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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00076999
• Other study ID #: 1182.14
• Status: Completed
• Phase: Phase 1
• First received: February 9, 2004
• Last updated: April 25, 2014
• Start date: November 2003

Study information

• Verified date: April 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia MedicaBrazil: Ministry of HealthCanada: Health CanadaFrance: Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS)Germany: Federal Institute for Drugs and Medical DevicesItaly: COMITATO ETICO PER LA SPERIMENTAZIONE DELL'AZ. OSP. DI PADOVAMexico: Comision Federal para la Proteccion contra Riesgos Sanitarios (COFEPRIS)Spain: Spanish Agency of MedicinesUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 115
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 18 Years

Eligibility

Inclusion criteria:

1. Males and females between 2 and 18 years of age.

2. 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

3. Viral load > 1500 RNA copies/mL.

4. 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

5. 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)

6. In the opinion of the investigator, an ability to take medications and comply with the requirements of the protocol.

Exclusion criteria:

1. 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)

2. 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.

3. Life expectancy < 12 months.

4. 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

5. Active substance abuse.

6. 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.

7. 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.

8. Any active opportunistic infection within 28 days before study entry or other clinically significant findings that may compromise the outcome of the study.

9. 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.

10. Evidence or symptoms of encephalopathy or developmental delay that would reduce compliance.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections

Intervention

Drug:
• TPV oral solution
Tipranavir oral solution
• TPV oral solution
Tipranavir oral solution
• RTV oral solution
Ritonavir oral solution
• RTV oral solution
Ritonavir oral solution

Locations

Country	Name	City	State
Argentina	1182.14.5401 Fundación Huésped	Capital Federal
Brazil	1182.14.55002	São Paulo
Brazil	1182.14.55003	São Paulo
Canada	1182.14.11001 Boehringer Ingelheim Investigational Site	Montreal	Quebec
Canada	1182.14.11002 Boehringer Ingelheim Investigational Site	Toronto	Ontario
France	1182.14.33004 Boehringer Ingelheim Investigational Site	Lyon cedex 3
France	1182.14.33005 Boehringer Ingelheim Investigational Site	Nantes cedex 1
France	1182.14.33002 Boehringer Ingelheim Investigational Site	Paris
France	1182.14.33006 Boehringer Ingelheim Investigational Site	Paris cedex 12
France	1182.14.33003 Boehringer Ingelheim Investigational Site	Paris cedex 14
France	1182.14.33001 Boehringer Ingelheim Investigational Site	Paris cedex 15
Germany	1182.14.49002 Boehringer Ingelheim Investigational Site	Berlin
Germany	1182.14.49001 Boehringer Ingelheim Investigational Site	Frankfurt/Main
Germany	1182.14.49004 Boehringer Ingelheim Investigational Site	München
Italy	1182.14.39001 Boehringer Ingelheim Investigational Site	Padova
Italy	1182.14.39003 Boehringer Ingelheim Investigational Site	Roma
Mexico	1182.14.52001 CLINDI (Clínica de Inmunodeficiencias)	México, D.F.
Mexico	1182.14.52002	México, D.F.
Puerto Rico	1182.14.00005 Boehringer Ingelheim Investigational Site	San Juan
Spain	1182.14.34002 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1182.14.34001 Boehringer Ingelheim Investigational Site	Madrid
United States	1182.14.00004 Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	1182.14.00002 Boehringer Ingelheim Investigational Site	Cleveland	Ohio
United States	1182.14.00010 Boehringer Ingelheim Investigational Site	Hartford	Connecticut
United States	1182.14.00003 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1182.14.00001 Boehringer Ingelheim Investigational Site	Los Angeles	California
United States	1182.14.00006 Boehringer Ingelheim Investigational Site	Los Angeles	California
United States	1182.14.00007 Boehringer Ingelheim Investigational Site	Memphis	Tennessee
United States	1182.14.00008 Boehringer Ingelheim Investigational Site	North Worcester	Massachusetts
United States	1182.14.00009 Boehringer Ingelheim Investigational Site	Springfield	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  France,  Germany,  Italy,  Mexico,  Puerto Rico,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 24 (Non-completers Considered Failures)		baseline, week 24	No
Secondary	Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 48 (Non-completers Considered Failures)		baseline, week 48	No
Secondary	Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 100 (Non-completers Considered Failures)		baseline, week 100	No
Secondary	Number Patients With HIV RNA <400 Copies/mL at Week 24 (Non-completers Considered Failures)		baseline, week 24	No
Secondary	Number Patients With HIV RNA <400 Copies/mL at Week 48 (Non-completers Considered Failures)		baseline, week 48	No
Secondary	Number Patients With HIV RNA <400 Copies/mL at Week 100 (Non-completers Considered Failures)		baseline, week 100	No
Secondary	Number Patients With HIV RNA <50 Copies/mL at Week 24 (Non-completers Considered Failures)		baseline, week 24	No
Secondary	Number Patients With HIV RNA <50 Copies/mL at Week 48 (Non-completers Considered Failures)		baseline, week 48	No
Secondary	Number Patients With HIV RNA <50 Copies/mL at Week 100 (Non-completers Considered Failures)		baseline, week 100	No
Secondary	Baseline Median Viral Load log10 Copies/mL		baseline	No
Secondary	Median Change From Baseline in Viral Load log10 Copies/mL at Week 24 (Last Observation Carried Forward)		baseline, week 24	No
Secondary	Median Change From Baseline in Viral Load log10 Copies/mL at Week 48 (Last Observation Carried Forward)		baseline, week 48	No
Secondary	Median Change From Baseline in Viral Load log10 Copies/mL at Week 100 (Last Observation Carried Forward)		baseline, week 100	No
Secondary	Baseline Median CD4+ Cell Count (Cells/mm3)		baseline	No
Secondary	Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 24 (Last Observation Carried Forward)		baseline, week 24	No
Secondary	Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 48 (Last Observation Carried Forward)		baseline, week 48	No
Secondary	Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 100 (Last Observation Carried Forward)		baseline, week 100	No
Secondary	Median Baseline CD4 Percent	Percentage of lymphocytes that are CD4 cells	baseline	No
Secondary	Median Change From Baseline in CD4 Percent at Week 24 (Last Observation Carried Forward)	Percentage of lymphocytes that are CD4 cells	baseline, week 24	No
Secondary	Median Change From Baseline in CD4 Percent at Week 48 (Last Observation Carried Forward)	Percentage of lymphocytes that are CD4 cells	baseline, week 48	No
Secondary	Median Change From Baseline in CD4 Percent at Week 100 (Last Observation Carried Forward)	Percentage of lymphocytes that are CD4 cells	baseline, week 100	No
Secondary	Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 8		week 8	No
Secondary	Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 16		week 16	No
Secondary	Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 24		week 24	No
Secondary	Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 48		week 48	No

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