Atazanavir Used in Combination With Other Anti-HIV Drugs in HIV-Infected Infants, Children, and Adolescents
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ClinicalTrials.gov Identifier: NCT00006604 |
Recruitment Status :
Completed
First Posted : August 31, 2001
Results First Posted : April 5, 2016
Last Update Posted : November 5, 2021
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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 or disease | Intervention/treatment | Phase |
---|---|---|
HIV Infections | Drug: ATV Drug: Ritonavir | Phase 1 Phase 2 |

Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 195 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (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 |
Study Start Date : | November 2000 |
Actual Primary Completion Date : | October 2011 |
Actual Study Completion Date : | September 2014 |

Arm | Intervention/treatment |
---|---|
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. |
- Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV [ Time Frame: From study entry up to week 96 ]
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 ]
- 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) ]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) ]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) ]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) ]Pharmacokinetics were determined by non-compartmental analysis and Apparent oral clearance (CL/F) was calculated as ATV dose divided by AUC0-24hr.
- Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 [ Time Frame: 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.
- Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 [ Time Frame: 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.
- Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 [ Time Frame: 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.
- Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 [ Time Frame: Baseline, Week 20 ]
- Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 [ Time Frame: Baseline, Week 48 ]
- Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 [ Time Frame: Baseline, Week 96 ]
- Change in CD4 Percent From Baseline to Week 20 [ Time Frame: Baseline, Week 20 ]
- Change in CD4 Percent From Baseline to Week 48 [ Time Frame: Baseline, Week 48 ]
- Change in CD4 Percent From Baseline to Week 96 [ Time Frame: Baseline, Week 96 ]

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Ages Eligible for Study: | 91 Days to 21 Years (Child, Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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:
- A type I second-degree atrioventricular (AV) block (Mobitz type I heart-block) occurring during waking hours on ECG at screening
- A type II second-degree AV-block (Mobitz type II heart-block) at any time on ECG at screening
- A complete AV-block at any time on ECG at screening
- 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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00006604

Study Chair: | Richard Rutstein, MD | Children's Hospital of Philadelphia |
Publications:
Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
ClinicalTrials.gov Identifier: | NCT00006604 |
Other Study ID Numbers: |
P1020A 10037 ( Registry Identifier: DAIDS ES ) IMPAACT P1020A PACTG P1020-A ACTG P1020-A |
First Posted: | August 31, 2001 Key Record Dates |
Results First Posted: | April 5, 2016 |
Last Update Posted: | November 5, 2021 |
Last Verified: | March 2016 |
Dose-Response Relationship, Drug Drug Therapy, Combination Drug Administration Schedule HIV Protease Inhibitors Reverse Transcriptase Inhibitors |
Anti-HIV Agents Pharmacokinetics Treatment Experienced Treatment Naive |
HIV Infections Blood-Borne Infections Communicable Diseases Infections Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Immunologic Deficiency Syndromes Immune System Diseases |
Ritonavir HIV Protease Inhibitors Viral Protease Inhibitors Protease 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 |