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

HIV Infections Clinical Trial

— PRINCE1  

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 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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01099579
• Other study ID #: AI424-397
• Secondary ID: 2009-016361-28
• Status: Completed
• Phase: Phase 3
• Start date: October 13, 2010
• Est. completion date: September 11, 2017

Study information

• Verified date: April 2018
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: September 11, 2017
• Est. primary completion date: October 4, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 66 Months

Eligibility

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.

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Atazanavir powder
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.
• Ritonavir oral solution
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.
• Atazanavir capsules
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.
• Ritonavir capsules
Oral, capsules, 100 mg, administered in Stage 2 with atazanavir capsules, dosed by weight.

Locations

Country	Name	City	State
Brazil	Local Institution	Sao Paolo	SAO Paulo
Chile	Local Institution	Santiago	Metropolitana
Chile	Local Institution	Santiago	Metropolitana
Mexico	Local Institution	Df	Distrito Federal
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Merida	Yucatan
Mexico	Local Institution	Oaxaca
Mexico	Local Institution	Puebla
Peru	Local Institution	Lima
Peru	Local Institution	Lima
South Africa	Local Institution	Bloemfontein	FREE State
South Africa	Local Institution	Cape Town	Western CAPE
South Africa	Local Institution	Congella	KWA ZULU Natal
South Africa	Local Institution	Coronationville	Gauteng
South Africa	Local Institution	Soweto	Gauteng
Thailand	Local Institution	Bangkok
Thailand	Local Institution	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

Brazil,  Chile,  Mexico,  Peru,  South Africa,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	Mean Change From Baseline in HIV RNA Levels at Week 48 by Prior Antiretroviral (ARV) Treatment Status		From Baseline to Week 48
Secondary	CD4 Cell Count Changes From Baseline at Week 48 by Treatment/Weight		From Baseline to Week 48
Secondary	CD4 Cell Count Changes From Baseline at Week 48 by Prior Antiretroviral (ARV) Treatment Status		From Baseline to Week 48
Secondary	Mean CD4 Percent Changes From Baseline at Week 48 by Treatment/Weight		From Baseline to Week 48
Secondary	Mean CD4 Percent Changes From Baseline at Week 48 by Antiretroviral (ARV) Treatment Status		From Baseline to Week 48
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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