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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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HIV

Intervention / Treatment
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* Drug: Atazanavir Sulphate
* Drug: Ritonavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: Atazanavir + Ritonavir<br>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: Atazanavir Sulphate<br> <br> * Other names: BMS-232632;Drug: Ritonavir<br> <br> * Other names: Norvir;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric