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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: TPV oral solution; Drug: RTV oral solution

• Study Type: Interventional
• Enrollment (Actual): 115
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Salazar JC, Cahn P, Della Negra M, De Aquino MZ, Robinson PA, Jelaska A, Mikl J. Efficacy and safety of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents: 5 years of experience. Pediatr Infect Dis J. 2014 Apr;33(4):396-400. doi: 10.1097/INF.0000000000000038.
• Salazar JC, Cahn P, Yogev R, Negra MD, Castelli-Gattinara G, Fortuny C, Flynn PM, Giaquinto C, Ruan PK, Smith ME, Mikl J, Jelaska A; PACTG 1051/BI Study Team. Efficacy, safety and tolerability of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents. AIDS. 2008 Sep 12;22(14):1789-98. doi: 10.1097/QAD.0b013e32830c481b.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 2003
• Primary Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: February 9, 2004
• First Submitted That Met QC Criteria: February 9, 2004
• First Posted (Estimate): February 10, 2004

Study Record Updates

• Last Update Posted (Estimate): May 12, 2014
• Last Update Submitted That Met QC Criteria: April 25, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Pharmaceutical Solutions
• Other Study ID Numbers: 1182.14