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

Purpose

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.

Condition	Intervention	Phase
HIV-1 HIV Infections	Drug: TMC114 Drug: Ritonavir	Phase 2


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

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Ritonavir Darunavir Darunavir ethanolate

U.S. FDA Resources

Further study details as provided by Tibotec Pharmaceuticals, Ireland:

Primary Outcome Measures:

Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC 0-12h) - Part 1 [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
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.
Predose Plasma Concentration (C0) - Part 1 [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
The C0 is the predose plasma concentration.
Maximum Observed Plasma Concentration (Cmax) - Part 1 [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
The Cmax is the maximum observed plasma concentration.
Recommended Dose of TMC114 per Body Weight [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
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.
Change From Baseline in Plasma Viral Load at Week 2 - Part 1 [ Time Frame: Baseline and Week 2 ] [ Designated as safety issue: No ]
Plasma viral load levels will be determined using Roche amplicor human immunodeficiency virus (HIV)-1 monitor test (Version 1.5).
Change From Baseline in Plasma Viral Load at Week 24- Part 2 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
Plasma viral load levels will be determined using Roche amplicor HIV-1 monitor test (Version 1.5).
Number of Participants With Adverse Events [ Time Frame: Week 2 ] [ Designated as safety issue: Yes ]
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.
Number of Participants With Adverse Events [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
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.

Secondary Outcome Measures:

Change From Baseline in Plasma Viral Load at Week 48 - Part 2 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
Plasma viral load levels will be determined using Roche amplicor HIV-1 monitor test (Version 1.5).
Change from Baseline in Cluster of Differentiation 4 (CD4+) cell count - Part 2 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
The immunologic change will be determined by changes in CD4+ cell count.
Number of Participants With Resistance - Part 2 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
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.
Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC 0-12h) - Part 2 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
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.
Predose Plasma Concentration (C0) - Part 2 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
The C0 is the predose plasma concentration.
Oral Clearance (CL/F) - Part 2 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
The CL/F is the oral clearance; that is clearance based on oral bioavailability.


Enrollment:	80
Study Start Date:	June 2006
Study Completion Date:	March 2011
Primary Completion Date:	August 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Group A with >= 20 kg to < 30 kg body weight 300 milligram (mg) of TMC114 tablet with 50 mg (which is equivalent to 0.625 milliliter [mL]) of ritonavir liquid (80 milligram/milliliter [mg/ml]) will be administered orally twice daily.	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. Other Name: Darunavir Drug: 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.
Experimental: Group A with >= 30 kg to < 40 kg body weight 300 mg of TMC114 tablet with 50 mg (which is equivalent to 0.625 milliliter [mL]) of ritonavir liquid (80 milligram/milliliter [mg/ml]) will be administered orally twice daily.	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. Other Name: Darunavir Drug: 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.
Experimental: Group A with >= 40 kg to < 50 kg body weight 450 mg of TMC114 tablet with 100 mg of ritonavir capsule will be administered orally twice daily.	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. Other Name: Darunavir Drug: 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.
Experimental: Group B with >= 20 kg to < 30 kg body weight 375 mg of TMC114 tablet with 50 mg (which is equivalent to 0.625 mL) of ritonavir liquid (80 mg/mL) will be administered orally twice daily.	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. Other Name: Darunavir Drug: 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.
Experimental: Group B with >= 30 kg to < 40 kg body weight 450 mg of TMC114 tablet with 60 mg (which is equivalent to 0.75 mL) of ritonavir liquid (80 mg/mL) will be administered orally twice daily.	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. Other Name: Darunavir Drug: 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.
Experimental: Group B with >= 40 kg to < 50 kg body weight 600 mg of TMC114 tablet with 100 mg of ritonavir capsule will be administered orally twice daily.	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. Other Name: Darunavir Drug: 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.
Experimental: Participants with >= 50 kg body weight 600 mg of TMC114 tablet with 100 mg of ritonavir capsule will be administered orally twice daily.	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. Other Name: Darunavir Drug: 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.

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


Ages Eligible for Study:	6 Years to 17 Years (Child)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00355524

Locations


United States, California

Los Angeles, California, United States
United States, District of Columbia

Washington, District of Columbia, United States
United States, Illinois

Chicago, Illinois, United States
United States, Massachusetts

Boston, Massachusetts, United States

Worcester, Massachusetts, United States
United States, Pennsylvania

Philadelphia, Pennsylvania, United States
United States, Tennessee

Memphis, Tennessee, United States
Argentina

Buenos Aires, Argentina
Brazil

Belo Horizonte, Brazil

Nova Iguacu, Brazil

Ribeirao Preto, Brazil

Rio De Janeiro, Brazil
Canada, Ontario

Toronto, Ontario, Canada
Canada, Quebec

Montreal, Quebec, Canada
France

Paris, France
Romania

Bucuresti, Romania

Constanta, Romania
South Africa

Cape Town Cape, South Africa

Durban, South Africa

Johannesburg Gauteng, South Africa
Spain

Esplugues De Llobregat, Spain

Madrid, Spain

Sponsors and Collaborators

Tibotec Pharmaceuticals, Ireland

Investigators


Study Director:	Tibotec Pharmaceuticals Limited, Ireland Clinical Trial	Tibotec Pharmaceuticals, Ireland

More Information

Additional Information:

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 This link exits the ClinicalTrials.gov site

This link exits the ClinicalTrials.gov site

Publications:

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.


Responsible Party:	Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier:	NCT00355524 History of Changes
Other Study ID Numbers:	CR002797 TMC114-C212
Study First Received:	July 21, 2006
Last Updated:	July 5, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Tibotec Pharmaceuticals, Ireland:


HIV-1 Darunavir Ritonavir TMC114

Additional relevant MeSH terms:


HIV Infections Acquired Immunodeficiency Syndrome Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases Ritonavir	Darunavir HIV Protease Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 23, 2016