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

• 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: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HIV	Drug: Atazanavir Sulphate; Drug: Ritonavir	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 160 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: May 27, 2011
• Actual Primary Completion Date: September 10, 2014
• Actual Study Completion Date: January 22, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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
3. 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.
4. 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.

Secondary Outcome Measures :

1. 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.
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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

Eligibility Criteria

• Ages Eligible for Study: 3 Months to 11 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, District of Columbia

Children'S National Medical Center

Washington, District of Columbia, United States, 20010

United States, New York

SUNY Upstate Medical University

Syracuse, New York, United States, 13210

Argentina

Local Institution

Buenos Aires, Bs As, Buenos Aires, Argentina, 1141

Local Institution

Bunos Aires, Buenos Aires, Argentina, 1425

Brazil

Local Institution

Recife, Pernambuco, Brazil, 50070-500

Local Institution

Porto Alegre, RIO Grande DO SUL, Brazil, 90020-090

Local Institution

Porto Alegre, RIO Grande DO SUL, Brazil, 90035-903

Local Institution

Ribeirao Preto, SAO Paulo, Brazil, 14049-900

Chile

Local Institution

Santiago, Metropolitana, Chile, 8380418

Local Institution

Santiago, Metropolitana, Chile

Mexico

Local Institution

Df, Distrito Federal, Mexico, 06720

Local Institution

Guadalajara, Jalisco, Mexico, 44160

Local Institution

Guadalajara, Jalisco, Mexico, 44280

Local Institution

Merida, Yucatan, Mexico, 97000

Local Institution

Oaxaca, Mexico, 71256

Local Institution

Puebla, Mexico, 72000

Poland

Local Institution

Warszawa, Poland, 01-201

Romania

Local Institution

Bucharest, Romania, 72205

Russian Federation

Local Institution

Smolensk, Russian Federation, 214006

Local Institution

St. Petersburg, Russian Federation, 189635

Local Institution

St.petersburg, Russian Federation, 198103

South Africa

Local Institution

Port Elizabeth, Eastern CAPE, South Africa, 6001

Local Institution

Port Elizabeth, Eastern CAPE, South Africa, 6014

Local Institution

Bloemfontein, FREE State, South Africa, 9301

Local Institution

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

Parrow Valley, Western CAPE, South Africa, 7505

Spain

Local Institution

Barcelona, Spain, 08950

Local Institution

Madrid, Spain, 28041

United Kingdom

Local Institution

Birmingham, WEST Midlands, United Kingdom, B9 5ST

Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

  Study Documents (Full-Text)

Documents provided by Bristol-Myers Squibb:

Study Protocol  [PDF] April 15, 2014

Statistical Analysis Plan  [PDF] November 2, 2017

More Information

Additional Information:

BMS Clinical Trial Patient Recruiting 

Investigator Inquiry Form 

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01335698
• Other Study ID Numbers: AI424-451; 2010-024537-23 ( EudraCT Number )
• First Posted: April 14, 2011
• Results First Posted: February 8, 2016
• Last Update Posted: November 9, 2018
• Last Verified: October 2018

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

Keywords provided by Bristol-Myers Squibb:

Pediatric

Additional relevant MeSH terms:

Atazanavir Sulfate; Ritonavir; 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