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

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 Intervention Model: Parallel Assignment Masking: None (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:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Atazanavir Darunavir Atazanavir sulfate Darunavir ethanolate Cobicistat

U.S. FDA Resources

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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
Percentage of Participants with Plasma HIV-1 RNA < 50 Copies/mL at Week 24 [ Time Frame: Week 24 ]
Percentage of Participants with Plasma HIV-1 RNA < 50 Copies/mL at Week 48 [ Time Frame: Week 48 ]
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 ]
Time to Pure Virologic Failure [ Time Frame: Up to 6 years ]
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 ]
Change from Baseline in log10 HIV-1 RNA (Copies/mL) at Week 48 [ Time Frame: Week 48 ]
Change from Baseline in log10 HIV-1 RNA (Copies/mL) Every 12 Weeks After Week 48 [ Time Frame: Every 12 weeks after Week 48 ]
Change from Baseline in CD4+ Cell Count (Cells/µL) at Week 24 [ Time Frame: Week 24 ]
Change from Baseline in CD4+ Cell Count (Cells/µL) at Week 48 [ Time Frame: Week 48 ]
Change from Baseline in CD4+ Cell Count (Cells/µL) Every 12 Weeks After Week 48 [ Time Frame: Every 12 weeks after Week 48 ]
Change from Baseline in CD4 Percentage at Week 24 [ Time Frame: Week 24 ]
Change from Baseline in CD4 Percentage at Week 48 [ Time Frame: Week 48 ]
Change from Baseline in CD4 Percentage Every 12 Weeks After Week 48 [ Time Frame: Every 12 weeks after Week 48 ]
Acceptability and Palatability of Cobicistat [ Time Frame: Up to Week 48 ]
Acceptability and palatability of cobicistat tablets and/or dispersible tablets in each cohort will be summarized.


Estimated Enrollment:	100
Actual Study Start Date:	January 16, 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)
Sexes Eligible for Study:	All
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, including observational studies, 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	Withdrawn
Los Angeles, California, United States, 90027
University of Southern California	Active, not recruiting
Los Angeles, California, United States, 90033
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	Not yet recruiting
Washington, D.C., 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	Not yet recruiting
Atlanta, Georgia, United States, 30308
Principal Investigator: Rana Chakraborty, MD
United States, Massachusetts
Boston Medical Center	Withdrawn
Boston, Massachusetts, United States, 02118
United States, New York
Bellevue Hospital	Not yet recruiting
New York, New York, United States, 10016
Principal Investigator: William Borkowsky, MD
SUNY Upstate Medical University	Not yet 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
Hospital General de Agudos Dr. Cosme Argerich	Not yet recruiting
Buenos Aires, Argentina, 1151
Principal Investigator: Diego Cecchini
Helios Salud S.A.	Recruiting
Buenos Aires, Argentina, C1131ACG
Principal Investigator: Maria R Bologna
Hospital Ramos Mejía	Not yet recruiting
Buenos Aires, Argentina, C1221ADC DF
Principal Investigator: Erica Stankievich
Fundacion Huesped	Not yet 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: Sivaporn Gatechompol

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 ( EudraCT Number )
Study First Received:	December 16, 2013
Last Updated:	August 29, 2017


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

Keywords provided by Gilead Sciences:


Pediatrics Adolescents HIV HIV-1 Treatment experienced

Additional relevant MeSH terms:


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

ClinicalTrials.gov processed this record on September 21, 2017