DRV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: DRV
Tablets or liquid oral suspension administered once daily according to dosing recommendations per product monograph
Other Name: Prezista®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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 <6 years old will receive cobicistat (dose to be determined) with either ATV or DRV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: DRV
Tablets or liquid oral suspension administered once daily according to dosing recommendations per product monograph
Other Name: Prezista®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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 <3 years old will receive cobicistat (dose to be determined) with ATV plus BR.
Drug: ATV
Capsules or powder administered once daily according to dosing recommendations per product monograph
Other Name: Reyataz®
Drug: Cobicistat
Tablets or dispersible tablets as an oral suspension administered orally once daily with food
Other Name: 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   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • HIV-1 infected treatment-experienced, virologically suppressed males and females aged 3 months to < 18 years at the Day 1 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 ≥ 25 kg (Cohorts 1 and 2), 15 kg to < 25 kg (Cohort 2), or to be determined (Cohorts 3 and 4) dependent upon age cohort
  • Adequate renal function
  • Adequate hematologic function
  • Adequate hepatic function defined as

    • Hepatic transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN)
    • Total bilirubin ≤ 1.5 mg/dL or a 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)

Key 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

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

  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, California
Pediatric Infectious Diseases Associate Recruiting
Long Beach, California, United States, 90806
Principal Investigator: Jagmohan Batra, MD         
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Principal Investigator: Joseph Church, MD         
University of Southern California Not yet recruiting
Los Angeles, California, United States, 90033
Principal Investigator: James Homans, MD, MPH         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Elizabeth McFarland, MD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20852
Principal Investigator: Natella Rakhmanina         
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         
Argentina
Fundacion Huesped Recruiting
Buenos Aires, Argentina
Principal Investigator: Pedro Cahn         
Thailand
Queen Savang Vadhana Memorial Hospital Not yet recruiting
Sriracha, Chonburi, Thailand
Principal Investigator: Wicharn Luesomboon         
Srinagarind Hospital Khon Kaen University Recruiting
Amphur Muang, Khon Kaen, Thailand
Principal Investigator: Pope Kosalaraksa         
Siriraj Hospital Mahidol University Recruiting
Bangkok, Krung Thep Maha Nakhon, Thailand
Principal Investigator: Kulkanya Chokephaibulkit         
The HIV NAT Research Collaboration Recruiting
Bangkok, Krung Thep Maha Nakhon, Thailand
Principal Investigator: Torsak Bunupuradah         
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Gilead Study Director Gilead Sciences
  More Information

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: December 1, 2016
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Thailand: Food and Drug Administration

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

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immune System Diseases
Slow Virus Diseases
Cobicistat
Atazanavir Sulfate
Darunavir
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
HIV Protease Inhibitors
Protease Inhibitors

ClinicalTrials.gov processed this record on December 08, 2016