Anti-epileptogenic Effects of Eslicarbazepine Acetate

Bial - Portela C S.A.129 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

129

Conditions

Post Stroke Epilepsy

Interventions

ESL 800 mgDRUG

800 mg ESL tablets for oral administration. In case a patient is unable to swallow the whole tablet, the tablet can be crushed or divided into equal doses at the score line.

PlaceboDRUG

Placebo tablets for oral administration, matching the test product. In case a patient is unable to swallow the whole tablet, the tablet can be crushed or divided into equal doses at the score line.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (22)

Outcomes

Primary Outcomes

Proportion of Patients Who Experience the First Unprovoked Seizures (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. To show that ESL (Group A) is superior to placebo (Group B), the primary null hypothesis will be tested against the alternative hypothesis

Time frame: First 6 months after randomisation

Secondary Outcomes

Proportion of Patients Who Experience the First US During the First 12 Months After Randomisation

Time frame: First 12 months after randomisation

Proportion of Patients Who Experience the First US During the Course of the Trial

Time frame: Until 18 months after randomisation

Number of Acute Symptomatic Seizure (ASS)

Number of ASSs will be summarised by means of descriptive statistics

Time frame: During the first 7 days after stroke

Probability of Failure at 6, 12, and 18 Months After Randomization

The time to first US after randomisation will be analysed and presented by means of the Kaplan-Meier estimate after 6, 12 and 18 months for the failure time. The time to first US will be analysed from the day of randomisation.

Data from ClinicalTrials.gov

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Klinikum am Wörthersee, Abteilung fur Neurologie

Klagenfurt, FeschnigstraBe 11, Austria

Medizinische Universität Innsbruck, Universitätsklinik für Neurologie

Innsbruck, Innrain 52, Austria

Kepler University Hospital, Med Campus III, Department of Neurology 2

Linz, Krankenhausstraße 9, Austria

Clinical Research Center Salzburg GmbH

Salzburg, Strubergasse 21, Austria

Kepler University Hospital GmbH, Neuromed Campus, Department of Neurology 1

Linz, Wagner-Jauregg-Weg 15, Austria

Hospices Civils de Lyon, Neurological Hospitals

Bron, Boulevard Pinel, 59, France

UKGM Universitatsklinikum Marburg, Klinik und Poliklinik fur Neurologie

Marburg, Baldingerstrabe, Germany

Neurologische Universitatsklinik

Tübingen, Hoppe-Seyler-Strabe 3, Germany

Universitatsklinikum Essen, Klinik fur Neurologie

Essen, Hufelandstr. 55, Germany

LMU Ludwig-Maximilians-Universitat, Munchen, Klinikum Grobhadern, Neurologische Klinik und Poliklinik, Experimentelle Neurologie

München, Marchioninistrabe 15, Germany

...and 12 more locations

Time frame: Over 18 months follow-up period

Time to First US After Stroke Occurrence.

Analysis of time to first US will be performed using the day of stroke (before randomisation) as Day 1. The secondary objective and endpoint "Time to first US after stroke occurrence" was decided to be deleted as it is closely related to the forth secondary endpoint "Time to first US after randomisation" and therefore would not really have any additional value.

Time frame: Over 18 months follow-up period

Number and 4-week Rate of USs (4-week Rate of USs Was Omitted With SAP, Final Version 1.0, 22 NOV 2023).

The total number and rate of USs, standardised per 4 weeks, in all patients and in patients with US(s) only will be summarised by means of descriptive statistics. The secondary objective and endpoint "4-week rate of USs" was decided to be deleted as this information will not be meaningful for this trial.

Time frame: Over 18 months follow-up period

Barthel Index (BI) Original 10-item Version

The Barthel Index at baseline and post-baseline visits of each patient will be calculated adding the individual scores from each item. Baseline is the value assessed before first IMP intake. Endpoint is the last non-missing value collected after the first IMP intake. The BI is a widely used score to measure the performance in activities of daily living of patients with stroke and other neuromuscular or musculoskeletal disorders in the following 10 categories: 1. Feeding (scored as 0, 5, 10) 2. Moving from a wheelchair to a bed and back again (scored as 0, 5, 10, 15) 3. Personal hygiene (scored as 0, 5) 4. Getting on and off the toilet (scored as 0, 5, 10) 5. Self-bathing (scored as 0, 5) 6. Walking on a level surface (scored as 0, 5, 10, 15) 7. Ascending and descending stairs (scored as 0, 5, 10) 8. Dressing (scored as 0, 5, 10) 9. Controlling bowels (scored as 0, 5, 10) 10. Controlling bladder (scored as 0, 5, 10) The minimum value means with help and maximum independent

Time frame: 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).

National Institutes of Health Stroke Scale (NIHSS)

The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficits. The following questions will be asked: 1a. Level of Consciousness (LOC) (scored as 0, 1, 2, 3) 1b. LOC Questions (scored as 0, 1, 2) 1c. LOC Commands (scored as 0, 1, 2) 2. Best Gaze (scored as 0, 1, 2) 3. Visual (scored as 0, 1, 2, 3) 4. Facial Palsy (scored as 0, 1, 2, 3) 5a. Motor Arm (Left Arm) (scored as 0, 1, 2, 3, 4) 5b. Motor Arm (Right Arm) (scored as 0, 1, 2, 3, 4) 6a. Motor Leg (Left Leg) (scored as 0, 1, 2, 3, 4) 6b. Motor Right (Right Leg) (scored as 0, 1, 2, 3, 4) 7. Limb Ataxia (scored as 0, 1, 2) 8. Sensory (scored as 0, 1, 2) 9. Best Language (scored as 0, 1, 2, 3) 10. Dysarthria (scored as 0, 1, 2) 11. Extinction and Inattention (formerly Neglect) (scored as 0, 1, 2) The sum of all 15 individual scores will provide the patient's total NIHSS score where 0 is "no stroke symptoms" and 42 is "severe stroke".

Time frame: 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).

Patient Health Questionnaire (PHQ-9)

The PHQ-9 can be used for screening, diagnosing and measuring the severity of depression in stroke patients. The patient will rate on a scale from 0 (not at all) to 3 (nearly every day) how often each of the 9 symptoms occurred during the past 2 weeks. The individual scores from each item of the PHQ-9 will be added to calculate the total PHQ-9 score for each time of examination.

Time frame: Over 18 months follow-up period

Overall Survival at 6, 12, and 18 Months After Randomization

Overall survival (time to death relative to the date of randomization) will be analysed and presented by means of the Kaplan-Meier estimates (including censored data e.g. withdrawals) after 6 months (Day 182), 12 months (Day 365) and 18 months (Day 547) for the survival rates.

Time frame: Over 18 months follow-up period

Treatment Emergent Adverse Events (TEAEs) Incl. Findings From Physical and Neurological Examinations

Adverse events (AEs) not considered treatment-emergent according to this definition or with missing data will be medically reviewed during the data review meeting and will be considered treatment emergent if appropriate

Time frame: Over 18 months follow-up period

Clinically Significant Haematology Abnormalities

Based on haemoglobin, haematocrit, red blood cell count (RBC), white blood cell count (WBC), differential - neutrophils, eosinophils, lymphocytes, monocytes and basophils, and platelet count. All laboratory values will be classified as normal or abnormal according to the laboratories normal ranges and as clinically significant according to the assessment of the investigator. For these tests, approximately 12 mL of blood will be collected at each blood withdrawal.

Time frame: Over 18 months follow-up period

Clinically Significant Biochemistry Abnormalities, Including eGFR (Estimated Glomerular Filtration Rate) and Coagulation

The biochemistry analysis is based on sodium (will be monitored for signs of hyponatraemia), potassium, chloride, calcium, phosphate, blood urea nitrogen, aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase, creatine phosphokinase (CPK), creatinine, glucose, C-reactive protein, albumin, total protein, total cholesterol, low-density lipoproteincholesterol, high-density lipoprotein-cholesterol, triglycerides, and total bilirubin (bilirubin will be fractionated direct/indirect if elevated). eGFR will be estimated based on serum creatinine value using the according CKD-EPI formula using age, sex and race. Coagulation is based on international normalised ratio and activated partial thromboplastin time (aPTT). All laboratory values will be classified as normal or abnormal according to the laboratories normal ranges and as clinically significant according to the assessment of the investigator.

Time frame: Over 18 months follow-up period

Clinically Significant Urinalysis Abnormalities

The urinalysis is based on pH, specific gravity, protein, blood, glucose, ketones, bilirubin, urobilinogen (local dipstick). Microscopy and other appropriate tests (as needed) will be performed if dipstick indicates any significant abnormality. All laboratory values will be classified as normal or abnormal according to the laboratories normal ranges and as clinically significant according to the assessment of the investigator.

Time frame: Over 18 months follow-up period

Clinically Significant Vital Sign Abnormalities: Blood Pressure

The systolic and diastolic blood pressure (mmHg) were to be measured after the patient had rested for at least 5 minutes. Painful procedures, like drawing blood, had to be performed after vital signs measurements (not before). The analyses of variables for vital sign parameters will focus on the evaluation of the change from baseline to the scheduled time points after baseline. Descriptive statistics of the time course and of changes from baseline to each post-baseline time point will be presented by treatment group.

Time frame: Over 18 months follow-up period

Clinically Significant Vital Sign Abnormalities: Heart Rate

The Heart Rate (bpm) were to be measured after the patient had rested for at least 5 minutes. Painful procedures, like drawing blood, had to be performed after vital signs measurements (not before). The analyses of variables for vital sign parameters will focus on the evaluation of the change from baseline to the scheduled time points after baseline. Descriptive statistics of the time course and of changes from baseline to each post-baseline time point will be presented by treatment group.

Time frame: Over 18 months follow-up period

Electrocardiogram (ECG)

The ECG equipment is to be calibrated to 1 cm/mV and recording is to be done at 25 mm/sec and performed for a minimum of 10 sec. At V1a the investigator should examine the ECG for signs of cardiac disease that should exclude the patient from the trial. An assessment of normal or abnormal will be recorded and if the ECG abnormality is considered clinically significant, the abnormality will be documented in the electronic case report form (eCRF). If an ECG was done after primary stroke, the results should be used and the examination does not need to be repeated at V1a. After each recording of a simultaneous 12-lead resting ECG, a copy of the originally printed ECG records will be printed, assessed and filed by the investigator, in order to ensure that maintenance of the data will not be affected by thermolability of the paper.

Time frame: 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).

Suicidal Ideation and Behaviour, Assessed by PHQ-9 (Question 9)

The individual scores from each item of the PHQ-9 will be added to calculate the total PHQ-9 score for each time of examination.Over the last 2 weeks, how often have you been bothered by any of the following problems? 1. Little interest or pleasure in doing things 2. Feeling down, depressed, or hopeless 3. Trouble falling or staying asleep, or sleeping too much 4. Feeling tired or having little energy 5. Poor appetite or overeating 6. Feeling bad about yourself - or that you are a failure or have let yourself or your family down 7. Trouble concentrating on things, such as reading the newspaper or watching television 8. Moving or speaking so slowly that other could have noticed. Or the opposite - being so fidgety or restless that you have been moving around a lot more than usual 9. Thoughts that you would be better off dead or of hurting yourself in some way The individual scores from each item of the PHQ-9 will be added to calculate the total PHQ-9 score for each time of examination.

Time frame: 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).

Number of Participants With and Without Seizures Based on Electroencephalogram (EEG)

Routine EEG assessment (standard 10-20 set of electrodes, digital recording with 256 Hz sampling rate) for a minimum of 20 min will be performed at the discretion of the investigator. The EEG will be performed as exploratory analysis to support the development of a predictor for the development of post-stroke epilepsy and is therefore an optional assessment. All EEG analyses will be presented for the EEG analysis subset (all patients in the full analysis set with a baseline and a post-baseline EEG recording available). EEG parameters will be evaluated exploratively using descriptive statistics. For this outcome was decided that results would be possibly explored in an manuscript.

Time frame: 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).