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 |
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E.1.1.1 | Medical condition in easily understood language |
Adult patients at high-risk to develop post-stroke epilepsy |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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. |
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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 |
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E.2.3 | Trial contains a sub-study | No |
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* 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.* NOT applicable in Sweden
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. Inclusion criteria at V1b 7. V1b is within 120 hours after stroke occurrence, 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 Sweden
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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 stroke (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 defined as total Child-Pugh score of 10-15. 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.
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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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months after randomisation |
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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 |
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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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | No |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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
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last visit of the last subject (LVLS) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |