TMC125-TiDP35-C213: Safety and Antiviral Activity of Etravirine (TMC125) in Treatment-Experienced, HIV Infected Children and Adolescents - Full Text View

Purpose

The purpose of this study is to determine the safety and antiviral activity of etravirine in treatment-experienced human immunodeficiency virus (HIV) infected children and adolescents.

Condition	Intervention	Phase
HIV-1	Drug: Etravirine (TMC125) Drug: Optimized background regimen (OBR)	Phase 2


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II, Open-label Trial, to Evaluate the Safety, Tolerability and Antiviral Activity of TMC125 in Antiretroviral Experienced HIV-1 Infected Children and Adolescents

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Etravirine

U.S. FDA Resources

Further study details as provided by Tibotec Pharmaceuticals, Ireland:

Primary Outcome Measures:

The Number of Patients With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
A treatment-emergent adverse event (TEAE) was defined as an event that occurred in the 48-week treatment period during which it emerged (i.e. started or worsened in severity, relation, or other attribute), and not in the subsequent study periods, even if the event continued to be present. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen
The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
The percentage of patients with a treatment-emergent adverse event (TEAE) (defined as an event that occurred in the 48-week treatment period during which it emerged [i.e. started or worsened in severity, relation, or other attribute], and not in the subsequent study periods, even if the event continued to be present] are provided below. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen

Secondary Outcome Measures:

Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h) [ Time Frame: Weeks 4-48 ] [ Designated as safety issue: No ]
The AUC12h is a Bayesian estimation based on a population pharmacokinetic model and sparse samples collected at each visit over the duration of trial. For each sparse sample taken, the time blood sample was recorded as well as the time of etravirine intake just prior to the time of blood sample.
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax) [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
Etravirine/TMC125 (ETR) Cmax was approximated for each individual using the median value of plasma ETR concentrations taken 4 hours postdose (± 1 hour), when available, on the day of the Week 4 visit as shown in the table below.
Percentage of Patients With Virologic Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
Virologic response was defined as the percentage of patients with plasma viral load < 50 copies/mL at Week 24 calculated according to the non-completer=failure (NC=F) imputation method.
Change From Baseline in Human Immunodeficiency Virus - Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
The Change From Baseline in CD4 Cell Counts Over Time [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures [ Time Frame: Baseline and Endpoint (up to Week 48) ] [ Designated as safety issue: No ]
Virologic failure (lack of response) was defined as: plasma viral load decline of < 0.5 log10 from Baseline by Week 8 and/or plasma viral load decline of <1.0 log10 from Baseline by Week 12. Virologic failure (loss of response) was defined as 2 consecutive measurements of plasma viral load > 0.5 log10 above the nadir after a minimum of 12 weeks of treatment. The table below provides data for 41 viologic failures of which 30 had mutation data available. In the table below, only the 4 most frequently emerging mutations are presented (emerging in at least 3 patients).


Enrollment:	103
Study Start Date:	November 2008
Study Completion Date:	August 2011
Primary Completion Date:	May 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Etravirine (TMC125)	Drug: Etravirine (TMC125) Patients will be dosed by body weight , i.e. 5.2 mg/kg twice daily (b.i.d.) up to a maximum of 200 mg b.i.d. for 48 weeks. Drug: Optimized background regimen (OBR) An investigator-selected optimized background regimen (OBR) comprising of a low-dose ritonavir (rtv)-boosted protease inhibitor (PI) (either lopinavir [LPV], darunavir [DRV], atazanavir [ATV] or saquinavir [SQV]) in combination with nucleos(t)ide reverse transcriptase inhibitor(s) (N[t]RTIs) to be dosed according to the drugs individual package inserts for 48 weeks.

Arms

Assigned Interventions

Experimental: Etravirine (TMC125)

Drug: Etravirine (TMC125)

Patients will be dosed by body weight , i.e. 5.2 mg/kg twice daily (b.i.d.) up to a maximum of 200 mg b.i.d. for 48 weeks.

Drug: Optimized background regimen (OBR)

An investigator-selected optimized background regimen (OBR) comprising of a low-dose ritonavir (rtv)-boosted protease inhibitor (PI) (either lopinavir [LPV], darunavir [DRV], atazanavir [ATV] or saquinavir [SQV]) in combination with nucleos(t)ide reverse transcriptase inhibitor(s) (N[t]RTIs) to be dosed according to the drugs individual package inserts for 48 weeks.

Detailed Description:

The study design is a single arm treatment (all patients assigned to receive etravirine), open label (patients will know the identity of the treatments they are receiving) safety and antiviral activity of Etravirine (TMC125) in treatment-experienced, HIV infected children and adolescents 6 to 17 years of age. Etravirine is a new drug belonging to the NNRTI (a non-nucleoside reverse transcriptase inhibitor) drug class that slows down the growth of the human immunodeficiency virus (HIV). This drug has been tested for safety and effectiveness in adults, however, there is no data on the drug's long-term safety and antiviral activity in children and adolescents. This study will last for a maximum of 48 weeks. A total of 100 ptients will receive etravirine tablets based on body weight and an investigator selected optimized background regimen (OBR) of at least 2 antiretrovirals (ARVs), consisting of a boosted protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor(s) (NRTI[s]). Use of enfuvirtide is optional. 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:

HIV-1 infected
Body weight according to age within the 10-90th percentile of CDC growth chart
On steady antiretroviral therapy regimen for at least 8 weeks at screening and willing to remain on that regimen until baseline
HIV viral load of 1,000 copies/ml or greater at study entry
Parent or legal guardian willing to provide informed consent, if necessary

Exclusion Criteria:

The Key Exclusion Criteria are: Evidence of resistance to etravirinel Any grade 3 or 4 toxicity (More information available in the protocol)
Use of disallowed concomitant therapy (specified in the protocol)
Currently active AIDS defining illness (category C)
Active hepatitis A, B or C virus infection
Any clinically significant diseases or findings that, in the opinion of the investigator, would interfere with the study
Receipt of any ARV or non-ARV investigational medication or investigational vaccine within 30 days prior to screening
History of clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication (TMC125)

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: NCT00665847

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Sponsors and Collaborators

Tibotec Pharmaceuticals, Ireland

Investigators


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

More Information


Responsible Party:	Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier:	NCT00665847 History of Changes
Obsolete Identifiers:	NCT00750542
Other Study ID Numbers:	CR002746 TMC125-TiDP35-C213 2007-007086-21
Study First Received:	April 22, 2008
Results First Received:	June 14, 2012
Last Updated:	April 2, 2015
Health Authority:	United States: Food and Drug Administration Ireland: Irish Agriculture and Food Development Authority Great Britain: Medicines and Healthcare Products Regulatory Agency United States: Federal Government United States: Institutional Review Board

Keywords provided by Tibotec Pharmaceuticals, Ireland:


HIV-1 TMC125-TiDP35-C213 TMC125-C213

Additional relevant MeSH terms:


Antiviral Agents Etravirine Anti-Infective Agents Reverse Transcriptase Inhibitors	Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Retroviral Agents

ClinicalTrials.gov processed this record on September 29, 2016