Clinical trial NCT00006604: Atazanavir Used in Combination With Other Anti-HIV Drugs in HIV-Infected Infants, Children, and Adolescents
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
First posted: 2001-08-31
Enrollment: 195
Sex: ALL
Minimum age (years): 91
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Advancements in HAART for HIV-infected children and adolescents are hindered by patient nonadherence. The availability of a powder formulation and the once-daily dosing schedule make ATV an attractive agent for improved adherence in pediatric treatment regimens. This study was designed to provide pharmacokinetic (PK) data to guide dosing recommendations for ATV, when given concurrently with or without low-dose RTV boost, in infants, children, and adolescents. During the study, the safety and tolerance of ATV (with or without low-dose RTV) were closely monitored, and virologic efficacy data were obtained.

There were two parts to this study. Step I took place in the United States and South Africa, and were further divided into two sets of groups, Parts A and B. Part A participants received ATV only and Part B participants received ATV with low-dose RTV boost. All participants received ATV once a day with 2 other antiretroviral drugs (not provided by the study). In Part B only, participants received ATV with a low dose of RTV. Participants were placed into 1 of 8 groups (Groups 1 to 4 for Part A; Groups 5 to 8 for Part B) with respect to age and study drug formulation. Participants in Groups 1 and 5 were infants between ages 3 months and 1 day (91 days) and 2 years (less than or exactly 730 days) and took ATV in powder form. Participants in Groups 2, 3, 6, and 7 were children between 2 years and 1 day (731 days) old and 13 years old. Groups 2 and 6 received ATV in powder form, while Groups 3 and 7 received the capsule form. Patients in Groups 4 and 8 were adolescents between 13 years and 1 day old and 21 years old (not including the 22nd birthday) and took ATV in capsule form. As of 01/02/2008 a new group, 5A was opened for enrollment. Participants in Group 5A were between 3 months and 6 months old and took ATV in powder form plus a low-dose RTV booster.

For each group, enrollment started with five participants per group. All participants were evaluated for PK and safety criteria, adjusting the dose of ATV until one was found that passes both sets of criteria. Then five additional participants were enrolled, with enrollment continuing for each group once all participants within that group meet the PK criteria. For groups receiving RTV (Groups 5 to 8), additional criteria must be met for each dose of ATV studied. In addition to the PK and safety evaluations, 24-hour post-dose concentrations (Cmin) were monitored in the first 10 participants enrolled for a dose of ATV before more participants were enrolled and studied at that same dose. Note that in Protocol Version 5.0, South African (S.A.) sites were allowed to enroll patients in study groups 3,4,5,6,7,8. As a result, the study design has been modified to further stratify study groups 3, 4, 5, 6, 7, 8 (at the final recommended dose), by country, i.e., U.S.A. versus S.A., such that 10 evaluable study subjects will be accrued in parallel to each study group-country cohort.

Clinic visits will be every 4 weeks through Week 48, then every 8 weeks until the last participant to enroll in the study has reached Week 96 of his/her treatment. If, after 56 weeks, a participant has a toxic reaction to a nucleoside/tide reverse transcriptase inhibitor (NRTI) in their medication regimen, the regimen may be changed to a different NRTI. At every visit, participants will undergo a complete medical history and physical exam, cardiac conduction evaluation, and urine and blood collection. Participants of childbearing age will have a pregnancy test performed at each visit.

Step II will only be open to South African subjects who are virologically responding to treatment when the last enrollee into either part of Step I (Part A or Part B) has completed 96 weeks of treatment (end of Step I) . All such participants will be given ATV in capsule form at the same dose they received at the end of Step I, as well as the other antiretrovirals they were receiving during Step I. Step II will continue until ATV is approved in South Africa and readily available by individual prescription, and participants will have a study visit every 12 weeks.

Note that the following ATV doses were independently evaluated for each group during the dose-finding stage based on the description above: Group 1 ATV Powder (310mg/m\^2, 620mg/m\^2); Group 2 ATV Powder (310mg/m\^2, 620mg/m\^2); Group 3 ATV Capsule (310mg/m\^2, 415mg/m\^2, 520mg/m\^2); Group 4 ATV Capsule (310mg/m\^2, 520mg/m\^2, 620mg/m\^2); Group 5 ATV Powder + RTV (310mg/m\^2); Group 6 ATV Powder +RTV (310mg/m\^2); Group 7 ATV Capsule + RTV (310mg/m\^2, 205mg/m\^2); Group 8 ATV Capsule + RTV (310mg/m\^2, 205mg/m\^2); Group 5A ATV Powder + RTV (310mg/m\^2). All these dosing groups are presented in Participant Flow groups to show the total number of participants enrolled, but only the participants enrolled at the final group doses are presented in the subsequent results.

The following groups satisfied the safety and PK guidelines specified in the protocol: Groups 3,4,6,7,8. Groups 5 and 5A did not satisfy the protocol-defined pharmacokinetic criteria. There was considerable inter-subject variability in systemic exposures in this age group, such that a dose escalation to 415mg/m\^2 may have resulted in ATV exposures greater than 90,000 ng\*hr/mL in some children. Thus, a further dose increase in Groups 5 and 5A was not attempted.

These are the final dose for each group: Groups 1 and 2 (Final dose was not established); Group 3 ATV Capsule (520mg/m\^2); Group 4 ATV Capsule (620mg/m\^2); Group 5 ATV Powder (310mg/m\^2) + RTV; Group 6 ATV Powder (310mg/m\^2) +RTV; Group 7 ATV Capsule (205mg/m\^2) + RTV; Group 8 ATV Capsule (205mg/m\^2) + RTV; Group 5A ATV Powder (310mg/m\^2) + RTV.

Eligibility 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

Primary outcomes:
measure: Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV
timeFrame: From study entry up to week 96
measure: Number of Participants Who Died
timeFrame: From study entry up to week 96
measure: Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h)
timeFrame: 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)
measure: Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24)
timeFrame: 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)
measure: Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax)
timeFrame: 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)
measure: Pharmacokinetic (PK) Parameter: Clearance (CL/F)
timeFrame: 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:
measure: Percentage of Participants With HIV RNA <400 Copies/mL at Week 24
timeFrame: Week 24
measure: Percentage of Participants With HIV RNA <400 Copies/mL at Week 48
timeFrame: Week 48
measure: Percentage of Participants With HIV RNA <400 Copies/mL at Week 96
timeFrame: Week 96
measure: Change in CD4 Count (Cells/mm^3) From Baseline to Week 20
timeFrame: Baseline, Week 20
measure: Change in CD4 Count (Cells/mm^3) From Baseline to Week 48
timeFrame: Baseline, Week 48
measure: Change in CD4 Count (Cells/mm^3) From Baseline to Week 96
timeFrame: Baseline, Week 96
measure: Change in CD4 Percent From Baseline to Week 20
timeFrame: Baseline, Week 20
measure: Change in CD4 Percent From Baseline to Week 48
timeFrame: Baseline, Week 48
measure: Change in CD4 Percent From Baseline to Week 96
timeFrame: Baseline, Week 96
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Pediatric Infectious Diseases CRS
state: Alabama
city: Alhambra
country: United States
facility: Usc La Nichd Crs
state: California
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS
state: California
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS
state: California
city: Los Angeles
country: United States
facility: UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
state: California
city: San Francisco
country: United States
facility: Univ. of California San Francisco NICHD CRS
state: California
city: Aurora
country: United States
facility: Univ. of Colorado Denver NICHD CRS
state: Colorado
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: South Florida CDTC Ft Lauderdale NICHD CRS
state: Florida
city: Columbus
country: United States
facility: Columbus Regional HealthCare System, The Med. Ctr.
state: Georgia
city: Chicago
country: United States
facility: Rush Univ. Cook County Hosp. Chicago NICHD CRS
state: Illinois
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ. New Orleans NICHD CRS
state: Louisiana
city: Baltimore
country: United States
facility: Univ. of Maryland Baltimore NICHD CRS
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Univ. Baltimore NICHD CRS
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS
state: Massachusetts
city: Worcester
country: United States
facility: WNE Maternal Pediatric Adolescent AIDS CRS
state: Massachusetts
city: Newark
country: United States
facility: Rutgers - New Jersey Medical School CRS
state: New Jersey
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital Center NICHD CRS
state: New York
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: New York
country: United States
facility: Nyu Ny Nichd Crs
state: New York
city: New York
country: United States
facility: Harlem Hosp. Ctr. NY NICHD CRS
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Med. Univ., Dept. of Peds.
state: New York
city: Durham
country: United States
facility: DUMC Ped. CRS
state: North Carolina
city: Philadelphia
country: United States
facility: Philadelphia IMPAACT Unit CRS
state: Pennsylvania
city: Philadelphia
country: United States
facility: St. Christopher's Hosp. for Children
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital CRS
state: Tennessee
city: Dallas
country: United States
facility: Children's Med. Ctr. Dallas
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital CRS
state: Texas
city: Norfolk
country: United States
facility: Children's Hosp. of the King's Daughters, Infectious Disease
state: Virginia
city: Norfolk
country: United States
facility: Childrens Hosp. of the Kings Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Research Institute CRS
state: Washington
city: Bayamon
country: Puerto Rico
facility: Univ. Hosp. Ramón Ruiz Arnau, Dept. of Peds.
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
city: Johannesburg
country: South Africa
facility: Soweto IMPAACT CRS
state: Gauteng
city: Johannesburg
country: South Africa
facility: Shandukani CRS
state: Gauteng
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Richard Rutstein, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.