A Phase 2 Study to Evaluate Pharmacokinetics, Safety and Efficacy of TMC114/Ritonavir (Rtv) in Human Immunodeficiency Virus (HIV)-1 Infected Children and Adolescents

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00355524
• Other study ID #: CR002797
• Secondary ID: TMC114-C212
• Status: Completed
• Phase: Phase 2
• First received: July 21, 2006
• Last updated: July 5, 2013
• Start date: June 2006
• Est. completion date: March 2011

Study information

• Verified date: July 2013
• Source: Tibotec Pharmaceuticals, Ireland
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: March 2011
• Est. primary completion date: August 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years to 17 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• HIV-1

Intervention

Drug:
• TMC114
TMC114 will be administered as oral tablets (75 milligram [mg] or 300 mg) twice daily at a dose ranging from 300-600 mg up to 48 weeks.
• Ritonavir
Ritonavir will be administered as oral capsules (100 mg) or liquid (80 mg/mL) twice daily at a dose ranging from 50 mg (0.625 mL)-100 mg up to 48 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Tibotec Pharmaceuticals, Ireland

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  France,  Romania,  South Africa,  Spain, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC 0-12h) - Part 1	The Area Under the Plasma Concentration-Time Curve (AUC) is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption.	Week 2	No
Primary	Predose Plasma Concentration (C0) - Part 1	The C0 is the predose plasma concentration.	Week 2	No
Primary	Maximum Observed Plasma Concentration (Cmax) - Part 1	The Cmax is the maximum observed plasma concentration.	Week 2	No
Primary	Recommended Dose of TMC114 per Body Weight	The recommended dose of TMC114 will be determined in participants with a body weight: greater than and equal to 20 Kilogram (kg) to less than 30 kg; greater than and equal to 30 kg to less than 40 kg; and greater than 40 kg.	Week 2	No
Primary	Change From Baseline in Plasma Viral Load at Week 2 - Part 1	Plasma viral load levels will be determined using Roche amplicor human immunodeficiency virus (HIV)-1 monitor test (Version 1.5).	Baseline and Week 2	No
Primary	Change From Baseline in Plasma Viral Load at Week 24- Part 2	Plasma viral load levels will be determined using Roche amplicor HIV-1 monitor test (Version 1.5).	Baseline and Week 24	No
Primary	Number of Participants With Adverse Events	Adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which does not necessarily have a causal relationship with the treatment.	Week 2	Yes
Primary	Number of Participants With Adverse Events	Adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which does not necessarily have a causal relationship with the treatment.	Week 24	Yes
Secondary	Change From Baseline in Plasma Viral Load at Week 48 - Part 2	Plasma viral load levels will be determined using Roche amplicor HIV-1 monitor test (Version 1.5).	Baseline and Week 48	No
Secondary	Change from Baseline in Cluster of Differentiation 4 (CD4+) cell count - Part 2	The immunologic change will be determined by changes in CD4+ cell count.	Baseline and Week 48	No
Secondary	Number of Participants With Resistance - Part 2	Resistance will be determined by viral phenotype and genotype determinations, which will be performed by Virco BVBA, by means of the antivirogram and Virco type HIV-1 respectively. Resistance determinations will only be generated if the viral load is greater than 1000 HIV-1 RNA copies/milliliter.	Week 48	No
Secondary	Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC 0-12h) - Part 2	The Area Under the Plasma Concentration-Time Curve (AUC) is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption.	Week 48	No
Secondary	Predose Plasma Concentration (C0) - Part 2	The C0 is the predose plasma concentration.	Week 48	No
Secondary	Oral Clearance (CL/F) - Part 2	The CL/F is the oral clearance; that is clearance based on oral bioavailability.	Week 48	No

External Links

•   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