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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Tibotec Pharmaceuticals, Ireland
ClinicalTrials.gov Identifier:
NCT00665847
First received: April 22, 2008
Last updated: December 27, 2012
Last verified: December 2012
Results First Received: June 14, 2012  
Study Type: Interventional
Study Design: Endpoint Classification: Safety Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: HIV-1
Interventions: Drug: Etravirine (TMC125)
Drug: Optimized background regimen (OBR)

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
TMC125 TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day

Participant Flow:   Overall Study
    TMC125  
STARTED     101  
COMPLETED     76  
NOT COMPLETED     25  
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  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
TMC125 TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day

Baseline Measures
    TMC125  
Number of Participants  
[units: participants]
  101  
Age  
[units: years]
Mean ± Standard Deviation
  12.2  ± 2.99  
Gender  
[units: participants]
 
Female     64  
Male     37  
Age Customized  
[units: participants]
 
>=6 to <12 years     41  
>=12 to <18 years     60  



  Outcome Measures
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1.  Primary:   The Number of Patients With Treatment-emergent Adverse Events (TEAEs)   [ Time Frame: 48 weeks ]

Measure Type Primary
Measure Title The Number of Patients With Treatment-emergent Adverse Events (TEAEs)
Measure 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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
The Number of Patients With Treatment-emergent Adverse Events (TEAEs)  
[units: 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  

No statistical analysis provided for The Number of Patients With Treatment-emergent Adverse Events (TEAEs)



2.  Primary:   The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs)   [ Time Frame: 48 weeks ]

Measure Type Primary
Measure Title The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs)
Measure 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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs)  
[units: 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  

No statistical analysis provided for The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs)



3.  Secondary:   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 ]

Measure Type Secondary
Measure Title Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h)
Measure 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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)."

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h)  
[units: ng.h/mL]
Mean ± Standard Deviation
  5216  ± 4305  

No statistical analysis provided for Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h)



4.  Secondary:   Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h)   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h)
Measure Description No text entered.
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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)."

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h)  
[units: ng/mL]
Mean ± Standard Deviation
  346  ± 342  

No statistical analysis provided for Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h)



5.  Secondary:   Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax)   [ Time Frame: Week 4 ]

Measure Type Secondary
Measure Title Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax)
Measure 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax)  
[units: ng/mL]
Mean ± Standard Deviation
  589  ± 486  

No statistical analysis provided for Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax)



6.  Secondary:   Percentage of Patients With Virologic Response at Week 24   [ Time Frame: Week 24 ]

Measure Type Secondary
Measure Title Percentage of Patients With Virologic Response at Week 24
Measure 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
Percentage of Patients With Virologic Response at Week 24  
[units: Percentage of Patients]
  52.5  


Statistical Analysis 1 for Percentage of Patients With Virologic Response at Week 24
Groups [1] TMC125
Proportion [2] 52.5
Standard Error of the mean ± 0.050
95% Confidence Interval ( 42.7 to 62.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  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:   Change From Baseline in Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time   [ Time Frame: Baseline, Week 48 ]

Measure Type Secondary
Measure Title Change From Baseline in Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time
Measure Description No text entered.
Time Frame Baseline, Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
Change From Baseline in Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time  
[units: log10 copies/mL]
Mean ± Standard Error
  -1.53  ± 0.132  

No statistical analysis provided for Change From Baseline in Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time



8.  Secondary:   The Change From Baseline in CD4 Cell Counts Over Time   [ Time Frame: Baseline, Week 48 ]

Measure Type Secondary
Measure Title The Change From Baseline in CD4 Cell Counts Over Time
Measure Description No text entered.
Time Frame Baseline, Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  101  
The Change From Baseline in CD4 Cell Counts Over Time  
[units: 10E6 cells/L]
Mean ± Standard Error
  156  ± 22.7  

No statistical analysis provided for The Change From Baseline in CD4 Cell Counts Over Time



9.  Secondary:   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) ]

Measure Type Secondary
Measure Title The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures
Measure 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)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The patients in the intent-to-treat (ITT) population classified as virologic failures were used for this analysis.

Reporting Groups
  Description
TMC125 TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day

Measured Values
    TMC125  
Number of Participants Analyzed  
[units: participants]
  41  
The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures  
[units: Patients]
 
V90I     3  
L100I     3  
E138A     3  
Y181C     8  

No statistical analysis provided for The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
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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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked Other disclosure agreement that restricts the right of the PI 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
e-mail: gdsmedt1@its.jnj.com


No publications provided


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: December 27, 2012
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