Clinical trial NCT00355524: A Phase 2 Study to Evaluate Pharmacokinetics, Safety and Efficacy of TMC114/Ritonavir (Rtv) in Human Immunodeficiency Virus (HIV)-1 Infected Children and Adolescents
Official title: A Phase II, Open-label Trial, to Investigate Pharmacokinetics, Safety, Tolerability and Antiviral Activity of TMC114/Rtv b.i.d in Treatment-Experienced HIV-1 Infected Children and Adolescents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1
HIV Infections
Keywords: HIV-1
Darunavir
Ritonavir
TMC114
Lead sponsor: Tibotec Pharmaceuticals, Ireland
Sponsor class: INDUSTRY
First posted: 2006-07-24
Enrollment: 80
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the pharmacokinetics (the study of the way a drug enters and leaves the blood and tissues over time), safety, tolerability and antiviral activity to support dose recommendations of TMC114 with ritonavir and other antiretroviral agents in treatment-experienced, human immunodeficiency virus (HIV)-1 infected children and adolescents.

Detailed description: This is an open-label (all people know the identity of the intervention) and randomized (study drug assigned by chance) study to evaluate pharmacokinetics, safety, tolerability, efficacy, antiviral activity, immunology and resistance characteristics of TMC114 with ritonavir in treatment-experienced, HIV-1 infected children and adolescent participants. The study consists of 3 periods: Screening period (maximum 4 weeks); Treatment period (maximum 48 weeks); and Follow-up period (4 weeks). The Treatment period consists of two parts: Part-1 for pediatric dose selection and Part-2 for the recommendation of pediatric or adult dose. Part-1 was further divided into two groups: Group A with adult equivalent dose of TMC114 with ritonavir twice daily and Group B with 20-33 percent higher dose of TMC114 with ritonavir twice daily. The recommended dose will be selected based on short-term safety, tolerability, antiviral activity and pharmacokinetics at Week 2. Once selected, all Part-1 participants who will not be on the selected dose will be switched to the selected dose at their next visit and will continue the study up to 48 weeks in Part-2. Participants with less than or equal to 18 years at Week 48 visit, and continued to benefit from treatment with TMC114 and will be living in a country where TMC114 pediatric use is not yet part of the label, will have the opportunity to roll-over to the extension phase where they will continue to receive TMC114/ritonavir until the participant became 18 years and TMC114 will be available through the local Health Care Systems or until TMC114 is indicated for use in pediatrics. Efficacy will primarily be evaluated by virologic response. Participants' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* Participants with documented human immunodeficiency virus (HIV)-1 infection failing their current antiretroviral therapy
* Body weight for Part 1: greater than or equal to 20 Kilogram (kg) but less than 50 kg and body weight for Part 2: greater than or equal to 50 kg and from greater than or equal to 20 but less than 50 kg after pediatric dose selection
* Able to swallow the TMC114 tablet formulations, the ritonavir capsule formulation, and to tolerate the ritonavir liquid formulation
* Stable cluster of differentiation 4 (CD4+) percentage; that is no more than 5 percent decrease in CD4+ percentage between the Screening visit and the last available CD4+ measurement
* Female participants who are sexually active and able to become pregnant must use a safe and effective birth control method

Exclusion Criteria:

* For Part 1: Use of the non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) efavirenz as part of the current regimen was not allowed and for Part 2: Use of efavirenz as part of the current regimen was allowed and use of any antiretroviral and non-antiretroviral investigational agents within 30 days prior to screening
* Presence of any currently active acquired immune deficiency syndrome (AIDS) defining illness (Category C conditions according to the Centers for Disease Control \[CDC\] Classification System for HIV Infection 1993 or according to the 1994 revised CDC Classification System for HIV infection in children less than 13 years of age)
* Pregnant or breastfeeding female participants
* Previous allergy or hypersensitivity to any excipients of the investigational medication (TMC114) or ritonavir
* Any Grade 3 or 4 toxicity as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) grading scale

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC 0-12h) - Part 1
timeFrame: Week 2
measure: Predose Plasma Concentration (C0) - Part 1
timeFrame: Week 2
measure: Maximum Observed Plasma Concentration (Cmax) - Part 1
timeFrame: Week 2
measure: Recommended Dose of TMC114 per Body Weight
timeFrame: Week 2
measure: Change From Baseline in Plasma Viral Load at Week 2 - Part 1
timeFrame: Baseline and Week 2
measure: Change From Baseline in Plasma Viral Load at Week 24- Part 2
timeFrame: Baseline and Week 24
measure: Number of Participants With Adverse Events
timeFrame: Week 2
measure: Number of Participants With Adverse Events
timeFrame: Week 24
Secondary outcomes:
measure: Change From Baseline in Plasma Viral Load at Week 48 - Part 2
timeFrame: Baseline and Week 48
measure: Change from Baseline in Cluster of Differentiation 4 (CD4+) cell count - Part 2
timeFrame: Baseline and Week 48
measure: Number of Participants With Resistance - Part 2
timeFrame: Week 48
measure: Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC 0-12h) - Part 2
timeFrame: Week 48
measure: Predose Plasma Concentration (C0) - Part 2
timeFrame: Week 48
measure: Oral Clearance (CL/F) - Part 2
timeFrame: Week 48
Other outcomes:
Locations:
city: Los Angeles
country: United States
state: California
city: Washington
country: United States
state: District of Columbia
city: Chicago
country: United States
state: Illinois
city: Boston
country: United States
state: Massachusetts
city: Worcester
country: United States
state: Massachusetts
city: Philadelphia
country: United States
state: Pennsylvania
city: Memphis
country: United States
state: Tennessee
city: Buenos Aires
country: Argentina
city: Belo Horizonte
country: Brazil
city: Nova Iguacu
country: Brazil
city: Ribeirao Preto
country: Brazil
city: Rio De Janeiro
country: Brazil
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Paris
country: France
city: Bucuresti
country: Romania
city: Constanta
country: Romania
city: Cape Town Cape
country: South Africa
city: Durban
country: South Africa
city: Johannesburg Gauteng
country: South Africa
city: Esplugues De Llobregat
country: Spain
city: Madrid
country: Spain
Study officials:
affiliation: Tibotec Pharmaceuticals, Ireland
name: Tibotec Pharmaceuticals Limited, Ireland Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Blanche S, Bologna R, Cahn P, Rugina S, Flynn P, Fortuny C, Vis P, Sekar V, van Baelen B, Dierynck I, Spinosa-Guzman S. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS. 2009 Sep 24;23(15):2005-13. doi: 10.1097/QAD.0b013e328330abaa.