Atazanavir Used in Combination With Other Anti-HIV Drugs in HIV-Infected Infants, Children, and Adolescents - Full Text View

Purpose

The purpose of this study was to find a safe and tolerable dose of the protease inhibitor (PI) atazanavir (ATV), with or without a low-dose boost of the PI ritonavir (RTV), when taken with other anti-HIV drugs in HIV infected infants, children, and adolescents.

Advancements in anti-HIV drugs for HIV infected children and adolescents have been hard to make, in part because these patients often do not take the drugs as prescribed. ATV may be a better option because it is available in the form of powder which children and adolescents may be more willing to take regularly. Using a low dose of RTV as a boosting agent for ATV may also increase the chances of virologic response of highly active antiretroviral treatment (HAART)-experienced patients. This study aimed to find safe and tolerable doses of ATV with or without low-dose RTV boost in infants, children, and adolescents. For this study, participants were enrolled in the United States and South Africa.

Condition	Intervention	Phase
HIV Infections	Drug: ATV Drug: Ritonavir	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I/II, Open-Label, Pharmacokinetic and Safety Study of a Novel Protease Inhibitor (BMS 232632, Atazanavir, ATV, Reyataz) in Combination Regimens in Antiretroviral Therapy (ART)-Naive and -Experienced HIV-Infected Infants, Children, and Adolescents

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS HIV/AIDS Medicines

Drug Information available for: Ritonavir Atazanavir Atazanavir sulfate

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV [ Time Frame: From study entry up to week 96 ] [ Designated as safety issue: Yes ]
Total Bilirubin >= 5.1xULN, ECG Events and Other Grade 3+ toxicities attributed to study treatment.

The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) Toxicity Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the study team.
Number of Participants Who Died [ Time Frame: From study entry up to week 96 ] [ Designated as safety issue: Yes ]
Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) [ Time Frame: Week 1 (Day 7) Intensive PK-24hr (Pre-Dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) ] [ Designated as safety issue: No ]
Pharmacokinetics were determined by non-compartmental analysis and AUC0-24hr calculated by the linear trapezoidal method.
Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) [ Time Frame: Week 1 (Day 7) Intensive PK-24hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) ] [ Designated as safety issue: No ]
Pharmacokinetics were determined by non-compartmental analysis. C24 determined visually, except in the instance when the patient re-dosed the study medication prior to the 24 hour blood draw or the 24 hour level was not obtained, in which case the C24 was calculated from the elimination rate (ke) and the last measured concentration.
Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) [ Time Frame: Week 1 (Day 7) Intensive PK-24 hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) ] [ Designated as safety issue: No ]
Pharmacokinetics were determined by non-compartmental analysis and Maximum concentration (Cmax) was determined visually.
Pharmacokinetic (PK) Parameter: Clearance (CL/F) [ Time Frame: Week 1 (Day 7) Intensive PK-24 hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) ] [ Designated as safety issue: No ]
Pharmacokinetics were determined by non-compartmental analysis and Apparent oral clearance (CL/F) was calculated as ATV dose divided by AUC0-24hr.

Secondary Outcome Measures:

Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa.
Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa.
Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa.
Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 [ Time Frame: Baseline, Week 20 ] [ Designated as safety issue: No ]
Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 [ Time Frame: Baseline, Week 96 ] [ Designated as safety issue: No ]
Change in CD4 Percent From Baseline to Week 20 [ Time Frame: Baseline, Week 20 ] [ Designated as safety issue: No ]
Change in CD4 Percent From Baseline to Week 48 [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
Change in CD4 Percent From Baseline to Week 96 [ Time Frame: Baseline, Week 96 ] [ Designated as safety issue: No ]


Enrollment:	195
Study Start Date:	November 2000
Study Completion Date:	September 2014
Primary Completion Date:	October 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Step I: Group 1 Group 1 enrolled participants between 91 days of age and 2 years of age. They received ATV (powder) and two NRTIs. ATV Dose Tested: 310 mg/m^2, 620 mg/m^2; Final Dose: Not Established	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Experimental: Step I: Group 2 Group 2 enrolled participants between 2 years and 1 day of age and 13 years of age. They received ATV (powder) and two NRTIs. ATV Dose Tested: 310 mg/m^2, 620 mg/m^2; Final Dose: Not Established	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Experimental: Step I: Group 3 Group 3 enrolled participants between 2 years and 1 day of age and 13 years of age. They received ATV (capsule) and two NRTIs. ATV Dose Tested: 310 mg/m^2, 415 mg/m2, 520 mg/m^2; Final Dose: 520 mg/m^2	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Experimental: Step I: Group 4 Group 4 enrolled participants between 13 years and 1 day of age and 21 years of age. They received ATV (capsule) and two NRTIs. ATV Dose Tested: 310 mg/m^2, 520 mg/m^2, 620 mg/m^2; Final Dose: 620 mg/m^2	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Experimental: Step I: Group 5 Group 5 enrolled participants between 91 days of age and 2 years of age. They received ATV (powder), ritonavir, and two NRTIs. ATV Dose Tested: 310 mg/m^2; Final Dose: 310 mg/m^2	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in. Drug: Ritonavir Administered as 100 mg capsules or oral solution.
Experimental: Step I: Group 5a Group 5a enrolled participants between 91 days of age and 180 days of age. They received ATV (powder), ritonavir, and two NRTIs. ATV Dose Tested: 310 mg/m^2; Final Dose: 310 mg/m^2	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in. Drug: Ritonavir Administered as 100 mg capsules or oral solution.
Experimental: Step I: Group 6 Group 6 enrolled participants between 2 years and 1 day of age and 13 years of age. They received ATV (powder), ritonavir, and two NRTIs. ATV Dose Tested: 310 mg/m^2; Final Dose: 310 mg/m^2	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in. Drug: Ritonavir Administered as 100 mg capsules or oral solution.
Experimental: Step I: Group 7 Group 7 enrolled participants between 2 years and 1 day of age and 13 years of age. They received ATV (capsule), ritonavir, and two NRTIs. ATV Dose Tested: 310 mg/m^2, 205 mg/m^2; Final Dose: 205 mg/m^2	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in. Drug: Ritonavir Administered as 100 mg capsules or oral solution.
Experimental: Step I: Group 8 Group 8 enrolled participants between 13 years and 1 day of age and 21 years of age. They received ATV (capsule), ritonavir, and two NRTIs. ATV Dose Tested: 310 mg/m^2, 205 mg/m^2; Final Dose: 205 mg/m^2	Drug: ATV Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in. Drug: Ritonavir Administered as 100 mg capsules or oral solution.

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Eligibility


Ages Eligible for Study:	91 Days to 21 Years (Child, Adult)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria for Step I:

Age: 91 days to 21 years of age (not including the 22nd birthday).
A confirmed diagnosis of HIV infection defined by the current definition of the IMPAACT Virology Core Laboratory Committee. More information about this criterion can be found in the protocol.
Viral load greater than or equal to 5,000 copies/mL
Any CDC clinical classification and immune status
Antiretroviral treatment-naïve or -experienced study candidates must be able to add two new NRTIs as part of their new therapy in this protocol, or have genotypic evidence of sensitivity to two NRTIs (the NRTIs must be used in combinations recommended in the Guidelines for the Use of Antiretroviral Agents in Pediatric and Adolescent HIV Infection). More information about this criterion can be found in the protocol.
Study candidates must show evidence of retained phenotypic sensitivity to ATV (resistance index ratio of less than 10) when the subject has failed (after at least 12 weeks of therapy) two or more courses of PI containing regimens. More information about this criterion can be found in the protocol.
Demonstrated ability and willingness to swallow study medications
Study candidate, parent, or legal guardian must be able and willing to provide signed informed consent
Female participants who are sexually active and able to become pregnant must use two methods of birth control. More information about this criterion can be found in the protocol.
Males participating in the study must not attempt to impregnate a female, or participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom.
Study candidates with a history of undefined syncope will require a complete cardiac conduction evaluation at screening [e.g., ECG, 24-hour monitoring (Holter), and exercise test (if age appropriate)]. This evaluation must rule-out any cardiac conduction abnormalities.

Exclusion Criteria for Step I:

Active hepatitis
Presence of an acute serious/invasive infection requiring therapy at the time of enrollment
Hypersensitivity to any component of the formulation of ATV
Chemotherapy for active malignancy
Pregnant or breastfeeding
Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the clinician's opinion, would compromise the outcome of this study
Any laboratory or clinical toxicity greater than Grade 2 at entry
Documented history of cardiac conduction abnormalities or significant cardiac dysfunction
History of undefined syncope that cannot be ruled out as related to cardiac conduction abnormalities
Family history of prolonged QTc-interval syndrome, Brugada syndrome, or right-ventricular (RV) dysplasia
Corrected QTc-Interval greater than 440 msec at screening
Prolonged PR-Interval greater than 0.200 seconds (200 ms) on ECG at screening (study candidates greater than or equal to 13 years of age)
PR-Interval greater than 98th percentile on ECG at screening (study candidates less than 13 years of age)
Cardiac rhythm abnormalities:
1. A type I second-degree atrioventricular (AV) block (Mobitz type I heart-block) occurring during waking hours on ECG at screening
2. A type II second-degree AV-block (Mobitz type II heart-block) at any time on ECG at screening
3. A complete AV-block at any time on ECG at screening
4. A heart rate less than the 2nd percentile for age of the normal heart rate range on ECG at screening
Prolonged therapy with intravenous pentamidine for acute Pneumocystis Carinii Pneumonia (PCP) within three months of entry

Inclusion Criteria for Step II:

Any South African subject enrolled into either part of Step I, who is virologically successful by Week 96 of when the last study participant enrolled into the respective part of Step I
Female participants who are sexually active and able to become pregnant must continue using two methods of birth control. More information about this criterion can be found in the protocol.
Males who continue participation in the study must not attempt to impregnate a woman, or participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom.

Exclusion Criteria for Step II:

A South African participant who meets any of the criteria for treatment discontinuation by Week 96 of when the last participant enrolled into either part of Step I
A South African participant who meets any of the exclusion criteria from Step I by Week 96 of when the last participant enrolled into either part of Step I

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00006604

Show 36 Study Locations

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Investigators


Study Chair:	Richard Rutstein, MD	Children's Hospital of Philadelphia

More Information

Additional Information:

DAIDS Toxicity Table for Grading Severity of Pediatric (> 3 mos of age) Adverse Experiences April, 1994. This link exits the ClinicalTrials.gov site

Publications:

Rutstein RM, Samson P, Fenton T, Fletcher CV, Kiser JJ, Mofenson LM, Smith E, Graham B, Mathew M, Aldrovani G; PACTG 1020A Study Team. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children and adolescents: the Pediatric AIDS Clinical Trials Group Protocol 1020A. Pediatr Infect Dis J. 2015 Feb;34(2):162-7. doi: 10.1097/INF.0000000000000538.

Kiser JJ, Rutstein RM, Samson P, Graham B, Aldrovandi G, Mofenson LM, Smith E, Schnittman S, Fenton T, Brundage RC, Fletcher CV. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011 Jul 31;25(12):1489-96. doi: 10.1097/QAD.0b013e328348fc41.

Aldrovandi G, Samson P, Fenton T, Schnittman S, Rutstein R, Ortiz A and the Pediatric AIDS Clinical Trial 1020A Group. Resistance to Atazanavir (ATV), Lopinavir (LPV), Tenofovir (TFV) Among Heavily Experienced Pediatric Patients. 12th International Symposium on HIV and Emerging Infectious Diseases in Toulon, France, June 2002.

Aldrovandi G, Samson P, Fenton T, Schnittman S, and Rutstein R for the P1020A Team. Genotypic and phenotypic resistance to BMS232632 (Atazanavir-ATV), among heavily experienced pediatric patients who were ATV-naïve. 9th Conference on Retroviruses and Opportunistic Infections, February 24 - 28, 2002, Seattle, WA.

Kiser J, Rutstein R, Aldrovandi G, Samson P, Graham B, Schnittman S, Smith M, Mofenson L, Fletcher C, and the PACTG 1020A Study Team. Pharmacokinetics of atazanavir/ritonavir in HIV-infected infants, children, and adolescents: PACTG 1020A. 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 2005.

Kiser J, Rutstein R, Samson P, Graham B, Aldrovandi G, Mofenson L, Smith E, Zhang J, Biguenet S, Fletcher C, and the P1020A team. Atazanavir dosing conversion and pharmacokinetics in HIV-infected children switching from atazanavir powder to capsules. 12 th International Workshop on Clinical Pharmacology of HIV Therapy, Miami, Florida, April 2011.

Meyers T, Rutstein R, Samson P, Violari A, Palmer M, Kiser J, Fletcher C, Fenton T, Mofenson L, Graham B, Schnittman S, Horga M, Aldrovandi G, for the PACTG 1020A Study. Treatment responses to atazanavir-containing HAART in a drug-naïve pediatric population in South Africa. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 2008.

Rutstein R, Samson P, Aldrovandi G, Graham B, Schnittman S, Fletcher C, Kiser J, Smith E, Mofenson L, Fenton T, and the PACTG 1020A Study Team. Effect of atazanavir on serum cholesterol and triglyceride levels in HIV-infected infants, children, and adolescents: PACTG 1020A. 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 2005.

Rutstein R, Samson P, Fenton T, Kiser J, Fletcher C, Schnittman S, Mofenson L, Smith E, Graham B, Aldrovandi G, PACTG 1020A Study. The NIH PACTG Protocol 1020A: ATAZANAVIR (ATV), +/- RITONAVIR in HIV-Infected Infants, Children and Adolescents. Presented at the 14th Conference on Retrovirus and Opportunistic Infection (CROI), Los Angeles, CA, February, 2007.

Samson P, Rutstein R, Schnittman S, Ortiz A, Graham B, Fenton T, Aldrovandi G and the Pediatric AIDS Clinical Trials Group P1020A Study Team. Effects of Antiretroviral (ARV) Exposure and Genotypic (Geno) Mutations in Predicting Phenotypic Resistance (PRS) to Atazanavir (ATV), Lopinavir (LPV), and Tenofovir (TDF) in Patients Naïve to these Drugs. 13th International Symposium on HIV and Emerging Infectious Diseases, Toulon, France, June 2004.

Samson P, Rutstein R, Fenton T, Kiser J, Fletcher C, Schnittman S, Mofenson L, Smith E, Graham B, Aldrovandi G, and the PACTG 1020A Study Team. Changes in cholesterol and triglyceride levels among pediatric subjects treated with atazanavir, with or without ritonavir boosting: the 1020A NIH PACTG protocol. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO, February 2006.


Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00006604 History of Changes
Other Study ID Numbers:	P1020A 10037 IMPAACT P1020A PACTG P1020-A ACTG P1020-A
Study First Received:	December 6, 2000
Results First Received:	January 29, 2016
Last Updated:	March 7, 2016
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):


Dose-Response Relationship, Drug Drug Therapy, Combination Drug Administration Schedule HIV Protease Inhibitors Reverse Transcriptase Inhibitors	Anti-HIV Agents Pharmacokinetics Treatment Experienced Treatment Naive

Additional relevant MeSH terms:


HIV Infections Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Ritonavir Atazanavir Sulfate HIV Protease Inhibitors	Protease Inhibitors Reverse Transcriptase 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 Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 27, 2016