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

Study Overview
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Brief Summary
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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.

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 HIV Infected Pediatric Patients Greater Than or Equal to 3 Months to Less Than 6 Years. (Pediatric Atazanavir International Clinical Evaluation: the PRINCE I Study)

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Atazanavir powder
* Drug: Ritonavir oral solution
* Drug: Atazanavir capsules
* Drug: Ritonavir capsules


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 66 Months

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atazanavir powder, 150 mg/Ritonavir oral solution, 80 mg<br>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<br>* 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.<br>* Other names: BMS-232632;Drug: Ritonavir oral solution<br>* 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.<br>* Other names: Norvir;Drug: Atazanavir capsules<br>* 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.<br>Drug: Ritonavir capsules<br>* Oral, capsules, 100 mg, administered in Stage 2 with atazanavir capsules, dosed by weight.<br>|
| Experimental: Atazanavir powder, 200 mg/Ritonavir oral solution, 80 mg<br>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<br>* 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.<br>* Other names: BMS-232632;Drug: Ritonavir oral solution<br>* 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.<br>* Other names: Norvir;Drug: Atazanavir capsules<br>* 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.<br>Drug: Ritonavir capsules<br>* Oral, capsules, 100 mg, administered in Stage 2 with atazanavir capsules, dosed by weight.<br>|
| Experimental: Atazanavir powder, 250 mg/Ritonavir oral solution, 80 mg<br>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<br>* 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.<br>* Other names: BMS-232632;Drug: Ritonavir oral solution<br>* 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.<br>* Other names: Norvir;Drug: Atazanavir capsules<br>* 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.<br>Drug: Ritonavir capsules<br>* Oral, capsules, 100 mg, administered in Stage 2 with atazanavir capsules, dosed by weight.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV RNA Levels <50 c/mL and <400 c/mL at Week 48 by Treatment/Weight | The definition of virologic success included HIV RNA levels <50 c/mL or 400 c/mL at the Week 48 analysis window. . | 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 | The definition of virologic success included HIV RNA levels <50 c/mL or <400 c/mL at the Week 48 analysis. | From Day 1 to Week 48 | 
| Mean Change From Baseline in HIV RNA Levels at Week 48 by Treatment/Weight | Participants who received at least 1 dose of atazanavir (ATV) and had an HIV RNA measurement on ATV powder at did not switch to the capsule formulation before Week 48 | 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 | 
| CD4 Cell Count Changes From Baseline at Week 48 by Prior Antiretroviral (ARV) Treatment Status |  | From Baseline to Week 48 | 
| Mean CD4 Percent Changes From Baseline at Week 48 by Treatment/Weight |  | From Baseline to Week 48 | 
| Mean CD4 Percent Changes From Baseline at Week 48 by Antiretroviral (ARV) Treatment Status |  | From Baseline to Week 48 | 
| Number of Participants Who Acquired Phenotypic Resistance to Atazanavir or Atazanovir/Ritonavir | Criteria for resistance testing= meeting at least 1 of the following: <1 log10 drop from baseline in HIV RNA level by Week 16 and confirmed by a second HIV RNA level; an HIV RNA level >200 copies/mL after Week 24, confirmed by a second HIV RNA level; repeated HIV RNA levels ≥50 copies/mL after Week 48; an HIV RNA level ≥400 copies/mL confirmed by a second HIV RNA level of ≥400 copies/mL at any time in a participant who had previously achieved a plasma HIV RNA level <50 copies/mL; or discontinued due to lack of efficacy. Virologic failure was defined as an incomplete virologic response to therapy or as a viral rebound after the achievement of virologic suppression. The phenotypic resistance to a drug is defined as a fold change (ie, ratio of the 50% inhibitory concentration [IC50] of the clinical isolate to the IC50 of the reference strain) greater than the cut-off for reduced susceptibility. | After Day 1 to Week 48 | 
| Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of Atazanavir and Ritonavir |  | At Week 2 at Hour 0 predose and at Hours 1.5, 2.5, 4, 6, 8, 12, and 24 postdose | 
| Area Under the Concentration Curve (in 1 Dosing Interval From Time 0 to 24 Hours Post Observed Dose) (AUC[TAU])of Atazanavir and Ritonavir |  | At Week 2 at Hour 0 predose and at Hours 1.5, 2.5, 4, 6, 8, 12, and 24 postdose | 
| Time to Maximum Observed Concentration (Tmax) of Atazanavir and Ritonavir |  | At Week 2 at Hour 0 predose and at Hours 1.5, 2.5, 4, 6, 8, 12, and 24 postdose | 
| Apparent Total Body Clearance (CLT/F) of Atazanavir and Ritonavir | Calculated as dose divided by AUC(TAU). AUC(TAU)=area under the concentration-time curve in 1 dosing interval from time 0 to 24 hours post observed dose. | At Week 2 | 
| Apparent Total Body Clearance Per Body Weight (CLT/F) Per Kilogram of Atazanavir and Ritonavir | Calculated as CLT/F divided by body weight | At Week 2 | 

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