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

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

Patrocinadores

Patrocinador principal: National Institute of Allergy and Infectious Diseases (NIAID)

Colaborador: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Fuente National Institute of Allergy and Infectious Diseases (NIAID)
Resumen breve

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.

Descripción detallada

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.

Estado general Completed
Fecha de inicio November 2000
Fecha de Terminación September 2014
Fecha de finalización primaria October 2011
Fase Phase 1/Phase 2
Tipo de estudio Interventional
Resultado primario
Medida Periodo de tiempo
Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV 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) 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) 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) 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) 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)
Resultado secundario
Medida Periodo de tiempo
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
Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 Baseline, Week 96
Change in CD4 Percent From Baseline to Week 20 Baseline, Week 20
Change in CD4 Percent From Baseline to Week 48 Baseline, Week 48
Change in CD4 Percent From Baseline to Week 96 Baseline, Week 96
Inscripción 195
Condición
Intervención

Tipo de intervención: Drug

Nombre de intervención: ATV

Descripción: 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.

Tipo de intervención: Drug

Nombre de intervención: Ritonavir

Descripción: Administered as 100 mg capsules or oral solution.

Elegibilidad

Criterios:

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

Género: All

Edad mínima: 91 Days

Edad máxima: 21 Years

Voluntarios Saludables: No

Oficial general
Apellido Papel Afiliación
Richard Rutstein, MD Study Chair Children's Hospital of Philadelphia
Ubicación
Instalaciones:
UAB Pediatric Infectious Diseases CRS | Birmingham, Alabama, 35233, United States
Usc La Nichd Crs | Alhambra, California, 91803, United States
University of California, UC San Diego CRS | La Jolla, California, 92093-0672, United States
Miller Children's Hosp. Long Beach CA NICHD CRS | Long Beach, California, 90806, United States
UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS | Los Angeles, California, 900951752, United States
Univ. of California San Francisco NICHD CRS | San Francisco, California, 94143, United States
Univ. of Colorado Denver NICHD CRS | Aurora, Colorado, 80045, United States
Howard Univ. Washington DC NICHD CRS | Washington, District of Columbia, 20060, United States
South Florida CDTC Ft Lauderdale NICHD CRS | Ft. Lauderdale, Florida, 33316, United States
Columbus Regional HealthCare System, The Med. Ctr. | Columbus, Georgia, 31901, United States
Rush Univ. Cook County Hosp. Chicago NICHD CRS | Chicago, Illinois, 60612, United States
Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS | Chicago, Illinois, 60614, United States
Tulane Univ. New Orleans NICHD CRS | New Orleans, Louisiana, 701122699, United States
Univ. of Maryland Baltimore NICHD CRS | Baltimore, Maryland, 21201, United States
Johns Hopkins Univ. Baltimore NICHD CRS | Baltimore, Maryland, 21287, United States
Boston Medical Center Ped. HIV Program NICHD CRS | Boston, Massachusetts, 02118, United States
WNE Maternal Pediatric Adolescent AIDS CRS | Worcester, Massachusetts, 016550001, United States
Rutgers - New Jersey Medical School CRS | Newark, New Jersey, 07103, United States
Bronx-Lebanon Hospital Center NICHD CRS | Bronx, New York, 10457, United States
Jacobi Med. Ctr. Bronx NICHD CRS | Bronx, New York, 10461, United States
Nyu Ny Nichd Crs | New York, New York, 10016, United States
Harlem Hosp. Ctr. NY NICHD CRS | New York, New York, 10037, United States
SUNY Upstate Med. Univ., Dept. of Peds. | Syracuse, New York, 13210, United States
DUMC Ped. CRS | Durham, North Carolina, 277103499, United States
Philadelphia IMPAACT Unit CRS | Philadelphia, Pennsylvania, 19104, United States
St. Christopher's Hosp. for Children | Philadelphia, Pennsylvania, 191341095, United States
St. Jude Children's Research Hospital CRS | Memphis, Tennessee, 38105, United States
Children's Med. Ctr. Dallas | Dallas, Texas, 75235, United States
Texas Children's Hospital CRS | Houston, Texas, 77030, United States
Children's Hosp. of the King's Daughters, Infectious Disease | Norfolk, Virginia, 23507, United States
Childrens Hosp. of the Kings Daughters | Norfolk, Virginia, 23507, United States
Seattle Children's Research Institute CRS | Seattle, Washington, 98105, United States
Univ. Hosp. Ramón Ruiz Arnau, Dept. of Peds. | Bayamon, 00956, Puerto Rico
San Juan City Hosp. PR NICHD CRS | San Juan, 00936, Puerto Rico
Soweto IMPAACT CRS | Johannesburg, Gauteng, 1864, South Africa
Shandukani CRS | Johannesburg, Gauteng, 2001, South Africa
Ubicacion Paises

Puerto Rico

South Africa

United States

Fecha de verificación

March 2016

Fiesta responsable

Tipo: Sponsor

Palabras clave
Tiene acceso ampliado No
Condición Examinar
Número de brazos 9
Grupo de brazo

Etiqueta: Step I: Group 1

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 2

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 3

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 4

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 5

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 5a

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 6

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 7

Tipo: Experimental

Descripción: 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

Etiqueta: Step I: Group 8

Tipo: Experimental

Descripción: 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

Información de diseño del estudio

Asignación: Non-Randomized

Modelo de intervención: Parallel Assignment

Propósito primario: Treatment

Enmascaramiento: None (Open Label)

Fuente: ClinicalTrials.gov