Clinical Trials Register

Summary
EudraCT Number:	2018-002747-29
Sponsor's Protocol Code Number:	BIA-2093-213
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-09-16
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Portugal - INFARMED

A.2

EudraCT number

2018-002747-29

A.3

Full title of the trial

Prevention of epilepsy in stroke patients at high risk of developing unprovoked seizures: anti-epileptogenic effects of eslicarbazepine acetate

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Prophylactic treatment of stroke patients with eslicarbazepine acetate to prevent the development of epilepsy

A.4.1

Sponsor's protocol code number

BIA-2093-213

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bial - Portela & Ca, S.A.
B.1.3.4	Country	Portugal
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bial - Portela & Ca, S.A.
B.4.2	Country	Portugal
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bial - Portela & Ca, S.A.
B.5.2	Functional name of contact point	Sponsor
B.5.3	Address:
B.5.3.1	Street Address	À Av. da Siderurgia Nacional
B.5.3.2	Town/ city	Coronado (S. Romão e S. Mamede)
B.5.3.3	Post code	4745-457
B.5.3.4	Country	Portugal
B.5.4	Telephone number	00351229866100
B.5.5	Fax number	00351229866192

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Eslicarbazepine Acetate
D.3.2	Product code	BIA 2-093
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ESLICARBAZEPINE ACETATE
D.3.9.1	CAS number	236395-14-5
D.3.9.2	Current sponsor code	BIA 2-093
D.3.9.3	Other descriptive name	ESLICARBAZEPINE ACETATE
D.3.9.4	EV Substance Code	SUB30424
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	800
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adult patients at high-risk to develop post-stroke epilepsy

E.1.1.1

Medical condition in easily understood language

Adult patients at high-risk to develop post-stroke epilepsy

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
E.1.2	Level	PT
E.1.2	Classification code	10076982
E.1.2	Term	Post stroke epilepsy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess if eslicarbazepine acetate (ESL) treatment (started within 120 hours after stroke occurrence and continued for 30 days) changes the incidence of unprovoked seizures (USs) within the first 6 months after randomisation as compared to placebo.

E.2.2

Secondary objectives of the trial

To assess if ESL treatment (started within 120 hours after stroke occurrence and continued for 30 days) 1. changes the incidence of USs within the first 12 months after randomisation as compared to placebo 2. changes the incidence of USs during the course of the trial - until 18 months after randomisation as compared to placebo
3.To assess the number of acute symptomatic seizures 4.Time to first US after randomisation 5.Time to first US after stroke occurrence 6.Number and 4-week rate of USs 7.Functional outcome, assessed by Barthel Index original 10-item version 8.Functional outcome, assessed by National Institutes of Health Stroke Scale 9.Post-stroke depression, assessed by Patient Health Questionnaire 10.Overall survival 11.Treatment emergent adverse events incl. findings from physical and neurological examinations 12.Laboratory parameters 13.Vital signs 14.Electrocardiogram 15. Suicidal ideation and behaviour, assessed by PHQ-9

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet ALL of the following criteria:
1. Male or female patient aged 18 years or above.
2. To have one of the following confirmed by magnetic resonance
imaging (MRI)/computed tomography (CT):
a. Acute ischaemic or intracerebral haemorrhagic stroke with
- an acute symptomatic seizure until 120 hours post-stroke and
- cerebral cortex involvement OR
b. Acute ischaemic stroke with
- National Institutes of Stroke Scale (NIHSS) ≥ 11 and
- cerebral cortex involvement and
- large-artery atherosclerosis and/or territory of middle cerebral artery
(MCA) OR
c. Acute ischaemic stroke with
- NIHSS 4-10 and
- cerebral cortex involvement and
- large-artery atherosclerosis and
- territory of MCA OR
d. Acute intracerebral haemorrhagic stroke with
- cerebral cortex involvement and
- volume of intracerebral haemorrhage > 10 mL.
3. Time of stroke occurrence is known and V1b is planned within 120
hours since the known time of stroke occurrence, or since last time seen
well.
4. Brain scan analysis has reliably excluded structural brain lesions that can mimic stroke, e.g. cerebral tumour or brain abscess, etc.
5. a. Patient is able to give informed consent and to write and has signed written informed consent OR
b. Patient is able to give informed consent, but unable to write and has provided verbal witnessed consent OR
c. Patient is unable to give informed consent, but likely to regain this ability until V2, and the informed consent is deferred * NOT applicable in Portugal [Text which is NOT applicable in Portugal is displayed in italics.] OR
d. Patient is unable to give informed consent, but likely to regain this ability until V2 * NOT applicable in Portugal [Text which is NOT applicable in Portugal is displayed in italics.] , and patient’s legal representative (according to the respective national/local requirements) has provided written informed consent.
6. Female patients without childbearing potential (2 years postmenopausal, bilateral oophorectomy or tubal ligation, or complete hysterectomy) are eligible. Female patients with childbearing potential must not be pregnant as confirmed by a negative pregnancy test and sexually active females must use a medically acceptable effective non-hormonal method of contraception up to the end of the current menstrual cycle after stopping treatment. Acceptable methods for women are surgical intervention (e.g. bilateral tubal occlusion), intrauterine device, double-barrier methods, true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient) and vasectomised male partner, provided that he is the sole partner of that patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
The requirements of the relevant ethics committees must be adhered to at all times. Written or verbal witnessed informed consent from the patient must be obtained until V2 – not applicable for Portugal.
Inclusion criteria at V1b
7. V1b is within 120 hours after stroke, or since last time seen well.
Inclusion criteria at V2 (only applicable for patients who were unable to give informed consent at V1a.)*
8. a. Patient is able to give informed consent and to write and has signed a written informed consent *OR
b. Patient is able to give informed consent, but unable to write and has provided verbal witnessed consent.*
* NOT applicable in Portugal [Text which is NOT applicable in Portugal is displayed in italics.]

E.4

Principal exclusion criteria

Patients are to be excluded from the trial for ANY ONE of the following reasons:
1. Contraindication to ESL, i.e. known hypersensitivity to ingredients of ESL formulation or other carboxamide derivatives (e.g., oxcarbazepine, carbamazepine), or second or third degree atrioventricular (AV) block.
2. Known Han Chinese or Thai ancestry.
3. History of previous clinical cerebral cortical (other than the one described in inclusion criteria no. 2 - 3) within the last two years prior to Visit 1a.
4. Sinus venous thrombosis.
5. Spontaneous sub-arachnoid haemorrhage due to e.g. aneurysmatic or arteriovenous malformation.
6. History of USs prior to primary (index) stroke.
7. Impaired pre-stroke level of function, i.e. modified Rankin Scale (mRS) score > 3 prior to first stroke occurrence.
8. History of AED use within the last 2 years as defined in the list of not allowed AEDs.
9. Use of ESL, unless provided as IMP of this trial, and oxcarbazepine.
10. Severe hepatic impairment.
11. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (measured at V1a).
12. Known or suspected acute or chronic alcoholism, delirium tremens, or toxic psychosis.
13. History of suicidal ideation or suicide attempt within the past 3 years.
14. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the trial treatment or may jeopardise the patient’s safety, compliance or adherence to protocol requirements, such as significant psychiatric, cardiovascular, respiratory, metabolic, endocrine, haematologic, infectious or neurological disease.
15. For women: Pregnancy or breast-feeding.
16. Previous enrolment in this trial or participation in any other investigational drug trial within the past 30 days (or 5 half-lives of IMP whichever is longer) prior to V1a.
17. Persons committed to an institution by virtue of an order issued either by the judicial or other authorities.
18. Employees of the investigator or trial centre, with direct involvement in the proposed trial or other studies under the direction of that investigator or trial centre, as well as family members of the employees or the investigator.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients who experience the first US within the first 6 months after randomisation (failure rate). Deaths before the first US or patients without evaluable assessment of the primary endpoint will be counted as treatment failures.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after randomisation

E.5.2

Secondary end point(s)

1. Proportion of patients who experience the first US during the first 12 months after randomisation (12 months failure rate)
2. Proportion of patients who experience the first US during the course of the trial – until 18 months after randomisation (18 months failure rate)
3. Number of ASs
4. Time to first US after randomisation
5. Time to first US after stroke occurrence
6. Number and 4-week rate of US
7. BI
8. NIHSS
9. PHQ-9
10. Overall survival
Safety endpoints:
11. TEAEs incl. findings from physical and neurological examinations
12. Laboratory parameters (haematology, biochemistry, including eGFR and coagulation, and urinalysis)
13. Vital signs
14. ECG
15. Suicidal ideation and behaviour (as per PHQ-9, question 9)
Exploratory endpoint:
16. EEG, optional

E.5.2.1

Timepoint(s) of evaluation of this end point

1. 12 months after randomisation (12 months failure rate)
2. 18 months after randomisation (18 months failure rate)
3. during the first 7 days after stroke
4. to 16. up to 18 months after randomisation

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Germany

Israel

Italy

Portugal

Spain

Sweden

United Kingdom

France

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

last visit of the last subject (LVLS)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

175

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

- Patients with acute intracerebral haemorrhage or acute ischaemic
stroke
- Patients unable to give informed consent(IC) at the time of inclusion into the trial, but IC given by legal representative of patient.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

180

F.4.2.2

In the whole clinical trial

220

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-11-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-09-11

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