PRINCE: Study of Atazanavir (ATV)/Ritonavir (RTV) (PRINCE1)

Bristol-Myers Squibb (BMS)

Status and phase: Completed; Phase 3

Conditions: HIV Infections

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT01099579

AI424-397

2009-016361-28 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 82 patients

Sex: All

Ages: 3 to 66 months old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

• 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.

Key Exclusion Criteria:

• 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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82 participants in 3 patient groups

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

Experimental group

Description:

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.

Treatment:

Drug: Ritonavir capsules

Drug: Ritonavir oral solution

Drug: Atazanavir powder

Drug: Atazanavir capsules

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

Experimental group

Description:

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.

Treatment:

Drug: Ritonavir capsules

Drug: Ritonavir oral solution

Drug: Atazanavir powder

Drug: Atazanavir capsules

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

Experimental group

Description:

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.

Treatment:

Drug: Ritonavir capsules

Drug: Ritonavir oral solution

Drug: Atazanavir powder

Drug: Atazanavir capsules