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

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ClinicalTrials.gov Identifier: NCT00665847
Recruitment Status : Completed
First Posted : April 24, 2008
Results First Posted : December 21, 2012
Last Update Posted : April 23, 2015
Sponsor:
Information provided by (Responsible Party):
Tibotec Pharmaceuticals, Ireland

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV-1
Interventions Drug: Etravirine (TMC125)
Drug: Optimized background regimen (OBR)
Enrollment 103

Recruitment Details In total, 41 investigators in 13 countries enrolled patients in study TMC125-C213. A total of 103 patients were documented as being enrolled in the study, however 2 patients were randomized in error. Therefore, 101 patients were enrolled and treated with etravirine (ETR) also known as TMC125 and included in the intent-to-treat (ITT) population.
Pre-assignment Details  
Arm/Group Title TMC125
Hide Arm/Group Description TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day
Period Title: Overall Study
Started 101
Completed 76
Not Completed 25
Reason Not Completed
Adverse Event             8
Withdrawal by Subject             2
Subject non-compliant             8
Subject reached a virologic endpoint             4
Resistance to TMC125             1
Subject ineligible to continue the trial             1
Switch to Commercial Medication             1
Arm/Group Title TMC125
Hide Arm/Group Description TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Baseline Participants 101
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 101 participants
12.2  (2.99)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants
Female
64
  63.4%
Male
37
  36.6%
Age Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 101 participants
>=6 to <12 years 41
>=12 to <18 years 60
1.Primary Outcome
Title The Number of Patients With Treatment-emergent Adverse Events (TEAEs)
Hide Description 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
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis was done on the intent-to-treat (ITT) population, which included all patients who received at least one dose of investigational medication.
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Measure Type: Number
Unit of Measure: Patients
Any TEAE 89
TEAEs that were fatal 0
TEAEs that were serious 5
TEAEs that were grade 3 or 4 in severity 14
TEAEs leading to temporary ETR discontinuation 8
TEAEs leading to permanent ETR discontinuation 8
TEAEs possibly related to ETR 23
TEAEs probably related to ETR 14
TEAEs very likely related to ETR 3
TEAEs at least possibly related to ETR 33
TEAEs possibly related to OBR 27
TEAEs probably related to OBR 12
TEAEs very likely related to OBR 5
TEAEs at least possibly related to OBR 36
TEAEs of at least grade 2 in severity 21
TEAEs of at least grade 3 in severity 3
TEAEs of interest: Skin event 31
TEAEs of interest: Rash 23
TEAEs of interest: severe cutaneous reactions 7
TEAEs of interest: angioedema 4
TEAEs of interest: neuropsychiatric events 2
TEAEs of interest: hepatic events 0
TEAEs of interest: cardiac events 0
TEAEs of interest: bleeding events 0
TEAEs of interest: pancreatic events 1
TEAEs of interest: lipid-related events 6
TEAEs of interest: neoplasms 1
2.Primary Outcome
Title The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs)
Hide Description 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
Time Frame 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis was done on the intent-to-treat (ITT) population, which included all patients who received at least one dose of investigational medication.
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Measure Type: Number
Unit of Measure: Percentage of patients
Any TEAE 88.1
TEAEs that were fatal 0
TEAEs that were serious 5.0
TEAEs that were grade 3 or 4 in severity 13.9
TEAEs leading to temporary ETR discontinuation 7.9
TEAEs leading to permanent ETR discontinuation 7.9
TEAEs possibly related to ETR 22.8
TEAEs probably related to ETR 13.9
TEAEs very likely related to ETR 3.0
TEAEs at least possibly related to ETR 32.7
TEAEs possibly related to OBR 26.7
TEAEs probably related to OBR 11.9
TEAEs very likely related to OBR 5.0
TEAEs at least possibly related to OBR 35.6
TEAEs of at least grade 2 in severity 20.8
TEAEs of at least grade 3 in severity 3.0
TEAEs of interest: Skin event 30.7
TEAEs of interest: Rash 22.8
TEAEs of interest: severe cutaneous reactions 6.9
TEAEs of interest: angioedema 4.0
TEAEs of interest: neuropsychiatric events 2.0
TEAEs of interest: hepatic events 0
TEAEs of interest: cardiac events 0
TEAEs of interest: bleeding events 0
TEAEs of interest: pancreatic events 1.0
TEAEs of interest: lipid-related events 5.9
TEAEs of interest: neoplasms 1.0
3.Secondary Outcome
Title Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h)
Hide Description 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.
Time Frame Weeks 4-48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken ETR at least once, regardless of their compliance with the protocol was used for this analysis. The table below shows results for "Overall (children and adolescents combined)."
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Mean (Standard Deviation)
Unit of Measure: ng.h/mL
5216  (4305)
4.Secondary Outcome
Title Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h)
Hide Description [Not Specified]
Time Frame Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken ETR at least once, regardless of their compliance with the protocol was used for this analysis. The table below shows results for "Overall (children and adolescents combined)."
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Mean (Standard Deviation)
Unit of Measure: ng/mL
346  (342)
5.Secondary Outcome
Title Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax)
Hide Description 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.
Time Frame Week 4
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Mean (Standard Deviation)
Unit of Measure: ng/mL
589  (486)
6.Secondary Outcome
Title Percentage of Patients With Virologic Response at Week 24
Hide Description 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.
Time Frame Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Measure Type: Number
Unit of Measure: Percentage of Patients
52.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TMC125
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion
Estimated Value 52.5
Confidence Interval (2-Sided) 95%
42.7 to 62.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.050
Estimation Comments The standard error for a proportion was calculated as the square root of the variance divided by the number of patients. The variance for a proportion is equal to p*(1-p), with p being the proportion.
7.Secondary Outcome
Title Change From Baseline in Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time
Hide Description [Not Specified]
Time Frame Baseline, Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Mean (Standard Error)
Unit of Measure: log10 copies/mL
-1.53  (0.132)
8.Secondary Outcome
Title The Change From Baseline in CD4 Cell Counts Over Time
Hide Description [Not Specified]
Time Frame Baseline, Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis.
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 101
Mean (Standard Error)
Unit of Measure: 10E6 cells/L
156  (22.7)
9.Secondary Outcome
Title The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures
Hide Description 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).
Time Frame Baseline and Endpoint (up to Week 48)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The patients in the intent-to-treat (ITT) population classified as virologic failures were used for this analysis.
Arm/Group Title TMC125
Hide Arm/Group Description:
TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: Patients
V90I 3
L100I 3
E138A 3
Y181C 8
Time Frame [Not Specified]
Adverse Event Reporting Description Only subjects who had at least one of the TEAEs listed in the Other (non Serious) AE table are included in the Total no. subjects with Non-Serious Adverse Events.
 
Arm/Group Title TMC125
Hide Arm/Group Description TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day
All-Cause Mortality
TMC125
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
TMC125
Affected / at Risk (%)
Total   5/101 (4.95%) 
Eye disorders   
Ulcerative keratitis * 1  1/101 (0.99%) 
General disorders   
Drug resistance * 1  1/101 (0.99%) 
Injury, poisoning and procedural complications   
Drug toxicity * 1  1/101 (0.99%) 
Overdose * 1  1/101 (0.99%) 
Investigations   
Immunoglobulins * 1  1/101 (0.99%) 
Lymphocyte morphology abnormal * 1  1/101 (0.99%) 
Weight decreased * 1  1/101 (0.99%) 
Social circumstances   
Treatment noncompliance * 1  1/101 (0.99%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 11.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
TMC125
Affected / at Risk (%)
Total   70/101 (69.31%) 
Eye disorders   
Conjunctivitis * 1  6/101 (5.94%) 
Gastrointestinal disorders   
Diarrhoea * 1  16/101 (15.84%) 
Nausea * 1  10/101 (9.90%) 
Vomiting * 1  11/101 (10.89%) 
General disorders   
Pyrexia * 1  9/101 (8.91%) 
Infections and infestations   
Bronchitis * 1  9/101 (8.91%) 
Oral herpes * 1  6/101 (5.94%) 
Pharyngitis * 1  8/101 (7.92%) 
Rhinitis * 1  6/101 (5.94%) 
Sinusitis * 1  6/101 (5.94%) 
Upper respiratory tract infection * 1  27/101 (26.73%) 
Nervous system disorders   
Headache * 1  9/101 (8.91%) 
Respiratory, thoracic and mediastinal disorders   
Cough * 1  13/101 (12.87%) 
Oropharyngeal pain * 1  6/101 (5.94%) 
Skin and subcutaneous tissue disorders   
Rash * 1  11/101 (10.89%) 
Rash maculo-papular * 1  9/101 (8.91%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 11.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Senior Director
Organization: Tibotec Pharmaceuticals, Ireland
Phone: 32 14 641 265
Responsible Party: Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier: NCT00665847     History of Changes
Obsolete Identifiers: NCT00750542
Other Study ID Numbers: CR002746
TMC125-TiDP35-C213 ( Other Identifier: Tibotec Pharmaceuticals, Ireland )
2007-007086-21 ( EudraCT Number )
First Submitted: April 22, 2008
First Posted: April 24, 2008
Results First Submitted: June 14, 2012
Results First Posted: December 21, 2012
Last Update Posted: April 23, 2015