Pharmacokinetics, Efficacy and Tolerability of BIA 2-093

• Sponsor: Bial - Portela C S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02170064
• Collaborator: (none)
• Enrollment: 35
• Location: 1
• Arms: 3
• Duration (Months): 10
• Patients Per Site Per Month: 3.5

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize the pharmacokinetics of Eslicarbazepine acetate in children and adolescents with epilepsy.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: BIA 2-093 (Eslicarbazepine acetate)	Phase 2

Detailed Description

This clinical study was planned to be performed as an open-label, single-centre, multiple-dose study, in 30 paediatric epileptic patients distributed by 3 age groups of 10 patients each: 2-6 years [Group 1], 7-11 years [Group 2], and 12-17 years [Group 3].

The study was constituted by a 4-week baseline phase, followed by 3 consecutive 4-week treatment periods with Eslicarbazepine acetate in which patients received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day (weeks 1-4), 15 mg/kg/day (weeks 5-8) and 30 mg/kg/day or 1800 mg/day, whichever less (weeks 9-12). At the end of each 4-week treatment period, patients were hospitalised and serial blood samples for drug assays were obtained over a dosing interval.

After the last treatment period or in the event of premature discontinuation, the dose had to be down-titrated during a 2-week period. After the last treatment period patient could continue receiving Eslicarbazepine acetate ("compassionate use") if both parent(s)/guardian(s) /patient and his/her physician agreed this was in the best patient's interest. A follow-up visit occurred approximately 4 weeks after the last hospitalisation or early discontinuation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics, Efficacy and Tolerability of BIA 2-093 in Children and Adolescents With Refractory Partial Epilepsy
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Apr 1, 2006
• Actual Study Completion Date: Apr 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 (2-6 yrs) At the end of the baseline phase, patients meeting the final selection criteria were admitted to three consecutive 4-week treatment periods in which they received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day in the first 4 weeks, 15 mg/kg/day in weeks 5-8 and 30 mg/kg/day or 1800 mg/day, whichever less, in weeks 9-12. After the last treatment period, dose was down-titrated during a 2-week period or patient continued receiving Eslicarbazepine acetate ("compassionate use") if both parent(s)/guardian(s)/patient and his/her physician agreed this was in the best patient's interest. For Group 1 (2-6 years), oral suspension 50 mg/mL was used. The dose was to be rounded to the nearest 25 mg unit.	Drug: BIA 2-093 (Eslicarbazepine acetate); Eslicarbazepine acetate administered at increasing daily doses of 5 mg/kg, 15 mg/kg, and 30 mg/kg (or 1800 mg, whichever less); once-daily; oral route
Experimental: Group 2 (7-11 years) At the end of the baseline phase, patients meeting the final selection criteria were admitted to three consecutive 4-week treatment periods in which they received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day in the first 4 weeks, 15 mg/kg/day in weeks 5-8 and 30 mg/kg/day or 1800 mg/day, whichever less, in weeks 9-12. After the last treatment period, dose was down-titrated during a 2-week period or patient continued receiving Eslicarbazepine acetate ("compassionate use") if both parent(s)/guardian(s)/patient and his/her physician agreed this was in the best patient's interest. For Group 2 (7-11 years) and Group 3 (12-17 years), Eslicarbazepine acetate strengths 200 mg, 400 mg, 600 mg and 800 mg tablets might be used. The dose was to be rounded to the nearest 100 mg unit. Half tablets might be used for dosage adjustment (tablets were scored).	Drug: BIA 2-093 (Eslicarbazepine acetate); Eslicarbazepine acetate administered at increasing daily doses of 5 mg/kg, 15 mg/kg, and 30 mg/kg (or 1800 mg, whichever less); once-daily; oral route
Experimental: Group 3 (12-17 years) At the end of the baseline phase, patients meeting the final selection criteria were admitted to three consecutive 4-week treatment periods in which they received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day in the first 4 weeks, 15 mg/kg/day in weeks 5-8 and 30 mg/kg/day or 1800 mg/day, whichever less, in weeks 9-12. After the last treatment period, dose was down-titrated during a 2-week period or patient continued receiving Eslicarbazepine acetate ("compassionate use") if both parent(s)/guardian(s)/patient and his/her physician agreed this was in the best patient's interest. For Group 2 (7-11 years) and Group 3 (12-17 years), Eslicarbazepine acetate strengths 200 mg, 400 mg, 600 mg and 800 mg tablets might be used. The dose was to be rounded to the nearest 100 mg unit. Half tablets might be used for dosage adjustment (tablets were scored).	Drug: BIA 2-093 (Eslicarbazepine acetate); Eslicarbazepine acetate administered at increasing daily doses of 5 mg/kg, 15 mg/kg, and 30 mg/kg (or 1800 mg, whichever less); once-daily; oral route

Outcome Measures

Primary Outcome Measures

1. Maximum Observed Plasma Drug Concentration (Cmax) Post-dose [pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose]

2. Time of Occurrence of Cmax (Tmax). [pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose]

Secondary Outcome Measures

1. Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase [Baseline, end of 5 mg/kg/day treatment period (4 weeks), 15 mg/kg/day treatment period (4 weeks) and 30 mg/kg/day treatment period (4 weeks).]

   The efficacy variables were the percentage change in seizure frequency during each 4-week treatment period compared to the baseline phase. Seizures were recorded in the patient's diary during the baseline phase and during the following 4-week treatment periods. Seizure frequency for each patient was standardised to a frequency per 28 days period (i.e., mean daily frequency multiplied by 28). Changes in seizure frequency were analysed for each age group separately.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

The following inclusion criteria were applied in selecting patients for participation in the trial.

Patient was eligible for entry into the baseline phase if he/she fulfilled the following criteria at Visit 1:

• Written informed consent given by the parent(s)/guardian(s), and by the patient when appropriate.

• Male or female patient aged between 2 and 17 years.

• Body weight within the 10th and 90th percentiles, by age and sex.

• A documented diagnosis of partial-onset seizures (simple or complex seizures with or without secondary generalisation), classified according to the International Classification of Epileptic Seizures.

• Currently treated with 1 to 3 AEDs (any except OXC or CBZ), in a stable dosage regimen during at least 1 month prior to screening.

• Good general health (apart from epilepsy) based on medical history and physical examination.

• In case of a female patient, she was premenarchal, surgically sterile or presented a urine pregnancy test consistent with a non-gravid state and practiced an effective non-hormonal contraception method.

At Visit 2, patient was eligible for entry into the Eslicarbazepine acetate treatment phase if he/she fulfilled the following criteria:

• At least 4 partial-onset seizures during the last 4 weeks of the baseline phase.

• Brain CT scan or MRI that excluded rapidly progressive neurological diseases.

• ECG without clinically significant abnormalities.

• Good general health (apart from epilepsy) based on medical history, physical examination and laboratory tests at screening.

• Diaries satisfactorily completed by the patient or his/her caregiver during the baseline phase.

• Satisfactory compliance with the study requirements during the baseline phase.

• In case of a female patient of childbearing potential, she presented a urine pregnancy test consistent with a non-gravid state and practiced an effective non-hormonal contraception method.

Exclusion Criteria:

Patient was not allowed for entry into the screening phase if he/she fulfilled the following criteria at Visit 1:

• Primarily generalised epilepsy.

• Clinically relevant medical condition, other than epilepsy.

• History of status epilepticus in the last 3 months.

• History of suicide attempt.

• History of alcohol or drug abuse.

• History of hypersensitivity or intolerance to OXC or CBZ.

• Use of any investigational drug or participated in any clinical trial within the previous 2 months.

• Patient and/or his/her caregiver(s) unlikely to co-operate with the requirements of the study.

• If female, she was sexually active and of child-bearing potential and she did not use reliable contraception.

• Patients with non-epileptic attacks (syncopes, pseudoseizures).

• Previous poor compliance with anti-epileptic therapy.

• Need for rescue benzodiazepines more frequently than twice per week on average.

• Previous use of Eslicarbazepine acetate or participation in a clinical study with Eslicarbazepine acetate.

• Any other condition or circumstance that, in the opinion of the investigator, might compromise the patient's ability to comply with the clinical trial protocol (CTP).

At Visit 2, patient was not eligible for entry into the Eslicarbazepine acetate treatment phase if he/she fulfilled the following criteria:

• Inadequate compliance to concomitant AEDs during the baseline phase.

• Clinically relevant clinical laboratory test abnormalities at screening.

• Occurrence of any other condition or circumstance that, in the opinion of the investigator, might compromise the patient's ability to comply with the CTP.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinica de Neurologie Pediatrica, Spitalul "Alexandru Obregia"	Bucharest		Romania	041914

Sponsors and Collaborators

• Bial - Portela C S.A.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bial - Portela C S.A.
• ClinicalTrials.gov Identifier: NCT02170064
• Other Study ID Numbers: BIA-2093-202
• First Posted: Jun 23, 2014
• Last Update Posted: Sep 20, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by Bial - Portela C S.A.: Epilepsy; BIA 2-093
• Additional relevant MeSH terms: Epilepsy; Eslicarbazepine acetate

Study Results

Participant Flow

Arm/Group Title	Group 1 (2-6 Yrs)	Group 2 (7-11 Years)	Group 3 (12-17 Years)
Arm/Group Description	At the end of the baseline phase, patients meeting the final selection criteria were admitted to three consecutive 4-week treatment periods in which they received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day in the first 4 weeks, 15 mg/kg/day in weeks 5-8 and 30 mg/kg/day or 1800 mg/day, whichever less, in weeks 9-12. After the last treatment period, dose was down-titrated during a 2-week period or patient continued receiving Eslicarbazepine acetate ("compassionate use") if both parent(s)/guardian(s)/patient and his/her physician agreed this was in the best patient's interest. For Group 1 (2-6 years), oral suspension 50 mg/mL was used. The dose was to be rounded to the nearest 25 mg unit.	At the end of the baseline phase, patients meeting the final selection criteria were admitted to three consecutive 4-week treatment periods in which they received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day in the first 4 weeks, 15 mg/kg/day in weeks 5-8 and 30 mg/kg/day or 1800 mg/day, whichever less, in weeks 9-12. After the last treatment period, dose was down-titrated during a 2-week period or patient continued receiving Eslicarbazepine acetate ("compassionate use") if both parent(s)/guardian(s)/patient and his/her physician agreed this was in the best patient's interest. For Group 2 (7-11 years) and Group 3 (12-17 years), Eslicarbazepine acetate strengths 200 mg, 400 mg, 600 mg and 800 mg tablets might be used. The dose was to be rounded to the nearest 100 mg unit. Half tablets might be used for dosage adjustment (tablets were scored).	At the end of the baseline phase, patients meeting the final selection criteria were admitted to three consecutive 4-week treatment periods in which they received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day in the first 4 weeks, 15 mg/kg/day in weeks 5-8 and 30 mg/kg/day or 1800 mg/day, whichever less, in weeks 9-12. After the last treatment period, dose was down-titrated during a 2-week period or patient continued receiving Eslicarbazepine acetate ("compassionate use") if both parent(s)/guardian(s)/patient and his/her physician agreed this was in the best patient's interest. For Group 2 (7-11 years) and Group 3 (12-17 years), Eslicarbazepine acetate strengths 200 mg, 400 mg, 600 mg and 800 mg tablets might be used. The dose was to be rounded to the nearest 100 mg unit. Half tablets might be used for dosage adjustment (tablets were scored).
Period Title: Overall Study
STARTED	15	9	11
Safety Population (SP)	12	8	11
Pharmacokinetic Population (PKP)	11	8	10
Efficacy Population (EP)	11	8	10
COMPLETED	9	7	10
NOT COMPLETED	6	2	1

Baseline Characteristics

Arm/Group Title	Group 1 (2-6 Yrs)	Group 2 (7-11 Yrs)	Group 3 (12-17 Yrs)	Total
Arm/Group Description	Efficacy population (EP)	Efficacy population (EP)	Efficacy population (EP)	Total of all reporting groups
Overall Participants	11	8	10	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.1 (1.38)	9.1 (1.55)	14.5 (1.58)	9.1 (4.73)
Sex: Female, Male (Count of Participants)
Female	8 72.7%	6 75%	3 30%	17 58.6%
Male	3 27.3%	2 25%	7 70%	12 41.4%

Outcome Measures

1. Primary Outcome

Title	Maximum Observed Plasma Drug Concentration (Cmax) Post-dose
Time Frame	pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 (2-6 Yrs)	Group 2 (7-11 Yrs)	Group 3 (12-17 Yrs)
Arm/Group Description	Efficacy population (EP)	Efficacy population (EP)	Efficacy population (EP)
Measure Participants	11	8	10
Dosage regimen 5 mg/kg/day	6921 (1794)	4820 (1693)	6382 (1854)
Dosage regimen 15 mg/kg/day	16183 (2609)	16395 (3680)	17194 (3410)
Dosage regimen 30 mg/kg/day	29935 (4627)	26890 (6944)	32400 (6005)

2. Primary Outcome

Title	Time of Occurrence of Cmax (Tmax).
Time Frame	pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 (2-6 Yrs)	Group 2 (7-11 Yrs)	Group 3 (12-17 Yrs)
Arm/Group Description	Efficacy population (EP)	Efficacy population (EP)	Efficacy population (EP)
Measure Participants	11	8	10
Dosage regimen 5 mg/kg/day	1 (1)	2 (1)	2 (1)
Dosage regimen 15 mg/kg/day	2 (1)	3 (1)	2 (1)
Dosage regimen 30 mg/kg/day	1 (0)	3 (1)	3 (2)

3. Secondary Outcome

Title	Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase
Description	The efficacy variables were the percentage change in seizure frequency during each 4-week treatment period compared to the baseline phase. Seizures were recorded in the patient's diary during the baseline phase and during the following 4-week treatment periods. Seizure frequency for each patient was standardised to a frequency per 28 days period (i.e., mean daily frequency multiplied by 28). Changes in seizure frequency were analysed for each age group separately.
Time Frame	Baseline, end of 5 mg/kg/day treatment period (4 weeks), 15 mg/kg/day treatment period (4 weeks) and 30 mg/kg/day treatment period (4 weeks).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 (2-6 Yrs)	Group 2 (7-11 Yrs)	Group 3 (12-17 Yrs)
Arm/Group Description	Efficacy population (EP)	Efficacy population (EP)	Efficacy population (EP)
Measure Participants	11	8	10
5Dosage regimen 5 mg/kg/day	-28.2	-11.7	-17.1
Dosage regimen 15 mg/kg/day	-24.8	5.0	-31.7
Dosage regimen 30 mg/kg/day	-40.6	12.2	-43.1

Adverse Events

Arm/Group Title	Group 1 (2-6 Yrs)		Group 2 (7-11 Yrs)		Group 3 (12-17 Yrs)
Arm/Group Description	Safety population (SP)		Safety population (SP)		Safety population (SP)
All Cause Mortality
	Group 1 (2-6 Yrs)		Group 2 (7-11 Yrs)		Group 3 (12-17 Yrs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Group 1 (2-6 Yrs)		Group 2 (7-11 Yrs)		Group 3 (12-17 Yrs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		1/8 (12.5%)		0/11 (0%)
Infections and infestations
Bronchopneumonia	1/12 (8.3%)		0/8 (0%)		0/11 (0%)
Nervous system disorders
Seizures	1/12 (8.3%)		1/8 (12.5%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Group 1 (2-6 Yrs)		Group 2 (7-11 Yrs)		Group 3 (12-17 Yrs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/12 (75%)		7/8 (87.5%)		7/11 (63.6%)
Eye disorders
Diplopia	0/12 (0%)		0/8 (0%)		3/11 (27.3%)
Gastrointestinal disorders
Stomatitis	1/12 (8.3%)		0/8 (0%)		0/11 (0%)
Abdominal pain	0/12 (0%)		2/8 (25%)		1/11 (9.1%)
Nausea	0/12 (0%)		1/8 (12.5%)		1/11 (9.1%)
Vomiting	0/12 (0%)		1/8 (12.5%)		2/11 (18.2%)
General disorders
Flu like symptoms	0/12 (0%)		0/8 (0%)		1/11 (9.1%)
Immune system disorders
Allergy to insect sting	1/12 (8.3%)		0/8 (0%)		0/11 (0%)
Infections and infestations
Upper respiratory tract infection	5/12 (41.7%)		3/8 (37.5%)		0/11 (0%)
Viral pharyngitis	1/12 (8.3%)		0/8 (0%)		0/11 (0%)
Viral tonsillitis	1/12 (8.3%)		0/8 (0%)		0/11 (0%)
Acute pharyngitis	0/12 (0%)		0/8 (0%)		2/11 (18.2%)
Metabolism and nutrition disorders
Inappetence	0/12 (0%)		1/8 (12.5%)		0/11 (0%)
Nervous system disorders
Incoordination	1/12 (8.3%)		0/8 (0%)		0/11 (0%)
Psychomotor agitation	0/12 (0%)		1/8 (12.5%)		0/11 (0%)
Somnolence	0/12 (0%)		3/8 (37.5%)		5/11 (45.5%)
Dizziness	0/12 (0%)		0/8 (0%)		1/11 (9.1%)
Drowsiness	1/12 (8.3%)		0/8 (0%)		0/11 (0%)
Equilibrium trouble	0/12 (0%)		0/8 (0%)		1/11 (9.1%)
Intention tremor	0/12 (0%)		2/8 (25%)		0/11 (0%)
Nystagmus	0/12 (0%)		0/8 (0%)		2/11 (18.2%)
Seizures	1/12 (8.3%)		1/8 (12.5%)		0/11 (0%)
Psychiatric disorders
Aggressive behaviour	0/12 (0%)		1/8 (12.5%)		0/11 (0%)
Aggression aggravated	0/12 (0%)		1/8 (12.5%)		0/11 (0%)
Respiratory, thoracic and mediastinal disorders
Interstitial pneumonia	1/12 (8.3%)		0/8 (0%)		0/11 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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