Clinical Trials Register

Summary
EudraCT Number:	2018-002747-29
Sponsor's Protocol Code Number:	BIA-2093-213
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-04-17
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

UK - MHRA

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

Preventive treatment of stroke patients with eslicarbazepine acetate to prevent development of epilepsy

A.3.2

Name or abbreviated title of the trial where available

prophylaxis of post-stroke 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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Scope International AG
B.5.2	Functional name of contact point	Angelika Kippert
B.5.3	Address:
B.5.3.2	Town/ city	Konard-Zuse-Ring 18
B.5.3.3	Post code	68163
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049621429399922
B.5.5	Fax number	00496214293940
B.5.6	E-mail	akippert@scope-international.com

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.2.1.1.1	Trade name	Eslicarbazepine Acetate
D.2.1.1.2	Name of the Marketing Authorisation holder	Bial - Portela & Cª
D.2.1.2	Country which granted the Marketing Authorisation	Portugal
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
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	AS1
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	400 to 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

Prophylaxis of epilepsy following stroke

E.1.1.1

Medical condition in easily understood language

To prevent patients getting epilepsy after they have had a stroke

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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 96 hours after stroke occurrence and continued for 30 days) changes the number of seizures within the first 6 months after starting treatment. ESL will be compared to a placebo

E.2.2

Secondary objectives of the trial

1.To assess if ESL treatment (started within 96 hours after stroke occurrence and continued for 30 days) changes the number of siezures within the first 12 months after starting treatment as compared to placebo
2. To assess if ESL treatment (started within 96 hours after stroke occurrence and continued for 30 days) changes the number of seizures within 18 months
after starting treatment as compared to placebo
3. To assess the number of seizures occurring within 7 days after stroke
To assess the effect of ESL treatment over 18 months follow-up period on:
4. Time to first seizure after starting treatment
5. Time to first seizure after stroke
6. Number and rate of seizures
7. changes in a questionnaire called the Barthel Index
8. changes in a questionnaire called National Institutes of Health Stroke Scale (NIHSS)
9. Post-stroke depression
10. Overall survival
Safety:
To assess the effect of ESL treatment on:
11. the number of side effects
12. blood samples
13. vital signs (heart rate, bo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patient aged 18 years or above.
2. Acute intracerebral haemorrhage with a CAVE score ≥ 3 or acute ischaemic stroke with a SeLECT score ≥ 6, in each case confirmed by magnetic resonance imaging (MRI)/computed tomography (CT).
3. Time of stroke occurrence is known and V1b is planned within 96 hours.
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 OR
d. Patient is unable to give informed consent, but likely to regain this ability until V2, 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 nonhormonal 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.
Inclusion criteria at V1b
7. V1b is within 96 hours after stroke occurrence.
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.

E.4

Principal exclusion criteria

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 not corrected with a permanent pacemaker.
2. Known Han Chinese or Thai ancestry.
3. History of previous stroke (other than the one described in inclusion criteria no. 2 - 3).
4. Sinus venous thrombosis.
5. Spontaneous sub-arachnoid haemorrhage due to e.g. aneurysmatic or arteriovenous malformation.
6. History of USs prior to primary 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 before primary stroke within the last 5 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)

The primary outcome measure is the proportion of patients who experience the first unprovoked seizures (US) which are epileptic seizure happening later than 7 days (≤7 days) after primary stroke and 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

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.5.2

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

France

Germany

Israel

Italy

Spain

Sweden

United Kingdom

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

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1