Clinical trial NCT06597084: Anti-epileptogenic Effects of Eslicarbazepine Acetate
Official title: Prevention of Epilepsy in Stroke Patients at High Risk of Developing Unprovoked Seizures: Anti-epileptogenic Effects of Eslicarbazepine Acetate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Post Stroke Epilepsy
Keywords: Prophylaxis
Post-stroke
Epilepsy
BIA 2-093
Unprovoked seizures
Eslicarbazepine acetate
Anti-epileptogenic
Bial - Portela & Ca, S.A.
Lead sponsor: Bial - Portela C S.A.
Sponsor class: INDUSTRY
First posted: 2024-09-19
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to assess if eslicarbazepine acetate (ESL) treatment (started within 96 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

Detailed description: This is a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial in patients with acute intracerebral haemorrhage with a Cortical involvement, Age \<65 years, Volume of intracerebral haemorrhage \> 10 ml and Early seizure within 7 days after intracerebral haemorrhage (CAVE) score ≥ 3 or an acute ischaemic stroke with a SeLECT score ≥ 6.

At the first visit (screening/baseline, V1a), patients will undergo several examinations to check eligibility. The next visit (V1b) has to be performed within 96 hours after primary stroke occurrence. After eligibility has been confirmed, patients will be randomised (randomisation ratio 1:1) to treatment with ESL 800 mg (Group A) or placebo (Group B).

Patients will start treatment with the investigational medicinal product (IMP), i.e. ESL or placebo, within 96 hours after primary stroke occurrence at V1b. They will continue treatment until Day 30 after randomisation and then be tapered off. Thereafter, patients will be followed up until 18 months after randomisation. Patients can concomitantly receive antiepileptic therapies, except commercially available ESL or oxcarbazepine, until Day 30.

Concomitant antiepileptic therapies have to be discontinued and down-titration has to be started according to the respective Summary of Product Characteristics (SmPC). If the antiepileptic drugs (AEDs)/benzodiazepine are not already discontinued before, downtitration must be started on Day 31 at the latest.

If one or more AS(s) occur(s) within 7 days after primary stroke, this will not result in change of IMP dose. Patients having a first US will discontinue IMP treatment and will be treated at the discretion of the investigator until 18 months after randomisation, except with commercially available ESL.

Further visits will be performed 7 days (V2, on-site), 37 days (V3, on-site), 12 weeks (V4, telephone), 26 weeks (V5, on-site), 38 weeks (V6, telephone), 52 weeks (V7, on-site), 64 weeks (V8, telephone) and 78 weeks (End of Trial (EoT) visit, on-site) after V1b.

Eligibility criteria: Inclusion Criteria:

Patients must meet ALL of the following 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.

   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.

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 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.

Primary outcomes:
measure: Proportion of Patients Who Experience the First Unprovoked Seizures (US) Within the First 6 Months After Randomisation (Failure Rate)
timeFrame: First 6 months after randomisation
Secondary outcomes:
measure: Proportion of Patients Who Experience the First US During the First 12 Months After Randomisation
timeFrame: First 12 months after randomisation
measure: Proportion of Patients Who Experience the First US During the Course of the Trial
timeFrame: Until 18 months after randomisation
measure: Number of Acute Symptomatic Seizure (ASS)
timeFrame: During the first 7 days after stroke
measure: Probability of Failure at 6, 12, and 18 Months After Randomization
timeFrame: Over 18 months follow-up period
measure: Time to First US After Stroke Occurrence.
timeFrame: Over 18 months follow-up period
measure: Number and 4-week Rate of USs (4-week Rate of USs Was Omitted With SAP, Final Version 1.0, 22 NOV 2023).
timeFrame: Over 18 months follow-up period
measure: Barthel Index (BI) Original 10-item Version
timeFrame: Barthel Index data is collected at Baseline, V3 (+37 days), V5 (+26 weeks), V7 (+52 weeks), End of trial visit (EOT, +78 weeks) or Early discontinuation visit (EDV, on average 30 days), and Endpoint (18 months).
measure: National Institutes of Health Stroke Scale (NIHSS)
timeFrame: National Institutes of Health Stroke Scale (NIHSS) data is collected at Baseline, V3 (+37 days), V5 (+26 weeks), V7 (+52 weeks), End of trial visit (EOT, +78 weeks) or Early discontinuation visit (EDV, on average 30 days), and Endpoint (18 months).
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: Over 18 months follow-up period
measure: Overall Survival at 6, 12, and 18 Months After Randomization
timeFrame: Over 18 months follow-up period
measure: Treatment Emergent Adverse Events (TEAEs) Incl. Findings From Physical and Neurological Examinations
timeFrame: Over 18 months follow-up period
measure: Clinically Significant Haematology Abnormalities
timeFrame: Over 18 months follow-up period
measure: Clinically Significant Biochemistry Abnormalities, Including eGFR (Estimated Glomerular Filtration Rate) and Coagulation
timeFrame: Over 18 months follow-up period
measure: Clinically Significant Urinalysis Abnormalities
timeFrame: Over 18 months follow-up period
measure: Clinically Significant Vital Sign Abnormalities: Blood Pressure
timeFrame: Over 18 months follow-up period
measure: Clinically Significant Vital Sign Abnormalities: Heart Rate
timeFrame: Over 18 months follow-up period
measure: Electrocardiogram (ECG)
timeFrame: A standard 12-lead electrocardiogram (ECG) is performed at Baseline, V2 (+7 days), V3 (+37 days), Early discontinuation visit (if EDV performed before V3, on average 30 days).
measure: Suicidal Ideation and Behaviour, Assessed by PHQ-9 (Question 9)
timeFrame: The PHQ-9 will be collected at Baseline, V3 (+37 Days), V5 (+26 weeks), V7 (+52 weeks), End of trial visit (EOT, +78 weeks) or Early discontinuation visit (if EDV performed before V3, on average 30 days), and Endpoint (18 months).
measure: Number of Participants With and Without Seizures Based on Electroencephalogram (EEG)
timeFrame: Two recordings were provided: one carried out before in the initial phase of enrollment into the trial at V1a (< 96 hours) and the second one after termination of eslicarpazepine acetate intake (EOT, +78 weeks).
Other outcomes:
Locations:
city: Klagenfurt
country: Austria
facility: Klinikum am Wörthersee, Abteilung fur Neurologie
state: FeschnigstraBe 11
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck, Universitätsklinik für Neurologie
state: Innrain 52
city: Linz
country: Austria
facility: Kepler University Hospital, Med Campus III, Department of Neurology 2
state: Krankenhausstraße 9
city: Salzburg
country: Austria
facility: Clinical Research Center Salzburg GmbH
state: Strubergasse 21
city: Linz
country: Austria
facility: Kepler University Hospital GmbH, Neuromed Campus, Department of Neurology 1
state: Wagner-Jauregg-Weg 15
city: Bron
country: France
facility: Hospices Civils de Lyon, Neurological Hospitals
state: Boulevard Pinel, 59
city: Marburg
country: Germany
facility: UKGM Universitatsklinikum Marburg, Klinik und Poliklinik fur Neurologie
state: Baldingerstrabe
city: Tübingen
country: Germany
facility: Neurologische Universitatsklinik
state: Hoppe-Seyler-Strabe 3
city: Essen
country: Germany
facility: Universitatsklinikum Essen, Klinik fur Neurologie
state: Hufelandstr. 55
city: München
country: Germany
facility: LMU Ludwig-Maximilians-Universitat, Munchen, Klinikum Grobhadern, Neurologische Klinik und Poliklinik, Experimentelle Neurologie
state: Marchioninistrabe 15
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Klinik für Neurologie
state: Pauwelsstr. 30
city: Erlangen
country: Germany
facility: Universitatsklinikum Erlangen, Neurologische Klinik
state: Schwabachanlage 6
city: Ramat Gan
country: Israel
facility: Sheba Medical Center, Neurology Department, Stroke Unit
state: Emek Ha'ella 1
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center, Neurology Division
state: Weizmann 6
city: Udine
country: Italy
facility: Clinica Neurologica e di Neuroriabllltazione - Azienda / Ospedallero-Universitarla S. Maria della Miserrcordia
state: P. Le S. Maria Della Misericordia, 15
city: Trieste
country: Italy
facility: Azienda Sanitaria Universitaria Integrata di Trieste - Ospedale Cattinara - Clinica Neurologica
state: Strada Di Fiume 447
city: Merano
country: Italy
facility: Azienda Sanitaria dell'Alto Adige - Ospedale di Merano
state: Via Rossini 5
city: Lisboa
country: Portugal
facility: Centro Hospitalar Universitário Lisboa Norte, E.P.E. - Hospital Santa Maria - Serviço de Neurologia
state: Avenida Prof. Egas Moniz
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Diaz
state: Avda. De Los Reyes Catolicos, 2
city: Göteborg
country: Sweden
facility: Sahlgrenska universitetssjukhuset, Neurosjukvarden
state: Bia Straket 7
city: London
country: United Kingdom
facility: King's College Hospital
state: Denmark Hill
city: London
country: United Kingdom
facility: Institute of Neurology
state: Queen Square
Study officials:
affiliation: Universitätsklinik für Neurologie
name: Eugen Trinka, MD MSc FRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: UCL Institute of Neurology
name: Matthias Koepp, MD PhD FRCP
role: PRINCIPAL_INVESTIGATOR
References: