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

• Sponsor: Tibotec Pharmaceuticals, Ireland (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00665847
• Collaborator: (none)
• Enrollment: 103
• Locations: 42
• Arm: 1
• Duration (Months): 33
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
HIV-1	Drug: Etravirine (TMC125); Drug: Optimized background regimen (OBR)	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

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.

Outcome Measures

Primary Outcome Measures

1. The Number of Patients With Treatment-emergent Adverse Events (TEAEs) [48 weeks]

   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

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

   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

1. Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h) [Weeks 4-48]

   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.

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

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

   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.

4. Percentage of Patients With Virologic Response at Week 24 [Week 24]

   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.

5. Change From Baseline in Human Immunodeficiency Virus - Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time [Baseline, Week 48]

6. The Change From Baseline in CD4 Cell Counts Over Time [Baseline, Week 48]

7. The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures [Baseline and Endpoint (up to Week 48)]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1		Mobile	Alabama	United States
2		Los Angeles	California	United States
3		Washington	District of Columbia	United States
4		New Orleans	Louisiana	United States
5		Saint Louis	Missouri	United States
6		New Brunswick	New Jersey	United States
7		Bronx	New York	United States
8		New York	New York	United States
9		Syracuse	New York	United States
10		Philadelphia	Pennsylvania	United States
11		Memphis	Tennessee	United States
12		Dallas	Texas	United States
13		Fort Worth	Texas	United States
14		Buenos Aires		Argentina
15		Belo Horizonte		Brazil
16		Ribeirao Preto		Brazil
17		Rio De Janeiro		Brazil
18		Ottawa	Ontario	Canada
19		Toronto	Ontario	Canada
20		Montreal	Quebec	Canada
21		Lyon Cedex 08		France
22		Nantes Cedex 1		France
23		Paris		France
24		Toulouse Cedex 3 N/A		France
25		Amsterdam Zuidoost		Netherlands
26		Almada		Portugal
27		Lisboa		Portugal
28		Porto		Portugal
29		Rio Piedras		Puerto Rico
30		San Juan		Puerto Rico
31		Bucuresti		Romania
32		Constanta		Romania
33		Dundee		South Africa
34		Durban		South Africa
35		Port Elizabeth		South Africa
36		Barcelona		Spain
37		Esplugues De Llobregat		Spain
38		Madrid		Spain
39		Sevilla		Spain
40		Bangkok		Thailand
41		Khon Kaen		Thailand
42		Birmingham		United Kingdom

Sponsors and Collaborators

• Tibotec Pharmaceuticals, Ireland

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tibotec Pharmaceuticals, Ireland
• ClinicalTrials.gov Identifier: NCT00665847
• Other Study ID Numbers: CR002746; TMC125-TiDP35-C213; 2007-007086-21; NCT00750542
• First Posted: Apr 24, 2008
• Last Update Posted: Apr 23, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by Tibotec Pharmaceuticals, Ireland: HIV-1; TMC125-TiDP35-C213; TMC125-C213
• Additional relevant MeSH terms: Etravirine

Study Results

Participant Flow

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.

Arm/Group Title	TMC125
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

Baseline Characteristics

Arm/Group Title	TMC125
Arm/Group Description	TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day
Overall Participants	101
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.2 (2.99)
Sex: Female, Male (Count of Participants)
Female	64 63.4%
Male	37 36.6%
Age Customized (participants) [Number]
>=6 to <12 years	41 40.6%
>=12 to <18 years	60 59.4%

Outcome Measures

1. Primary Outcome

Title	The Number of Patients With Treatment-emergent Adverse Events (TEAEs)
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

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
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)
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

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
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)
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

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
Mean (Standard Deviation) [ng.h/mL]	5216 (4305)

4. Secondary Outcome

Title	Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h)
Time Frame	Week 48

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
Mean (Standard Deviation) [ng/mL]	346 (342)

5. Secondary Outcome

Title	Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax)
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

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
Mean (Standard Deviation) [ng/mL]	589 (486)

6. Secondary Outcome

Title	Percentage of Patients With Virologic Response at Week 24
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

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
Number [Percentage of Patients]	52.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMC125
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
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
Time Frame	Baseline, Week 48

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
Mean (Standard Error) [log10 copies/mL]	-1.53 (0.132)

8. Secondary Outcome

Title	The Change From Baseline in CD4 Cell Counts Over Time
Time Frame	Baseline, Week 48

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	101
Mean (Standard Error) [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
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)

Outcome Measure Data

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
Arm/Group Description	TMC125 dosed based on body weight (kg) from 100 mg to 200 mg twice a day
Measure Participants	41
V90I	3
L100I	3
E138A	3
Y181C	8

Adverse Events

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
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 (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	TMC125
	Affected / at Risk (%)	# Events
Total	5/101 (5%)
Eye disorders
Ulcerative keratitis	1/101 (1%)
General disorders
Drug resistance	1/101 (1%)
Injury, poisoning and procedural complications
Drug toxicity	1/101 (1%)
Overdose	1/101 (1%)
Investigations
Immunoglobulins	1/101 (1%)
Lymphocyte morphology abnormal	1/101 (1%)
Weight decreased	1/101 (1%)
Social circumstances
Treatment noncompliance	1/101 (1%)
Other (Not Including Serious) Adverse Events
	TMC125
	Affected / at Risk (%)	# Events
Total	70/101 (69.3%)
Eye disorders
Conjunctivitis	6/101 (5.9%)
Gastrointestinal disorders
Diarrhoea	16/101 (15.8%)
Nausea	10/101 (9.9%)
Vomiting	11/101 (10.9%)
General disorders
Pyrexia	9/101 (8.9%)
Infections and infestations
Bronchitis	9/101 (8.9%)
Oral herpes	6/101 (5.9%)
Pharyngitis	8/101 (7.9%)
Rhinitis	6/101 (5.9%)
Sinusitis	6/101 (5.9%)
Upper respiratory tract infection	27/101 (26.7%)
Nervous system disorders
Headache	9/101 (8.9%)
Respiratory, thoracic and mediastinal disorders
Cough	13/101 (12.9%)
Oropharyngeal pain	6/101 (5.9%)
Skin and subcutaneous tissue disorders
Rash	11/101 (10.9%)
Rash maculo-papular	9/101 (8.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.