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

NCT00006604 | Completed Phase 1 Results

• 5 other identifiers: P1020A10037IMPAACT P1020APACTG P1020-AACTG P1020-A
• Study Type: interventional
• Target: 195
• Locations: 3 countries
• Sites: 36

Brief Summary

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.

Conditions

HIV Infections

Keywords

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

Outcome Measures

Primary Outcomes (6)

• Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV

  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.

  From study entry up to week 96

• Number of Participants Who Died

  From study entry up to week 96

• Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h)

  Pharmacokinetics were determined by non-compartmental analysis and AUC0-24hr calculated by the linear trapezoidal method.

  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)

• Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24)

  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.

  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)

• Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax)

  Pharmacokinetics were determined by non-compartmental analysis and Maximum concentration (Cmax) was determined visually.

  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)

• Pharmacokinetic (PK) Parameter: Clearance (CL/F)

  Pharmacokinetics were determined by non-compartmental analysis and Apparent oral clearance (CL/F) was calculated as ATV dose divided by AUC0-24hr.

  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)

Secondary Outcomes (9)

• Percentage of Participants With HIV RNA <400 Copies/mL at Week 24

  Week 24

• Percentage of Participants With HIV RNA <400 Copies/mL at Week 48

  Week 48

• Percentage of Participants With HIV RNA <400 Copies/mL at Week 96

  Week 96

• Change in CD4 Count (Cells/mm^3) From Baseline to Week 20

  Baseline, Week 20

• Change in CD4 Count (Cells/mm^3) From Baseline to Week 48

  Baseline, Week 48

Study Arms (9)

Step I: Group 1

EXPERIMENTAL

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

Step I: Group 2

EXPERIMENTAL

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

Step I: Group 3

EXPERIMENTAL

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

Step I: Group 4

EXPERIMENTAL

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

Step I: Group 5

EXPERIMENTAL

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; Drug: Ritonavir

Step I: Group 5a

EXPERIMENTAL

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; Drug: Ritonavir

Step I: Group 6

EXPERIMENTAL

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; Drug: Ritonavir

Step I: Group 7

EXPERIMENTAL

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; Drug: Ritonavir

Step I: Group 8

EXPERIMENTAL

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; Drug: Ritonavir

Interventions

ATV DRUG

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.

Step I: Group 1; Step I: Group 2; Step I: Group 3; Step I: Group 4; Step I: Group 5; Step I: Group 5a; Step I: Group 6; Step I: Group 7; Step I: Group 8

Ritonavir DRUG

Administered as 100 mg capsules or oral solution.

Step I: Group 5; Step I: Group 5a; Step I: Group 6; Step I: Group 7; Step I: Group 8

Eligibility Criteria

• Age: 91 Days - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• A type I second-degree atrioventricular (AV) block (Mobitz type I heart-block) occurring during waking hours on ECG at screening

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• International Maternal Pediatric Adolescent AIDS Clinical Trials Group: collaborator

Study Sites (36)

UAB Pediatric Infectious Diseases CRS

Birmingham, Alabama, 35233, United States

Location

Usc La Nichd Crs

Alhambra, California, 91803, United States

Location

University of California, UC San Diego CRS

La Jolla, California, 92093-0672, United States

Location

Miller Children's Hosp. Long Beach CA NICHD CRS

Long Beach, California, 90806, United States

Location

UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS

Los Angeles, California, 900951752, United States

Location

Univ. of California San Francisco NICHD CRS

San Francisco, California, 94143, United States

Location

Univ. of Colorado Denver NICHD CRS

Aurora, Colorado, 80045, United States

Location

Howard Univ. Washington DC NICHD CRS

Washington D.C., District of Columbia, 20060, United States

Location

South Florida CDTC Ft Lauderdale NICHD CRS

Fort Lauderdale, Florida, 33316, United States

Location

Columbus Regional HealthCare System, The Med. Ctr.

Columbus, Georgia, 31901, United States

Location

Rush Univ. Cook County Hosp. Chicago NICHD CRS

Chicago, Illinois, 60612, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS

Chicago, Illinois, 60614, United States

Location

Tulane Univ. New Orleans NICHD CRS

New Orleans, Louisiana, 701122699, United States

Location

Univ. of Maryland Baltimore NICHD CRS

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins Univ. Baltimore NICHD CRS

Baltimore, Maryland, 21287, United States

Location

Boston Medical Center Ped. HIV Program NICHD CRS

Boston, Massachusetts, 02118, United States

Location

WNE Maternal Pediatric Adolescent AIDS CRS

Worcester, Massachusetts, 016550001, United States

Location

Rutgers - New Jersey Medical School CRS

Newark, New Jersey, 07103, United States

Location

Nyu Ny Nichd Crs

New York, New York, 10016, United States

Location

Harlem Hosp. Ctr. NY NICHD CRS

New York, New York, 10037, United States

Location

SUNY Upstate Med. Univ., Dept. of Peds.

Syracuse, New York, 13210, United States

Location

Bronx-Lebanon Hospital Center NICHD CRS

The Bronx, New York, 10457, United States

Location

Jacobi Med. Ctr. Bronx NICHD CRS

The Bronx, New York, 10461, United States

Location

DUMC Ped. CRS

Durham, North Carolina, 277103499, United States

Location

Philadelphia IMPAACT Unit CRS

Philadelphia, Pennsylvania, 19104, United States

Location

St. Christopher's Hosp. for Children

Philadelphia, Pennsylvania, 191341095, United States

Location

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, 38105, United States

Location

Children's Med. Ctr. Dallas

Dallas, Texas, 75235, United States

Location

Texas Children's Hospital CRS

Houston, Texas, 77030, United States

Location

Children's Hosp. of the King's Daughters, Infectious Disease

Norfolk, Virginia, 23507, United States

Location

Childrens Hosp. of the Kings Daughters

Norfolk, Virginia, 23507, United States

Location

Seattle Children's Research Institute CRS

Seattle, Washington, 98105, United States

Location

Univ. Hosp. Ramón Ruiz Arnau, Dept. of Peds.

Bayamón, 00956, Puerto Rico

Location

San Juan City Hosp. PR NICHD CRS

San Juan, 00936, Puerto Rico

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1864, South Africa

Location

Shandukani CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Related Publications (11)

• 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.

  PMID: 25232777 BACKGROUND

• 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.

  PMID: 21610486 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

Related Links

• DAIDS Toxicity Table for Grading Severity of Pediatric (\> 3 mos of age) Adverse Experiences April, 1994.

MeSH Terms

Conditions

HIV Infections

Interventions

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)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Richard Rutstein, MD

  Children's Hospital of Philadelphia

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2000
• First Posted: August 31, 2001
• Study Start: November 1, 2000
• Primary Completion: October 1, 2011
• Study Completion: September 1, 2014
• Last Updated: November 5, 2021
• Results First Posted: April 5, 2016

Record last verified: 2016-03

Locations

US (32); ZA (2); PR (2)