Pharmacokinetics and Safety Study of Tipranavir in Combination With Low Dose Ritonavir in Human Immunodeficiency Virus (HIV)-Infected Children

Study Overview
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Brief Summary
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The primary objective of this study is to assess the safety and tolerability of tipranavir (TPV) oral formulation and soft gelatin capsules together with low-dose ritonavir in HIV-infected children and adolescents, to provide information concerning the pharmacokinetic characteristics of tipranavir and ritonavir in this age group, and to determine the relative bioavailability of the TPV liquid formulation and TPV capsule formulation in adolescents switching from liquid to capsule. The secondary objective of this study is the determination of the dose of topranavir and ritonavir (TPV/r) in children and adolescents between 2 and 18 years of age required for an adult equivalent systemic exposure of TPV/r 500 mg / 200 mg.

Official Title
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Multiple-dose, Open-label, Randomized, Safety and Pharmacokinetic Study of Tipranavir in Combination With Low-dose Ritonavir in HIV-infected Pediatric Patients

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: TPV oral solution
* Drug: TPV oral solution
* Drug: RTV oral solution
* Drug: RTV oral solution


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Males and females between 2 and 18 years of age. A confirmed diagnosis of HIV-1 infection as defined by two positive assays from two different samples taken at least two weeks apart. The two results may be any combination of the following: HIV ribonucleic acid (RNA) detected by reverse transcriptase (RT)-polymerase chain reaction(PCR) or HIV proviral deoxyribonucleic acid (DNA) detected by PCR HIV culture p24 antigen detection Licensed HIV enzyme-linked immunosorbent assay (ELISA) with confirmatory Western blot Viral load > 1500 RNA copies/mL. Acceptable screening laboratory values indicative of adequate baseline organ function. Laboratory values are considered acceptable if severity is no higher than Grade 1 for all tests defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading Severity of Pediatric Adverse Experiences (> 3 months of age) with the following exceptions: Grade 2 gamma-glutamyl transferase Grade 2 cholesterol Grade 2 triglycerides Signed informed consent prior to study participation from the patient or a legal guardian. Active assent must be given by the patient if the child and/or adolescent is capable of understanding the provided study information (this applies to children with the intellectual age of 7 years or greater) In the opinion of the investigator, an ability to take medications and comply with the requirements of the protocol. Exclusion criteria: Female patients of childbearing potential who: have a positive serum pregnancy test at screening are breast feeding are planning on becoming pregnant are not willing to use two methods of contraception to include at least one barrier method (e.g. latex condom plus spermicidal jelly/foam) Active hepatitis B or C disease defined as hepatitis B surface antigen (HBsAg) positivity or hepatitis C (HCV) antibody or RNA positivity with aspartate aminotransferase(AST)/ alanine aminotransferase(ALT) > Grade 2. Life expectancy < 12 months. Patients who are unwilling to abstain from ingesting contraindicated medications and substances which may significantly affect plasma levels of the study medications, notably: Grapefruit juice or Seville oranges Herbal preparations containing St. John's Wort or milk thistle Garlic supplements Active substance abuse. Use of investigational medications or vaccines within 28 days before study entry or during the trial. Some expanded access antiretroviral medications may be acceptable, but must be approved by sponsor. Requirement for any therapy for malignancy or immunomodulatory drug (e.g. interferon, cyclosporine, hydroxyurea, interleukin-2) within 28 days of study entry. Replacement intravenous gamma globulin treatment is acceptable. Any active opportunistic infection within 28 days before study entry or other clinically significant findings that may compromise the outcome of the study. Patients with malabsorption, severe chronic diarrhea or vomiting (more than two episodes of moderate or severe intensity, not attributed to medication therapy and lasting more than four days) within 28 days of the study. Evidence or symptoms of encephalopathy or developmental delay that would reduce compliance.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPV/r 290/115 mg/m^2<br>TPV and RTV oral solution low dose | Drug: TPV oral solution<br>* Tipranavir oral solution<br>Drug: RTV oral solution<br>* Ritonavir oral solution<br>|
| Experimental: TPV/r 375/150 mg/m^2<br>TPV and RTV oral solution high dose | Drug: TPV oral solution<br>* Tipranavir oral solution<br>Drug: RTV oral solution<br>* Ritonavir oral solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Severe (DAIDS Grades 3 or 4) Adverse Events Related to Drug for Treated Patients by Age Group and Formulation | Intensity of adverse events were graded by the investigator based on the DAIDS standardized table (Division of AIDS, National Institute of Health). DAIDS Grade 3 (Severe) and Grade 4 (Life Threatening) were identified. | up to 288 weeks | 
| Number of Patients With Severe (DAIDS Grades 3 or 4) Laboratory Abnormalities by Age Group and Formulation | Intensity of adverse events were graded by the investigator based on the DAIDS standardized table (Division of AIDS, National Institute of Health). DAIDS Grade 3 (Severe) and Grade 4 (Life Threatening) were identified. | up to 288 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 24 (Non-completers Considered Failures) |  | baseline, week 24 | 
| Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 48 (Non-completers Considered Failures) |  | baseline, week 48 | 
| Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 100 (Non-completers Considered Failures) |  | baseline, week 100 | 
| Number Patients With HIV RNA <400 Copies/mL at Week 24 (Non-completers Considered Failures) |  | baseline, week 24 | 
| Number Patients With HIV RNA <400 Copies/mL at Week 48 (Non-completers Considered Failures) |  | baseline, week 48 | 
| Number Patients With HIV RNA <400 Copies/mL at Week 100 (Non-completers Considered Failures) |  | baseline, week 100 | 
| Number Patients With HIV RNA <50 Copies/mL at Week 24 (Non-completers Considered Failures) |  | baseline, week 24 | 
| Number Patients With HIV RNA <50 Copies/mL at Week 48 (Non-completers Considered Failures) |  | baseline, week 48 | 
| Number Patients With HIV RNA <50 Copies/mL at Week 100 (Non-completers Considered Failures) |  | baseline, week 100 | 
| Baseline Median Viral Load log10 Copies/mL |  | baseline | 
| Median Change From Baseline in Viral Load log10 Copies/mL at Week 24 (Last Observation Carried Forward) |  | baseline, week 24 | 
| Median Change From Baseline in Viral Load log10 Copies/mL at Week 48 (Last Observation Carried Forward) |  | baseline, week 48 | 
| Median Change From Baseline in Viral Load log10 Copies/mL at Week 100 (Last Observation Carried Forward) |  | baseline, week 100 | 
| Baseline Median CD4+ Cell Count (Cells/mm3) |  | baseline | 
| Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 24 (Last Observation Carried Forward) |  | baseline, week 24 | 
| Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 48 (Last Observation Carried Forward) |  | baseline, week 48 | 
| Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 100 (Last Observation Carried Forward) |  | baseline, week 100 | 
| Median Baseline CD4 Percent | Percentage of lymphocytes that are CD4 cells | baseline | 
| Median Change From Baseline in CD4 Percent at Week 24 (Last Observation Carried Forward) | Percentage of lymphocytes that are CD4 cells | baseline, week 24 | 
| Median Change From Baseline in CD4 Percent at Week 48 (Last Observation Carried Forward) | Percentage of lymphocytes that are CD4 cells | baseline, week 48 | 
| Median Change From Baseline in CD4 Percent at Week 100 (Last Observation Carried Forward) | Percentage of lymphocytes that are CD4 cells | baseline, week 100 | 
| Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 8 |  | week 8 | 
| Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 16 |  | week 16 | 
| Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 24 |  | week 24 | 
| Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 48 |  | week 48 |