Efficacy and Safety Study of BIA 2-093 in Combination With Other Anti-Epileptic Drugs to Treat Partial Epilepsy

• Sponsor: Bial - Portela C S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00957047
• Collaborator: (none)
• Enrollment: 395
• Location: 1
• Arms: 5
• Duration (Months): 42
• Patients Per Site Per Month: 9.4

Study Details

Study Description

Brief Summary

The primary objective of the study is to evaluate the efficacy of eslicarbazepine acetate once-daily at doses of 400 mg, 800 mg and 1200 mg compared with placebo as adjunctive therapy in patients with refractory partial epilepsy over a 12-week maintenance period. Patients who complete Part I may enter a 1-year open-label extension.

Condition or Disease	Intervention/Treatment	Phase
Partial Epilepsy	Drug: eslicarbazepine acetate; Drug: placebo; Drug: ESL - Part II	Phase 3

Detailed Description

Part I was a 22-week parallel-group, randomized, placebo-controlled period (8 weeks baseline, 2 weeks double-blind titration, and 12 weeks maintenance). After completing the baseline period, patients were randomized in a 1:1:1:1 ratio to 1 of the 3 ESL dose levels or to placebo.

Part II was a 1-year open-label extension for patients who had completed Part I. The starting dose was 800 mg once daily and could be titrated up or down at 400-mg intervals between 400 and 1200 mg.

Study Design

• Study Type: Interventional
• Actual Enrollment: 395 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of BIA 2-093 as Adjunctive Therapy for Refractory Partial Seizures in a Double-blind, Randomised, Placebo-controlled, Parallel-group, Multicentre Clinical Trial
• Study Start Date: Jul 1, 2004
• Actual Primary Completion Date: Aug 1, 2006
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ESL 400 mg once daily Eslicarbazepine acetate (ESL) was supplied in 400 mg tablets for Part I	Drug: eslicarbazepine acetate; oral tablets; Other Names: Zebinix
Experimental: ESL 800 mg once daily Eslicarbazepine acetate (ESL) was supplied in 800-mg tablets for Part I	Drug: eslicarbazepine acetate; oral tablets; Other Names: Zebinix
Experimental: ESL 1200 mg once daily Eslicarbazepine acetate (ESL) was supplied in 400-mg and 800-mg tablets for Part I	Drug: eslicarbazepine acetate; oral tablets; Other Names: Zebinix
Placebo Comparator: placebo Placebo tablets matching the 400-mg and 800-mg active substance tablets were supplied	Drug: placebo; once daily placebo comparator; Other Names: Sugar pill
Experimental: ESL - Part II All patients in Part II (Open-label Extension ) received ESL on an open-label basis, starting at 800 mg once daily.	Drug: ESL - Part II; Eslicarbazepine acetate was supplied as scored 800-mg tablets for daily oral administration.; Other Names: Eslicarbazepine acetate (ESL), BIA 2-093

Outcome Measures

Primary Outcome Measures

1. PART I - Seizure Frequency [12-week maintenance period]

   The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on the ITT population. Efficacy analyses were performed chiefly using data from the 12-week maintenance period in Part I of the study. The primary efficacy variable is the ln transformation of the seizure frequency per 4 weeks. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA that models seizure frequency as a function of baseline seizure frequency and treatment.

2. PART II - Nº of Treatment-Emergent Adverse Events (TEAE) [1 year]

   Safety assessments were based primarily on AEs (Number of patients who experienced at least one AEs), and on whether these were related to the study medication, were serious, led to permanent discontinuation of study participation, or led to death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• written informed consent signed by patient

• aged 18 years or more

• documented diagnosis of simple or complex partial seizures with or without secondary generalisation since at least 12 months prior to screening

• at least 4 partial seizures in each 4 week period during the last 8 weeks prior to screening, currently treated with 1 or 2 AEDs (any except oxcarbazepine and felbamate), in a stable dose regimen during at least 2 months prior to screening (patients using vigabatrin should have been on this medication for at least 1 year with no deficit in visual field identified)

• excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination and laboratory tests

• post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation; in case of woman of childbearing potential, patient must present a serum beta-hCG test consistent with a non-gravid state and agree to remain abstinent or use reliable contraception (oral contraception should be combined with a barrier method

Exclusion Criteria:

• only simple partial seizures with no motor symptomatology (classified as A2-4 according to the International Classification of Epileptic Seizures) that are not video-EEG documented

• primarily generalised epilepsy

• known rapid progressive neurological disorder; history of status epilepticus or cluster seizures (i.e., 3 or more seizures within 30 minutes) within the 3 months prior to screening

• seizures of psychogenic origin within the last 2 years

• history of schizophrenia or suicide attempt

• currently on or with exposure to felbamate or oxcarbazepine more within one month of screening

• using benzodiazepines on more than on an occasional basis (except when used chronically as AED)

• previous use of ESL or participation in a clinical study with ESL

• known hypersensitivity to carbamazepine, oxcarbazepine or chemically related substances

• history of abuse of alcohol, drugs or medications within the last 2 years

• uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder

• second or third-degree atrioventricular blockade not corrected with a pacemaker

• relevant clinical laboratory abnormalities

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bial - Portela & Cª, S.A.	S. Mamede do Coronado		Portugal	4745-457

Sponsors and Collaborators

• Bial - Portela C S.A.

Investigators

• Principal Investigator: Elinor Ben-Menachem, MD, Sahlgren University Hospital, Göteborg, Sweden
• Principal Investigator: Alberto Alain Gabbai, MD, Rua Pedro de Toledo 655, Vila Clemento, Sao Paulo, Brazil

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bial - Portela C S.A.
• ClinicalTrials.gov Identifier: NCT00957047
• Other Study ID Numbers: BIA-2093-302
• First Posted: Aug 12, 2009
• Last Update Posted: Jul 2, 2014
• Last Verified: Jun 1, 2014

• Keywords provided by Bial - Portela C S.A.: refractory; partial; epilepsy
• Additional relevant MeSH terms: Epilepsy; Epilepsies, Partial; Eslicarbazepine acetate

Study Results

Participant Flow

Recruitment Details	STUDY DATES: PART I - From: 01 Sep 2004 To: 19 Dec 2006; PART II - From: 02 February 2005 To: 29 January 2008 Patients were screened at 46 sites in 13 countries for Part I and Patients from 42 sites in 12 countries continued in part II.;
Pre-assignment Detail	Part I was a 22-week parallel-group, randomized, placebo controlled period. After completing the baseline period, patients were randomized in a 1:1:1:1 ratio to 1 of the 3 ESL dose levels or to placebo. For Part I 400 patients were planned; of 503 patients screened, 395 were randomized. 325 patients who completed Part I were enrolled in Part II.

Arm/Group Title	Placebo	ESL 400 mg Once Daily	ESL 800 mg Once Daily	ESL 1200 mg Once Daily	ESL - Part II
Arm/Group Description	placebo : once daily placebo comparator	eslicarbazepine acetate : oral tablets	eslicarbazepine acetate : oral tablets	eslicarbazepine acetate : oral tablets	All patients in Part II received ESL on an open-label basis, starting at 800 mg once daily.
Period Title: PART I
STARTED	100	96	101	98	0
Randomized/Safety Population	100	96	101	98	0
Intention-to-treat (ITT) Population	100	96	100	97	0
Per-Protocol Population	81	70	75	54	0
COMPLETED	94	83	80	68	0
NOT COMPLETED	6	13	21	30	0
Period Title: PART I
STARTED	0	0	0	0	325
Terminated Prematurely	0	0	0	0	102
COMPLETED	0	0	0	0	223
NOT COMPLETED	0	0	0	0	102

Baseline Characteristics

Arm/Group Title	ESL 1200 mg Once Daily	ESL 400 mg Once Daily	ESL 800 mg Once Daily	Placebo	Total
Arm/Group Description	eslicarbazepine acetate : oral tablets	eslicarbazepine acetate : oral tablets	eslicarbazepine acetate : oral tablets	placebo : once daily placebo comparator	Total of all reporting groups
Overall Participants	98	96	101	100	395
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	98 100%	96 100%	101 100%	98 98%	393 99.5%
>=65 years	0 0%	0 0%	0 0%	2 2%	2 0.5%
Sex: Female, Male (Count of Participants)
Female	46 46.9%	57 59.4%	50 49.5%	48 48%	201 50.9%
Male	52 53.1%	39 40.6%	51 50.5%	52 52%	194 49.1%

Outcome Measures

1. Primary Outcome

Title	PART I - Seizure Frequency
Description	The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on the ITT population. Efficacy analyses were performed chiefly using data from the 12-week maintenance period in Part I of the study. The primary efficacy variable is the ln transformation of the seizure frequency per 4 weeks. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA that models seizure frequency as a function of baseline seizure frequency and treatment.
Time Frame	12-week maintenance period

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis was an ANCOVA that assessed reduction in seizure frequency per 4 weeks for the ITT population during the 12-week maintenance period

Arm/Group Title	ESL 1200 mg Once Daily	ESL 400 mg Once Daily	ESL 800 mg Once Daily	Placebo
Arm/Group Description	eslicarbazepine acetate : oral tablets	eslicarbazepine acetate : oral tablets	eslicarbazepine acetate : oral tablets	placebo : once daily placebo comparator
Measure Participants	97	96	100	100
Least Squares Mean (95% Confidence Interval) [ln (Seizures) per 4 weeks]	7	8.7	7.1	9.8

2. Primary Outcome

Title	PART II - Nº of Treatment-Emergent Adverse Events (TEAE)
Description	Safety assessments were based primarily on AEs (Number of patients who experienced at least one AEs), and on whether these were related to the study medication, were serious, led to permanent discontinuation of study participation, or led to death.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TEAE	TEAE With Onset Within the 1st 4 Weeks	TEAE With Onset After 1st 4 Weeks	Treatment-related TEAE	TEAE Leading to Discontinuation	Serious TEAE	TEAE Leading to Death
Arm/Group Description
Measure Participants	325	325	325	325	325	325	325
Number [participants]	270 275.5%	151 157.3%	240 237.6%	194 194%	37 9.4%	28 NaN	3 NaN

Adverse Events

Arm/Group Title	Placebo		ESL 400 mg		ESL 800 mg		ESL 1200 mg		ESL PART II
Arm/Group Description	Tablets; oral route		Tablets; oral route		Tablets; oral route		Tablets; oral route		All patients in Part II received ESL
All Cause Mortality
	Placebo		ESL 400 mg		ESL 800 mg		ESL 1200 mg		ESL PART II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		ESL 400 mg		ESL 800 mg		ESL 1200 mg		ESL PART II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/100 (0%)		4/96 (4.2%)		6/101 (5.9%)		2/98 (2%)		28/325 (8.6%)
Cardiac disorders
Arteriosclerosis coronary artery	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0	1/325 (0.3%)	0
Atrial flutter	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Eye disorders
Diplopia	0/100 (0%)	0	2/96 (2.1%)	2	0/101 (0%)	0	0/98 (0%)	0	0/325 (0%)	0
Gastrointestinal disorders
Appendix disorder	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Dyskinesia oesophageal	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Nausea	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Vomiting	0/100 (0%)	0	1/96 (1%)	1	2/101 (2%)	2	1/98 (1%)	1	0/325 (0%)	1
General disorders
Asthenia	0/100 (0%)		0/0 (NaN)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Drowning	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Sudden death	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Infections and infestations
Gastroenteritis	0/100 (0%)	0	0/96 (0%)	0	1/101 (1%)	1	0/98 (0%)	0	1/325 (0.3%)	0
Pneumonia	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Pyelonephritis	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Injury, poisoning and procedural complications
Drug toxicity	0/100 (0%)	0	0/96 (0%)	0	1/101 (1%)	1	0/98 (0%)	0	1/325 (0.3%)	0
Head injury	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Hepatic rupture	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Skin laceration	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Spinal fracture	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Investigations
Lymphocyte count decreased	0/100 (0%)		0/96 (0%)		0/0 (NaN)		0/98 (0%)		1/325 (0.3%)
Monocyte count decreased	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Neutrophil count decreased	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
White blood cell count decreased	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Metabolism and nutrition disorders
Hyponatraemia	0/100 (0%)	0	0/96 (0%)	0	1/101 (1%)	1	0/98 (0%)	0	0/325 (0%)	0
Musculoskeletal and connective tissue disorders
Mobility decreased	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Follicle centre lymphoma, follicular grade I, II, III	0/100 (0%)	0	0/96 (0%)	0	1/101 (1%)	1	0/98 (0%)	0	0/325 (0%)	0
Insulinoma	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Nervous system disorders
Convulsion	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		3/325 (0.9%)
Coordination abnormal	0/100 (0%)	0	1/96 (1%)	1	2/101 (2%)	2	1/98 (1%)	1	1/325 (0.3%)	1
Dizziness	0/100 (0%)	0	1/96 (1%)	1	0/101 (0%)	0	1/98 (1%)	1	0/325 (0%)	1
Grand mal convulsion	0/100 (0%)	0	1/96 (1%)	1	0/101 (0%)	0	0/98 (0%)	0	0/325 (0%)	0
Nervous system disorder	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Somnolence	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		2/325 (0.6%)
Status epilepticus	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		2/325 (0.6%)
Vasculitis cerebral	0/100 (0%)	0	1/96 (1%)	1	0/101 (0%)	0	0/98 (0%)	0	0/325 (0%)	0
Pregnancy, puerperium and perinatal conditions
Pregnancy	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Psychiatric disorders
Acute psychosis	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Aggression	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Depression	0/100 (0%)	0	1/96 (1%)	1	0/101 (0%)	0	0/98 (0%)	0	0/325 (0%)	0
Nervousness	0/100 (0%)	0	1/96 (1%)	1	0/101 (0%)	0	0/98 (0%)	0	0/325 (0%)	0
Psychotic disorder	0/100 (0%)	0	1/96 (1%)	1	0/101 (0%)	0	0/98 (0%)	0	2/325 (0.6%)	0
Schizoaffective disorder	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Renal and urinary disorders
Renal failure acute	0/100 (0%)	0	0/96 (0%)	0	1/101 (1%)	1	0/98 (0%)	0	0/325 (0%)	0
Reproductive system and breast disorders
Endometriosis	0/100 (0%)	0	0/96 (0%)	0	1/101 (1%)	1	0/98 (0%)	0	0/325 (0%)	0
Ovarian mass	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		1/325 (0.3%)
Other (Not Including Serious) Adverse Events
	Placebo		ESL 400 mg		ESL 800 mg		ESL 1200 mg		ESL PART II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/100 (59%)		75/96 (78.1%)		84/101 (83.2%)		78/98 (79.6%)		270/325 (83.1%)
Eye disorders
Diplopia	4/100 (4%)	4	8/96 (8.3%)	8	15/101 (14.9%)	15	10/98 (10.2%)	10	28/325 (8.6%)	10
Vision blurred	2/100 (2%)	2	7/96 (7.3%)	7	8/101 (7.9%)	8	7/98 (7.1%)	7	17/325 (5.2%)	7
Gastrointestinal disorders
Nausea	4/100 (4%)	4	8/96 (8.3%)	8	12/101 (11.9%)	12	15/98 (15.3%)	15	21/325 (6.5%)	15
Vomiting	3/100 (3%)	3	4/96 (4.2%)	4	13/101 (12.9%)	13	10/98 (10.2%)	10	22/325 (6.8%)	10
Diarrhoea	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		18/325 (5.5%)
General disorders
Fatigue	5/100 (5%)	5	4/96 (4.2%)	4	5/101 (5%)	5	7/98 (7.1%)	7	0/325 (0%)	7
Infections and infestations
Nasopharyngitis	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		20/325 (6.2%)
Investigations
Blood pressure diastolic decreased	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		28/325 (8.6%)
Musculoskeletal and connective tissue disorders
Back pain	0/100 (0%)		0/96 (0%)		0/101 (0%)		0/98 (0%)		17/325 (5.2%)
Nervous system disorders
Coordination abnormal	5/100 (5%)	5	5/96 (5.2%)	5	13/101 (12.9%)	13	11/98 (11.2%)	11	28/325 (8.6%)	11
Dizziness	10/100 (10%)	10	22/96 (22.9%)	22	30/101 (29.7%)	30	43/98 (43.9%)	43	86/325 (26.5%)	43
Headache	9/100 (9%)	9	12/96 (12.5%)	12	15/101 (14.9%)	15	19/98 (19.4%)	19	51/325 (15.7%)	19
Somnolence	17/100 (17%)	17	15/96 (15.6%)	15	17/101 (16.8%)	17	21/98 (21.4%)	21	39/325 (12%)	21

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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