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

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:

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:

Plasma concentration of drug over time (AUCtau) of ATV and DRV on Day 10 [ Time Frame: Predose and postdose on Day 10 ] [ Designated as safety issue: No ]
Incidence of treatment-emergent adverse events and laboratory abnormalities [ Time Frame: Up to 5 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 profiles of ATV and DRV [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
This composite endpoint will measure the plasma PK profiles of ATV and DRV. PK parameters that will be measured include Ctau, Cmax, CL/F.
PK profile of cobicistat [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
This composite endpoint will measure the plasma PK profile of cobicistat. PK parameters that will be measured include AUCtau, Cmax, Ctau, CL/F, and Vz/F.
Percentage of participants with plasma HIV-1 RNA < 50 copies/mL [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
The time to pure virologic failure [ Time Frame: Up to 5 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) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
Change from baseline in CD4+ cell count (cells/µL) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
Acceptability (assessed by adherence) and palatability of cobicistat [ Time Frame: Up to 5 years ] [ 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: Up to 5 years ] [ Designated as safety issue: No ]
Change from baseline in CD4 percentage in participants < 5 years old [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]


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 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 (COBI) 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 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 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 (COBI) 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 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 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 (COBI) 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 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 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 (COBI) 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 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 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 (COBI) 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 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 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 (COBI) 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 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 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 (COBI) 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 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 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 (COBI) 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 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

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

Locations


United States, California
Pediatric Infectious Diseases Associate
Long Beach, California, United States, 90806
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
University of Southern California
Los Angeles, California, United States, 90033
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20852
United States, Florida
University of South Florida Clinic at Children's Medical Services
Tampa, Florida, United States, 33620
United States, Georgia
Grady Health System
Atlanta, Georgia, United States, 30308
United States, Massachusetts
Boston Medical Center
Boston, Massachusetts, United States, 02118
United States, New York
Bellevue Hospital
New York, New York, United States, 10016
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
University of Texas Health Science Center of Houston
Houston, Texas, United States, 77030
Argentina
Fundacion Huesped
Buenos Aires, Argentina
Thailand
Queen Savang Vadhana Memorial Hospital
Sriracha, Chonburi, Thailand
Srinagarind Hospital Khon Kaen University
Amphur Muang, Khon Kaen, Thailand
Siriraj Hospital Mahidol University
Bangkok, Krung Thep Maha Nakhon, Thailand
The HIV NAT Research Collaboration
Bangkok, Krung Thep Maha Nakhon, Thailand

Sponsors and Collaborators

Gilead Sciences

Investigators


Study Director:	Cheryl Pikora, MD	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:	July 8, 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 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 Atazanavir Sulfate	Darunavir 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 28, 2016