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

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ClinicalTrials.gov Identifier: NCT01335698
Recruitment Status : Completed
First Posted : April 14, 2011
Results First Posted : February 8, 2016
Last Update Posted : November 9, 2018
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Tracking Information
First Submitted Date  ICMJE April 13, 2011
First Posted Date  ICMJE April 14, 2011
Results First Submitted Date  ICMJE October 26, 2015
Results First Posted Date  ICMJE February 8, 2016
Last Update Posted Date November 9, 2018
Actual Study Start Date  ICMJE May 27, 2011
Actual Primary Completion Date September 10, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 11, 2018)
  • 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 [ Time Frame: Day one to week 300 (approximately 22-Jan-2018) ]
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment.
  • Number of Participants Who Experienced a SAE on ATV Powder [ Time Frame: Day one to week 300 (approximately 22-Jan-2018) ]
    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
  • Number of Participants With A Center of Disease Control and Prevention (CDC) Class C AIDS Event on ATV Powder [ Time Frame: Day one to week 300 (approximately 22-Jan-2018) ]
    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.
  • Number of Participants With Laboratory Test Results Meeting the Criteria for Grade 3-4 Abnormality on ATV Powder [ Time Frame: Day one to week 300 (approximately 22-Jan-2018) ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 13, 2011)
The frequency of serious adverse events, of Adverse event (AE)s leading to discontinuation, of AEs and of laboratory abnormalities. [ Time Frame: 48 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 11, 2018)
  • 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 [ Time Frame: Day 1 of treatment to weeks 24 and 48 ]
    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.
  • Mean Change From Baseline in HIV RNA on ATV Powder [ Time Frame: Baseline to Weeks 24 and 48 ]
    Human immunodeficiency virus ribonucleic acid (HIV RNA) change from baseline using observed values
  • Mean Change From Baseline in CD4 Percent on ATV Powder [ Time Frame: Baseline to Weeks 24 and 48 ]
    Change in CD4 percent using observed values
  • CD4 Cell Count Changes From Baseline on ATV Powder [ Time Frame: Baseline to Weeks 24 and 48 ]
    CD4 cell count change from baseline using observed values
  • Number of Participants With Emergent Genotypic Substitutions on ATV Powder Through Week 48 [ Time Frame: Baseline 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
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Baseline to Week 2 ]
    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
  • Minimum Plasma Concentration (Cmin) [ Time Frame: Baseline to Week 2 ]
    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
  • Area Under the Concentration-Time Curve [AUC(TAU)] [ Time Frame: Baseline to Week 2 ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: April 13, 2011)
  • Proportions of subjects with HIV ribonucleic acid (RNA) < 50 c/mL and < 400 c/mL at week 48 [ Time Frame: 48 weeks ]
  • ATV maximum concentration of drug (Cmax) for subjects weighing ≥ 25 - <35 kg and/or aged ≥ 6 - < 8 years [ Time Frame: 2 weeks after reaching this weight/age band ]
  • ATV minimum concentration of drug (Cmin) for subjects weighing ≥ 25 - <35 kg and/or aged ≥ 6 - < 8 years [ Time Frame: 2 weeks after reaching this weight/age band ]
  • ATV area under the curve (AUC) for subjects weighing ≥ 25 - <35 kg and/or aged ≥ 6 - < 8 years [ Time Frame: 2 weeks after reaching this weight/age band ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase IIIB Study Evaluating the Effects of Atazanavir Powder With Ritonavir in HIV-infected Pediatric Patients
Official Title  ICMJE 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)
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV
Intervention  ICMJE
  • Drug: Atazanavir Sulphate
    Other Names:
    • Reyataz
    • BMS-232632
  • Drug: Ritonavir
    Other Name: Norvir
Study Arms  ICMJE 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)
Interventions:
  • Drug: Atazanavir Sulphate
  • Drug: Ritonavir
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 19, 2017)
160
Original Estimated Enrollment  ICMJE
 (submitted: April 13, 2011)
75
Actual Study Completion Date  ICMJE January 22, 2018
Actual Primary Completion Date September 10, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Months to 11 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Brazil,   Chile,   Mexico,   Poland,   Romania,   Russian Federation,   South Africa,   Spain,   United Kingdom,   United States
Removed Location Countries Puerto Rico
 
Administrative Information
NCT Number  ICMJE NCT01335698
Other Study ID Numbers  ICMJE AI424-451
2010-024537-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bristol-Myers Squibb
Study Sponsor  ICMJE Bristol-Myers Squibb
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
PRS Account Bristol-Myers Squibb
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP