Phase IIIB Study Evaluating the Effects of Atazanavir Powder With Ritonavir in HIV-infected Pediatric Patients (PRINCE2)

A Prospective Single Arm, Open-label, International, Multicenter Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Atazanavir (ATV) Powder Boosted With Ritonavir (RTV) With an Optimized NRTI Background Therapy, in Human Immunodeficiency Virus (HIV) Infected, Antiretroviral, Naive and Experienced Pediatric Subjects From 3 Months to Less Than 11 Years.(Pediatric Atazanavir International Clinical Evaluation: the PRINCE II Study)

The purpose of this study is to describe the safety, efficacy, and pharmacokinetics of a regimen of atazanavir powder boosted with ritonavir and an optimized dual nucleoside reverse transcriptase inhibitor in pediatric patients aged ≥3 months to <11 years.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Ritonavir; Drug: Atazanavir Sulphate

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Buenos Aires, Bs As, Buenos Aires, Argentina, 1141
      • Local Institution
    • Bunos Aires, Buenos Aires, Argentina, 1425
      • Local Institution
• Brazil
  • Pernambuco
    • Recife, Pernambuco, Brazil, 50070-500
      • Local Institution
  • RIO Grande DO SUL
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90035-903
      • Local Institution
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90020-090
      • Local Institution
  • SAO Paulo
    • Ribeirao Preto, SAO Paulo, Brazil, 14049-900
      • Local Institution
• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile
      • Local Institution
    • Santiago, Metropolitana, Chile, 8380418
      • Local Institution
• Mexico
  • Oaxaca, Mexico, 71256
    • Local Institution
  • Puebla, Mexico, 72000
    • Local Institution
  • Distrito Federal
    • Df, Distrito Federal, Mexico, 06720
      • Local Institution
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44160
      • Local Institution
    • Guadalajara, Jalisco, Mexico, 44280
      • Local Institution
  • Yucatan
    • Merida, Yucatan, Mexico, 97000
      • Local Institution
• Poland
  • Warszawa, Poland, 01-201
    • Local Institution
• Romania
  • Bucharest, Romania, 72205
    • Local Institution
• Russian Federation
  • Smolensk, Russian Federation, 214006
    • Local Institution
  • St. Petersburg, Russian Federation, 189635
    • Local Institution
  • St.petersburg, Russian Federation, 198103
    • Local Institution
• South Africa
  • Eastern CAPE
    • Port Elizabeth, Eastern CAPE, South Africa, 6014
      • Local Institution
    • Port Elizabeth, Eastern CAPE, South Africa, 6001
      • Local Institution
  • FREE State
    • Bloemfontein, FREE State, South Africa, 9301
      • Local Institution
  • Gauteng
    • Benoni, Gauteng, South Africa, 1501
      • Local Institution
    • Coronationville, Gauteng, South Africa, 2092
      • Local Institution
    • Pretoria, Gauteng, South Africa, 0001
      • Local Institution
    • Soweto, Gauteng, South Africa, 2001
      • Local Institution
  • Western CAPE
    • Parrow Valley, Western CAPE, South Africa, 7505
      • Local Institution
• Spain
  • Barcelona, Spain, 08950
    • Local Institution
  • Madrid, Spain, 28041
    • Local Institution
• United Kingdom
  • WEST Midlands
    • Birmingham, WEST Midlands, United Kingdom, B9 5ST
      • Local Institution
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • New York
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Key Inclusion Criteria:

• Confirmed HIV-1 infection diagnosed by protocol criteria
• Screening HIV RNA level ≥1000 copies/mL
• ≥3 months to <11 years of age at time of first treatment
• Antiretroviral-naive or -experienced
• At screening, all participants must have genotypic sensitivity to atazanavir and at least 2 nucleoside reverse transcriptase inhibitors (NRTIs), which must be approved for pediatric use at the local country.
• Antiretroviral-experienced patients must also have documented phenotypic sensitivity at screening to atazanavir (Fold Change in susceptibility <2.2) and to at least 2 NRTIs that are approved in their country

Key Exclusion Criteria:

• Experienced participants who received atazanavir or atazanavir/ritonavir at any time prior to study enrollment or who have a history of 2 or more protease inhibitor failures
• Antiretroviral-naïve or -experienced HIV-1-infected patients with contraindication to study medications
• Cardiac rhythm abnormalities
• Need for tenofovir
• Weight <5 or ≥35kg
• >Grade 2 abnormality in aspartate transaminase/alanine transaminase levels
• Coinfection with either hepatitis B or C virus
• Any active Centers for Disease Control and Prevention Category C clinical condition

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Stage 1: Atazanavir + Ritonavir; Participants received atazanavir powder orally (dosed by weight: 5 to <10 kg=150 mg, 5 to <10 kg=200 mg, 10 to <15 kg=200 mg, 15 to <25 kg=250 mg, 25 to <35 kg=300 mg) once daily for 24 to 48 weeks or a weight ≥35 kg. Participants also received ritonavir once daily for 24 to 48 weeks or weight ≥35 kg in the form of 80-mg/mL solution, orally (dosed by weight 5 to <25 kg=80 mg, 25 to <35 kg=100 mg); 100-mg capsule, orally (dosed by weight 25 to <35 kg=100 mg); or 100-mg tablet, orally (dosed by weight 25 to <35 kg=100 mg)

Drug: Ritonavir; Other Names: Norvir; Drug: Atazanavir Sulphate; Other Names: Reyataz; BMS-232632

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Died and With Adverse Events (AEs) Leading to Discontinuation, Hyperbilirubinemia, Jaundice, First-degree Arterioventricular Block, Tachycardia, and Rash on ATV Powder	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment.	Day one to week 300 (approximately 22-Jan-2018)
Number of Participants Who Experienced a SAE on ATV Powder	SAE= any of the the following: is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event (defined as a medical event(s) that may not be immediately life threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization	Day one to week 300 (approximately 22-Jan-2018)
Number of Participants With A Center of Disease Control and Prevention (CDC) Class C AIDS Event on ATV Powder	The CDC disease staging system assesses the severity of HIV disease by CD4 cell counts and by the presence of specific HIV-related conditions. CD4 counts are classified as 1: ≥500 cells/µL, 2: 200-499 cells/µL, and 3: <200 cells/µL. Children with HIV infection are also classified in each of several categories. Category N: Not symptomatic. Category A: Mildly symptomatic. Category B: Moderately symptomatic. Category C: Severely symptomatic.	Day one to week 300 (approximately 22-Jan-2018)
Number of Participants With Laboratory Test Results Meeting the Criteria for Grade 3-4 Abnormality on ATV Powder	Criteria of the Division of AIDS for grading the severity of adult and pediatric adverse events as follows: Grade (Gr) 1=mild; Gr 2=moderate; Gr 3=severe; Gr 4=potentially life-threatening. Neutrophils (absolute) (adult and infants >7 days): Gr 1=1.000-1300/mm^3; Gr 2=750-999 mm^3; Gr 3=500-749 mm^3; Gr 4= <500 mm^3. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase: Gr 1=1.25-2.5*upper limit of normal (ULN); Gr 2=2.6-5.0*ULN; Gr 3=5.1-10.0*ULN; Gr 4= >10.0*ULN. Bilirubin, total (adults and infants >14 days): Gr 1=1.1-1.5*ULN; Gr 2=1.6-2.5*ULN; Gr 3=2.6-5.0*ULN; Gr 4= >5.0*ULN. Lipase: Gr 1=1.1-1.5*ULN; Gr 2=1.6-3.0*ULN; Gr 3=3.1-5.0*ULN; Gr 4= >5.0*ULN. Bicarbonate, serum low: Gr 1=16.0 mEq/L-<lower limit of normal; Gr 2=11.0-15.9 mEq/L; Gr 3=8.0-10.9 mEq/L; Gr 4= <8 mEq/L. By criteria of the World Health Organization: Amylase: Gr 1=1.0-1.39*ULN; Gr 2=1.40-2.09*ULN; Gr 3.=2.10-5.0*ULN; Gr 4= >5.0*ULN.	Day one to week 300 (approximately 22-Jan-2018)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With HIV RNA <50 Copies/mL and <400 Copies/mL in the Week 24 Atazanavir Powder Cohort and the Eligible Week 48 Atazanavir Powder Cohort	Virologic success includes patients with HIV RNA <50 copies/mL. Two cohorts were assessed: The Atazanavir Powder Cohort=patients who received treatment and did not switch to capsule before analysis Week 24 or before their HIV RNA Week 24 assessment, and the Eligible Week 48 Atazanavir Powder Cohort=patients who initiated study treatment at least 48 weeks before last person last visit and did not switch to capsule before analysis Week 48 or before their HIV RNA Week 48 assessment.	Day 1 of treatment to weeks 24 and 48
Mean Change From Baseline in HIV RNA on ATV Powder	Human immunodeficiency virus ribonucleic acid (HIV RNA) change from baseline using observed values	Baseline to Weeks 24 and 48
Mean Change From Baseline in CD4 Percent on ATV Powder	Change in CD4 percent using observed values	Baseline to Weeks 24 and 48
CD4 Cell Count Changes From Baseline on ATV Powder	CD4 cell count change from baseline using observed values	Baseline to Weeks 24 and 48
Number of Participants With Emergent Genotypic Substitutions on ATV Powder Through Week 48	Newly emergent substitutions are on-treatment substitutions that were not detected at baseline.Viral rebound in the resistance analysis was defined as: Less than a 1 log10 drop from baseline in plasma HIV RNA level by Week 16, confirmed by a second plasma HIV RNA level redrawn within 2 and 4 weeks from original sample. Or, a plasma HIV RNA level >200 c/mL after Week 24, confirmed by a second plasma HIV RNA level redrawn within 2 and 4 weeks from original sample. Or, repeated plasma HIV RNA level ≥50 c/mL after Week 48. Viral rebound was defined as a plasma HIV RNA level ≥400 c/mL at any time in a patient who had previously achieved a plasma HIV RNA level <50 c/mL. Or, a plasma HIV RNA level ≥50 c/mL and <1,000 c/mL followed by a return to virologic suppression was considered a viral blip and not a viral rebound. NRTI=nucleoside reverse transcriptase inhibitor	Baseline through Week 48
Maximum Observed Plasma Concentration (Cmax)	To describe the PK profile of ATV powder formulation with RTV in pediatric subjects weighing 25 - < 35 kg and/or 6 to < 11 years of age and for the new 5 - < 10 kg cohort (200 mg ATV and 80 mg RTV) in terms of ATV Cmax	Baseline to Week 2
Minimum Plasma Concentration (Cmin)	To describe the PK profile of ATV powder formulation with RTV in pediatric subjects weighing 25 - < 35 kg and/or 6 to < 11 years of age and for the new 5 - < 10 kg cohort (200 mg ATV and 80 mg RTV) in terms of ATV Cmin	Baseline to Week 2
Area Under the Concentration-Time Curve [AUC(TAU)]	To describe the PK profile of ATV powder formulation with RTV in pediatric subjects weighing 25 - < 35 kg and/or 6 to < 11 years of age and for the new 5 - < 10 kg cohort (200 mg ATV and 80 mg RTV) in terms of ATV AUC	Baseline to Week 2

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2011
• Primary Completion (Actual): September 10, 2014
• Study Completion (Actual): January 22, 2018

Study Registration Dates

• First Submitted: April 13, 2011
• First Submitted That Met QC Criteria: April 13, 2011
• First Posted (Estimate): April 14, 2011

Study Record Updates

• Last Update Posted (Actual): November 9, 2018
• Last Update Submitted That Met QC Criteria: October 11, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Pediatric
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Atazanavir Sulfate
• Other Study ID Numbers: AI424-451; 2010-024537-23 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No