Clinical trial NCT00076999: Pharmacokinetics and Safety Study of Tipranavir in Combination With Low Dose Ritonavir in Human Immunodeficiency Virus (HIV)-Infected Children
Official title: Multiple-dose, Open-label, Randomized, Safety and Pharmacokinetic Study of Tipranavir in Combination With Low-dose Ritonavir in HIV-infected Pediatric Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2004-02-10
Enrollment: 115
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Severe (DAIDS Grades 3 or 4) Adverse Events Related to Drug for Treated Patients by Age Group and Formulation
timeFrame: up to 288 weeks
measure: Number of Patients With Severe (DAIDS Grades 3 or 4) Laboratory Abnormalities by Age Group and Formulation
timeFrame: up to 288 weeks
Secondary outcomes:
measure: Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 24 (Non-completers Considered Failures)
timeFrame: baseline, week 24
measure: Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 48 (Non-completers Considered Failures)
timeFrame: baseline, week 48
measure: Number Patients With at Least 1 log10 Viral Load Reduction From Baseline at Week 100 (Non-completers Considered Failures)
timeFrame: baseline, week 100
measure: Number Patients With HIV RNA <400 Copies/mL at Week 24 (Non-completers Considered Failures)
timeFrame: baseline, week 24
measure: Number Patients With HIV RNA <400 Copies/mL at Week 48 (Non-completers Considered Failures)
timeFrame: baseline, week 48
measure: Number Patients With HIV RNA <400 Copies/mL at Week 100 (Non-completers Considered Failures)
timeFrame: baseline, week 100
measure: Number Patients With HIV RNA <50 Copies/mL at Week 24 (Non-completers Considered Failures)
timeFrame: baseline, week 24
measure: Number Patients With HIV RNA <50 Copies/mL at Week 48 (Non-completers Considered Failures)
timeFrame: baseline, week 48
measure: Number Patients With HIV RNA <50 Copies/mL at Week 100 (Non-completers Considered Failures)
timeFrame: baseline, week 100
measure: Baseline Median Viral Load log10 Copies/mL
timeFrame: baseline
measure: Median Change From Baseline in Viral Load log10 Copies/mL at Week 24 (Last Observation Carried Forward)
timeFrame: baseline, week 24
measure: Median Change From Baseline in Viral Load log10 Copies/mL at Week 48 (Last Observation Carried Forward)
timeFrame: baseline, week 48
measure: Median Change From Baseline in Viral Load log10 Copies/mL at Week 100 (Last Observation Carried Forward)
timeFrame: baseline, week 100
measure: Baseline Median CD4+ Cell Count (Cells/mm3)
timeFrame: baseline
measure: Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 24 (Last Observation Carried Forward)
timeFrame: baseline, week 24
measure: Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 48 (Last Observation Carried Forward)
timeFrame: baseline, week 48
measure: Median Change From Baseline in CD4+ Cell Count (Cells/mm3) at Week 100 (Last Observation Carried Forward)
timeFrame: baseline, week 100
measure: Median Baseline CD4 Percent
timeFrame: baseline
measure: Median Change From Baseline in CD4 Percent at Week 24 (Last Observation Carried Forward)
timeFrame: baseline, week 24
measure: Median Change From Baseline in CD4 Percent at Week 48 (Last Observation Carried Forward)
timeFrame: baseline, week 48
measure: Median Change From Baseline in CD4 Percent at Week 100 (Last Observation Carried Forward)
timeFrame: baseline, week 100
measure: Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 8
timeFrame: week 8
measure: Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 16
timeFrame: week 16
measure: Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 24
timeFrame: week 24
measure: Number Patients With Compliance With Tipranavir Treatment Between 95 and 120 Percent at Week 48
timeFrame: week 48
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: 1182.14.00001 Boehringer Ingelheim Investigational Site
state: California
city: Los Angeles
country: United States
facility: 1182.14.00006 Boehringer Ingelheim Investigational Site
state: California
city: Hartford
country: United States
facility: 1182.14.00010 Boehringer Ingelheim Investigational Site
state: Connecticut
city: Chicago
country: United States
facility: 1182.14.00004 Boehringer Ingelheim Investigational Site
state: Illinois
city: North Worcester
country: United States
facility: 1182.14.00008 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Springfield
country: United States
facility: 1182.14.00009 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Cleveland
country: United States
facility: 1182.14.00002 Boehringer Ingelheim Investigational Site
state: Ohio
city: Memphis
country: United States
facility: 1182.14.00007 Boehringer Ingelheim Investigational Site
state: Tennessee
city: Houston
country: United States
facility: 1182.14.00003 Boehringer Ingelheim Investigational Site
state: Texas
city: Capital Federal
country: Argentina
facility: 1182.14.5401 Fundación Huésped
city: São Paulo
country: Brazil
facility: 1182.14.55002
city: São Paulo
country: Brazil
facility: 1182.14.55003
city: Toronto
country: Canada
facility: 1182.14.11002 Boehringer Ingelheim Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: 1182.14.11001 Boehringer Ingelheim Investigational Site
state: Quebec
city: Lyon cedex 3
country: France
facility: 1182.14.33004 Boehringer Ingelheim Investigational Site
city: Nantes cedex 1
country: France
facility: 1182.14.33005 Boehringer Ingelheim Investigational Site
city: Paris cedex 12
country: France
facility: 1182.14.33006 Boehringer Ingelheim Investigational Site
city: Paris cedex 14
country: France
facility: 1182.14.33003 Boehringer Ingelheim Investigational Site
city: Paris cedex 15
country: France
facility: 1182.14.33001 Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1182.14.33002 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1182.14.49002 Boehringer Ingelheim Investigational Site
city: Frankfurt/Main
country: Germany
facility: 1182.14.49001 Boehringer Ingelheim Investigational Site
city: München
country: Germany
facility: 1182.14.49004 Boehringer Ingelheim Investigational Site
city: Padova
country: Italy
facility: 1182.14.39001 Boehringer Ingelheim Investigational Site
city: Roma
country: Italy
facility: 1182.14.39003 Boehringer Ingelheim Investigational Site
city: México, D.F.
country: Mexico
facility: 1182.14.52001 CLINDI (Clínica de Inmunodeficiencias)
city: México, D.F.
country: Mexico
facility: 1182.14.52002
city: San Juan
country: Puerto Rico
facility: 1182.14.00005 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1182.14.34002 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1182.14.34001 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.