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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00006604
• Other study ID #: P1020A
• Secondary ID: 10037IMPAACT P10
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 2000
• Est. completion date: September 2014

Study information

• Verified date: March 2016
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 195
• Est. completion date: September 2014
• Est. primary completion date: October 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 91 Days to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections

Intervention

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.
• Ritonavir
Administered as 100 mg capsules or oral solution.

Locations

Country	Name	City	State
Puerto Rico	Univ. Hosp. Ramón Ruiz Arnau, Dept. of Peds.	Bayamon
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
South Africa	Shandukani CRS	Johannesburg	Gauteng
South Africa	Soweto IMPAACT CRS	Johannesburg	Gauteng
United States	Usc La Nichd Crs	Alhambra	California
United States	Univ. of Colorado Denver NICHD CRS	Aurora	Colorado
United States	Johns Hopkins Univ. Baltimore NICHD CRS	Baltimore	Maryland
United States	Univ. of Maryland Baltimore NICHD CRS	Baltimore	Maryland
United States	UAB Pediatric Infectious Diseases CRS	Birmingham	Alabama
United States	Boston Medical Center Ped. HIV Program NICHD CRS	Boston	Massachusetts
United States	Bronx-Lebanon Hospital Center NICHD CRS	Bronx	New York
United States	Jacobi Med. Ctr. Bronx NICHD CRS	Bronx	New York
United States	Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS	Chicago	Illinois
United States	Rush Univ. Cook County Hosp. Chicago NICHD CRS	Chicago	Illinois
United States	Columbus Regional HealthCare System, The Med. Ctr.	Columbus	Georgia
United States	Children's Med. Ctr. Dallas	Dallas	Texas
United States	DUMC Ped. CRS	Durham	North Carolina
United States	South Florida CDTC Ft Lauderdale NICHD CRS	Fort Lauderdale	Florida
United States	Texas Children's Hospital CRS	Houston	Texas
United States	University of California, UC San Diego CRS	La Jolla	California
United States	Miller Children's Hosp. Long Beach CA NICHD CRS	Long Beach	California
United States	UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS	Los Angeles	California
United States	St. Jude Children's Research Hospital CRS	Memphis	Tennessee
United States	Tulane Univ. New Orleans NICHD CRS	New Orleans	Louisiana
United States	Harlem Hosp. Ctr. NY NICHD CRS	New York	New York
United States	Nyu Ny Nichd Crs	New York	New York
United States	Rutgers - New Jersey Medical School CRS	Newark	New Jersey
United States	Children's Hosp. of the King's Daughters, Infectious Disease	Norfolk	Virginia
United States	Childrens Hosp. of the Kings Daughters	Norfolk	Virginia
United States	Philadelphia IMPAACT Unit CRS	Philadelphia	Pennsylvania
United States	St. Christopher's Hosp. for Children	Philadelphia	Pennsylvania
United States	Univ. of California San Francisco NICHD CRS	San Francisco	California
United States	Seattle Children's Research Institute CRS	Seattle	Washington
United States	SUNY Upstate Med. Univ., Dept. of Peds.	Syracuse	New York
United States	Howard Univ. Washington DC NICHD CRS	Washington	District of Columbia
United States	WNE Maternal Pediatric Adolescent AIDS CRS	Worcester	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
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

Countries where clinical trial is conducted

United States,  Puerto Rico,  South Africa, 

References & Publications (11)

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.

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.

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.

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. — View 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.

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.

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. — View 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.

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.

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Number of Participants Who Died		From study entry up to week 96
Primary	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)
Primary	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)
Primary	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)
Primary	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	Percentage of Participants With HIV RNA <400 Copies/mL at Week 24	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.	Week 24
Secondary	Percentage of Participants With HIV RNA <400 Copies/mL at Week 48	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.	Week 48
Secondary	Percentage of Participants With HIV RNA <400 Copies/mL at Week 96	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.	Week 96
Secondary	Change in CD4 Count (Cells/mm^3) From Baseline to Week 20		Baseline, Week 20
Secondary	Change in CD4 Count (Cells/mm^3) From Baseline to Week 48		Baseline, Week 48
Secondary	Change in CD4 Count (Cells/mm^3) From Baseline to Week 96		Baseline, Week 96
Secondary	Change in CD4 Percent From Baseline to Week 20		Baseline, Week 20
Secondary	Change in CD4 Percent From Baseline to Week 48		Baseline, Week 48
Secondary	Change in CD4 Percent From Baseline to Week 96		Baseline, Week 96

External Links

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