PRINCE: Study of Atazanavir (ATV)/Ritonavir (RTV)

NCT01099579 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: AI424-3972009-016361-28
• Study Type: interventional
• Target: 82
• Locations: 6 countries
• Sites: 18

Brief Summary

The purpose of this study is to determine whether atazanavir powder combined with ritonavir is safe and well tolerated and produces appropriate drug exposure in children ≥3 months to \<6 years of age.

Conditions

HIV Infections

Keywords

HIV, Pediatric

Outcome Measures

Primary Outcomes (4)

• Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation

  AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

  From Day 1 to Week 48

• Number of Participants With Laboratory Test Results With Worst Toxicity of Grade 3-4

  ALT=alanine aminotransferase; SGPT=serum glutamic-pyruvic transaminase; AST=aspartate aminotransferase; SGOT=serum glutamic-oxaloacetic transaminase; ULN=upper limit of normal. Grading by the National Institute of Health Division of AIDs and World Health Organization criteria. Hemoglobin (g/dL): Grade (Gr)1=9.5-11.0; Gr 2=8.0-9.4; Gr 3=6.5-7.9; Gr 4=\<6.5. Neutrophils, absolute (/mm\^3): Gr 1=\>=1000-\<1500; Gr 2= \>=750-\<1000; Gr 3=\>=500-\<750; Gr 4=\<500. ALT/SGPT (\*ULN): Gr 1=1.25-2.5; Gr 2=2.6-5; Gr 3=5.1-10; Gr 4=\>10. AST/SGOT (\*ULN): Gr 1=1.25-2.5; Gr 2=2.6-5; Gr 3=5.1-10; Gr 4=\>10. Alkaline phosphatase(\*ULN): Gr 1=1.25-2.5; Gr 2=2.6-5: Gr 3=5.1-10; Gr 4=\>10. Total bilirubin (\*ULN): Gr 1=1.1-1; Gr 2=1.6-2.5; Gr 3=2.6-5; Gr 4=\>5. Amylase (\*ULN): Gr 1=1.10-39; Gr 2=1.40-2; Gr 3=2.10-5.0; Gr 4=\>5.0. Lipase (\*ULN): Gr 1=1.10-1.39: Gr 2=1.40-2; Gr 3=2.10-5.0; Gr 4=\>5.0. Uric acid (mg/dL): Gr 1=7.5-10.0; Gr 2=10.1-12.0; Gr 3=12.1-15.0; Gr 4=\>15.

  After Day 1 to Week 48

• Electrocardiogram Changes From Baseline in PR Interval, QTC Bazett, and QTC Fridericia at Week 48

  Electrocardiogram parameters were measured at baseline for QTC Bazett, QTC Fridericia, and PR interval. The mean change from baseline at week 48 is reported by arm in milliseconds.

  From Baseline to Week 48

• Number of Participants With Centers for Disease Control (CDC) Class C AIDS Events

  CDC Class C events are AIDS-defining events that include recurrent bacterial pneumonia (\>=2 episodes in 12 months); candidiasis of the bronchi, trachea, lungs, or esophagus; invasive cervical carcinoma; disseminated or extrapulmonary coccidioidomycosis; extrapulmonary cryptococcosis; chronic intestinal cryptosporidiosis (\>1 month); cytomegalovirus disease; HIV-related encephalopathy; herpes simplex: chronic ulcers, or bronchitis, pneumonitis, or esophagitis; disseminated or extrapulmonary histoplasmosis; chronic intestinal isosporiasis; Kaposi sarcoma; immunoblastic or primary brain Burkitt lymphoma; mycobacterium avium complex, kansasii, or tuberculosis; mycobacterium, other species; Pneumocystis carinii pneumonia; progressive multifocal leukoencephalopathy; Salmonella septicemia; recurrent toxoplasmosis of brain; HIV wasting syndrome (involuntary weight loss \>10% of baseline body weight) with chronic diarrhea or chronic weakness and documented fever for ≥1 month.

  From Day 1 to Week 48

Secondary Outcomes (14)

• Percentage of Participants With HIV RNA Levels <50 c/mL and <400 c/mL at Week 48 by Treatment/Weight

  At Week 48

• Percentage of Participants With HIV RNA Levels <50 c/mL and <400 c/mL at Week 48 by Prior Antiretroviral (ARV) Treatment Status

  From Day 1 to Week 48

• Mean Change From Baseline in HIV RNA Levels at Week 48 by Treatment/Weight

  From Baseline to Week 48

• Mean Change From Baseline in HIV RNA Levels at Week 48 by Prior Antiretroviral (ARV) Treatment Status

  From Baseline to Week 48

• CD4 Cell Count Changes From Baseline at Week 48 by Treatment/Weight

  From Baseline to Week 48

Study Arms (3)

Atazanavir powder, 150 mg/Ritonavir oral solution, 80 mg

EXPERIMENTAL

Patients weighing 5 to \<10 kg received atazanavir (ATV), 150-mg powder dosed in 50-mg packets, and ritonavir (RTV) oral solution, 80 mg. Stage 1: Initial dose was determined by patient's weight on the day of first on-treatment study visit (Day 1). ATV dispersible powder was mixed with a small amount of food or beverage. All of the mixture must have been consumed to obtain the full dose. The RTV oral solution was taken immediately before or after the ATV powder preparation. Stage 2: Patients who reached the age of 6 years or a weight of ≥25kg transitioned from the powder to the capsule formulation of ATV. Patients who weighed 15 to \<20 kg received ATV, 150 mg with RTV, 100 mg; those who weighed 20 to \<40 kg received ATV, 200 mg, and RTV, 100 mg; and those who weighed at least 40 kg received ATV, 300 mg with RTV, 100 mg. RTV capsules or tablets were ingested with food immediately before or after ATV intake.

Drug: Atazanavir powder; Drug: Ritonavir oral solution; Drug: Atazanavir capsules; Drug: Ritonavir capsules

Atazanavir powder, 200 mg/Ritonavir oral solution, 80 mg

EXPERIMENTAL

Patients weighing 10 to \<15 kg received ATV powder, 200 mg, dosed in 50-mg sachet packets and RTV oral solution, 80 mg. Stage 1: Initial dose was determined by the patient's weight on the day of the first on-treatment study visit (Day 1). ATV dispersible powder was mixed with a small amount of food or beverage (water, milk, chocolate milk, liquid infant formula, applesauce, or yogurt). All of the mixture must have been consumed to obtain the full dose. The RTV oral solution was taken immediately before or after the ATV powder preparation. Stage 2: Patients who reached the age of 6 years or a weight of ≥25kg transitioned from the powder to the capsule formulation of ATV. Patients who weighed 15 to \<20 kg received ATV, 150 mg with RTV, 100 mg; those who weighed 20 to \<40 kg received ATV, 200 mg, and RTV, 100 mg; and those who weighed at least 40 kg received ATV, 300 mg with RTV, 100 mg. RTV capsules or tablets were ingested with food immediately before or after ATV intake.

Drug: Atazanavir powder; Drug: Ritonavir oral solution; Drug: Atazanavir capsules; Drug: Ritonavir capsules

Atazanavir powder, 250 mg/Ritonavir oral solution, 80 mg

EXPERIMENTAL

Patients weighing 15 to \<25 kg received 250 mg of ATV powder dosed in 50-mg sachet packets, with 80 mg of RTV solution. Stage 1: Initial dose was determined by the patient's weight on the day of the first on-treatment study visit (Day 1). ATV dispersible powder was mixed with a small amount of food or beverage (water, milk, chocolate milk, liquid infant formula, applesauce, or yogurt). All of the mixture must have been consumed to obtain the full dose. The RTV oral solution was taken immediately before or after the ATV powder preparation. Stage 2: Patients who reached the age of 6 years or a weight of ≥25kg transitioned from powder to the capsule formulation of ATV. Patients who weighed 15 to \<20 kg received ATV, 150 mg with RTV, 100 mg; those who weighed 20 to \<40 kg received ATV, 200 mg, and RTV, 100 mg; and those who weighed at least 40 kg received ATV, 300 mg with RTV, 100 mg. RTV capsules or tablets were ingested with food immediately before or after ATV intake.

Drug: Atazanavir powder; Drug: Ritonavir oral solution; Drug: Atazanavir capsules; Drug: Ritonavir capsules

Interventions

Atazanavir powder DRUG

Powder, oral, dosed by weight. Participants who weighed 5 to \<10 kg received atazanavir (ATV), 150 mg, and ritonavir (RTV), 80 mg; those who weighed 10 to \<15 kg received ATV, 200 mg, and RTV, 80 mg; and those who weighed 15 to \<25 kg received ATV, 250 mg, and RTV, 80 mg, once per day for 48 weeks or until pediatric indication is locally approved and participant meets requirements to receive appropriate formulation.

Also known as: Reyataz, BMS-232632

Atazanavir powder, 150 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 200 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 250 mg/Ritonavir oral solution, 80 mg

Ritonavir oral solution DRUG

Oral solution, 80 mg/mL, once per day for 48 weeks or until pediatric indication is locally approved and participant meets requirements to receive appropriate formulation.

Also known as: Norvir

Atazanavir powder, 150 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 200 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 250 mg/Ritonavir oral solution, 80 mg

Atazanavir capsules DRUG

Capsules, oral, dosed by weight in Stage 2. Patients who reached the age of 6 years or a weight of ≥25 kg transitioned from the powder to the capsule formulation of atazanavir (ATV). Patients who weighed 15 to \<20 kg received ATV, 150 mg with RTV, 100 mg; those who weighed 20 to \<40 kg received ATV, 200 mg, and RTV, 100 mg; and those who weighed at least 40 kg received ATV, 300 mg with RTV, 100 mg. RTV capsules or tablets were ingested with food immediately before or after ATV intake.

Atazanavir powder, 150 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 200 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 250 mg/Ritonavir oral solution, 80 mg

Ritonavir capsules DRUG

Oral, capsules, 100 mg, administered in Stage 2 with atazanavir capsules, dosed by weight.

Atazanavir powder, 150 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 200 mg/Ritonavir oral solution, 80 mg; Atazanavir powder, 250 mg/Ritonavir oral solution, 80 mg

Eligibility Criteria

• Age: 3 Months - 66 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Confirmed human immunodeficiency virus (HIV)-1 infection diagnosed by a positive virologic test result on 2 separate occasions by:
• HIV DNA polymerase chain reaction
• HIV RNA with values ≥1,000 copies/mL
• Positive HIV enzyme-linked immunosorbent assay at ≥18 months of age, with confirmatory Western blot or indirect immunoflourescence antibody
• Infants and children of either sex, aged ≥3 months to \<5 years and 6 months at time of first treatment, and weight \>5 to \<25 kg with any screening baseline plasma viral load
• Screening plasma viral load ≥1,000 copies/mL by Roche Amplicor® HIV RNA Assay
• Documented genotypic and phenotypic sensitivity at screening to ATV (fold change in susceptibility \<2.2) and to at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) approved in the infant's country
• Genotypic sensitivity at screening to atazanavir (ATV) and at least 2 NRTIs
• Antiretroviral (ARV) treatment-naive or ARV treatment-experienced. Treatment-experienced participants are defined by previous exposure to ARVs through either prior treatment for HIV infection or through postnatal treatment with ≥1 ARV for the prevention of mother to child transmission. For the purposes of this study, participants exposed to ARVs in utero or intrapartum may be included in the study but will be considered treatment naive. ATV-naive participants must have genotypic sensitivity at screening to ATV (fold change in susceptibility \<2.2) and to both components of the local NRTI backbone. The NRTIs must have been approved for pediatric use at the local country level.

You may not qualify if:

• Experienced participants who received ATV or ATV/ritonavir (RTV) at any time prior to study enrollment or with a history of 2 or more protease inhibitor failures
• ARV-naïve or -experienced HIV-1 infected patients with contraindication to study medications syncope
• Family history of QTc interval syndrome, Brugada syndrome, right ventricular dysplasia, or a corrected QTc interval at screening of \>440 ms
• One of the following cardiac rhythm abnormalities documented on screening electrocardiogram: 1st degree atrioventricular (AV) block as defined by protocol, type I 2nd degree AV block while awake, type II 2nd degree AV block at any time, complete AV block at any time, or age-adjusted heart rate \<2nd percentile) History of pancreatitis, peripheral neuropathy, malignancy that requires systemic therapy, or any medical condition which, in the opinion of the investigator, added undue risk to trial participation
• Malabsorption syndrome
• Presence of a newly diagnosed HIV-related opportunistic infection or any medical condition requiring acute therapy at the time of enrollment
• Weight \<5 or ≥25 kg at date of first dose (Day 1).
• \>Grade 2 aspartate transaminase or alanine transaminase abnormalities
• Hypersensitivity to any component of the study medication formulations (ATV/RTV, or a locally prescribed NRTI with a pediatric indication)
• Infants and children of either gender \<3 months or ≥5 years and 6 months at the time of first treatment.

Sponsors & Collaborators

• Bristol-Myers Squibb: lead

Study Sites (18)

Local Institution

São Paulo, São Paulo, 01246-900, Brazil

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Santiago, Santiago Metropolitan, 8380418, Chile

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Santiago, Santiago Metropolitan, Chile

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Guadalajara, Jalisco, 44160, Mexico

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Guadalajara, Jalisco, 44280, Mexico

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Df, Mexico City, 06720, Mexico

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Mérida, Yucatán, 97000, Mexico

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Oaxaca City, 71256, Mexico

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Puebla City, 72000, Mexico

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Lima, 1, Peru

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Lima, Peru

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Bloemfontein, Free State, 9301, South Africa

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Coronationville, Gauteng, 2092, South Africa

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Soweto, Gauteng, 2001, South Africa

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KwaKhangela, KwaZulu-Natal, 4013, South Africa

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Cape Town, Western Cape, 7505, South Africa

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Bangkok, 10330, Thailand

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Bangkok, 10700, Thailand

Location

Related Links

• BMS Clinical Trial Patient Recruiting
• Investigator Inquiry Form

MeSH Terms

Conditions

HIV Infections

Interventions

Atazanavir Sulfate; Ritonavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2010
• First Posted: April 7, 2010
• Study Start: October 13, 2010
• Primary Completion: October 4, 2012
• Study Completion: September 11, 2017
• Last Updated: May 24, 2018
• Results First Posted: February 6, 2014

Record last verified: 2018-04

Locations

PE (2); ME (6); BR (1); TH (2); CL (2); ZA (5)