A Phase 2 interventional study of ESL 800 mg and Placebo in Post Stroke Epilepsy, sponsored by Bial - Portela C S.A.. Completed at 22 sites in 9 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-05-02.
Sponsored by Bial - Portela C S.A. · Phase 2, Interventional, and Treatment
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.
Inclusion Criteria:
Patients must meet ALL of the following criteria:
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
Exclusion Criteria:
Patients are to be excluded from the trial for ANY ONE of the following reasons:
ESL 800 mg
Drug: ESL 800 mg
Placebo
Drug: Placebo
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.
Also known as: Eslicarbazepine acetate, BIA 2-093
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.
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
Proportion of Patients Who Experience the First US During the First 12 Months After Randomisation
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 12 months after randomisation
Proportion of Patients Who Experience the First US During the Course of the Trial
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: 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.
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).
| Milestone | Group A | Group B |
|---|---|---|
| Started | 62 | 63 |
| Safety set | 61 | 62 |
| Full analysis set | 61 | 62 |
| Electroencephalogram (eeg) analysis subset | 31 | 34 |
| Completed | 43 | 41 |
| Not completed | 19 | 22 |
| Withdrew: Withdrawal by subject | 4 | 9 |
| Withdrew: Consent was not given by the patient until v2 | 0 | 3 |
| Withdrew: Physician decision | 1 | 0 |
| Withdrew: Adverse event | 3 | 2 |
| Withdrew: Death | 4 | 0 |
| Withdrew: Stroke more than 7 days after primary stroke | 2 | 6 |
| Withdrew: Lost to follow-up | 4 | 2 |
| Withdrew: Other. not specified | 1 | 0 |
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
| Participants | Group A | Group B |
|---|---|---|
| Failures - Unprovoked seizure | 2 | 7 |
| Failures - Death | 3 | 0 |
| Failures - Withdrawn | 12 | 16 |
| Non-failures | 44 | 39 |
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
| Participants | Group A | Group B |
|---|---|---|
| Failures - Unprovoked seizure | 3 | 8 |
| Failures - Death | 3 | 0 |
| Failures - Withdrawn | 13 | 18 |
| Non-failures | 42 | 36 |
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
| Participants | Group A | Group B |
|---|---|---|
| Failures - Unprovoked seizure | 5 | 9 |
| Failures - Death | 4 | 0 |
| Failures - Withdrawn | 14 | 18 |
| Non-failures | 38 | 35 |
Number of ASSs will be summarised by means of descriptive statistics
| Participants | Group A | Group B |
|---|---|---|
| Patients without an ASS | 51 | 47 |
| Patients with at least one ASS | 10 | 15 |
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.
| Percentage of failure | Group A | Group B |
|---|---|---|
| Kaplan - Meier failure probability estimate at Month 6 (Day 182) | 3.50 | 14.55 |
| Kaplan - Meier failure probability estimate at Month 12 (Day 365) | 5.74 | 16.86 |
| Kaplan - Meier failure probability estimate at Month 18 (Day 547) | 10.34 | 19.17 |
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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
| Score on a scale | Group A | Group B |
|---|---|---|
| Baseline - Observed Value | 66.1 (0 to 100) | 61.9 (0 to 100) |
| V3 - Observed Value | 85.5 (0 to 100) | 87.2 (0 to 100) |
| V5 - Observed Value | 94.3 (0 to 100) | 95.7 (0 to 100) |
| V7 - Observed Value | 92.2 (0 to 100) | 96.3 (0 to 100) |
| EDV - Observed Value | 66.0 (0 to 100) | 96.3 (0 to 100) |
| EoT - Observed Value | 92.4 (0 to 100) | 94.9 (0 to 100) |
| Endpoint | 87.5 (0 to 100) | 93.6 (0 to 100) |
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".
| Score on a scale | Group A | Group B |
|---|---|---|
| Baseline - Observed Value | 8.5 (0 to 42) | 8.8 (0 to 42) |
| V2 - Observed Value | 4.6 (0 to 42) | 3.0 (0 to 42) |
| V3 - Observed Value | 2.5 (0 to 42) | 1.5 (0 to 42) |
| V5 - Observed Value | 1.9 (0 to 42) | 0.6 (0 to 42) |
| V7 - Observed Value | 1.6 (0 to 42) | 0.8 (0 to 42) |
| Early discontinuation visit - Observed Value | 3.4 (0 to 42) | 0 (0 to 42) |
| End of trial visit - Observed Value | 1.5 (0 to 42) | 0.6 (0 to 42) |
| Endpoint - Observed Value | 2.9 (0 to 42) | 1.5 (0 to 42) |
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.
| Points | Group A | Group B |
|---|---|---|
| Baseline - Observed Value | 3.7 ± 3.34 | 3.4 ± 4.43 |
| Endpoint - Observed Value | 4.1 ± 3.96 | 4.3 ± 5.25 |
| Endpoint - Change from Baseline | 0.5 ± 4.61 | 0.7 ± 6.13 |
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.
| Percentage of death probability | Group A | Group B |
|---|---|---|
| Kaplan - Meier death probability estimate at Month 6 (Day 182) | 5.64 | 0.00 |
| Kaplan - Meier death probability estimate at Month 12 (Day 365) | 5.64 | 0.00 |
| Kaplan - Meier death probability estimate at Month 18 (Day 547) | 7.74 | 0.00 |
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
| Participants | Group A | Group B |
|---|---|---|
| TEAE | 50 | 51 |
| Non-serious TEAE | 50 | 48 |
| Serious TEAE | 12 | 13 |
| Related TEAE | 23 | 12 |
| Serious related TEAE | 3 | 0 |
| Severe TEAE | 9 | 8 |
| TEAE leading to discontinuation of IMP | 16 | 6 |
| TEAE leading to dose reduction | 0 | 2 |
| TEAE requiring medication | 36 | 46 |
| TEAE leading to death | 2 | 0 |
| Ongoing TEAE at the end of the trial | 31 | 30 |
| TEAE leading to study discontinuation | 4 | 4 |
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.
| Participants | Group A | Group B |
|---|---|---|
| Eosinophils - Low to CS high | 1 | 0 |
| Eosinophils abs. - Low to CS high | 1 | 0 |
| Lymphocytes - Low to CS low | 1 | 0 |
| Lymphocytes abs - Low to CS low | 1 | 0 |
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.
| Participants | Group A | Group B |
|---|---|---|
| Sodium - Normal to CS low | 1 | 0 |
| Potassium - Normal to CS low | 1 | 0 |
| Potassium - Normal to CS high | 1 | 0 |
| Potassium - Missing to CS high | 1 | 0 |
| Blood urea nitrogen - Missing to CS high | 1 | 0 |
| Aspartate transaminase - Normal to CS high | 1 | 0 |
| Alanine transaminase - Normal to CS high | 1 | 0 |
| Alanine transaminase - High to CS high | 1 | 0 |
| Gamma-glutamyl transferase - Normal to CS high | 3 | 0 |
| Lactate dehydrogenase - Low to CS high | 1 | 0 |
| Alkaline phosphatase - Normal to CS high | 2 | 1 |
| Creatinine - Normal to CS high | 1 | 1 |
| Creatinine - Missing to CS high | 1 | 0 |
| C-reactive protein - High to CS high | 2 | 0 |
| LDL-cholesterol - Normal to CS high | 1 | 0 |
| HDL-cholesterol - Normal to CS low | 2 | 0 |
| Triglycerides - Normal to CS high | 0 | 1 |
| Total bilirubin - Normal to CS high | 1 | 0 |
| Bilirubin direct - Missing to CS high | 1 | 0 |
| Glomerular filtration rate - Normal to CS low | 1 | 0 |
| International normalised ratio - High to CS high | 1 | 0 |
| Activated partial thromboplastin time - Normal to CS high | 2 | 0 |
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.
| Participants | Group A | Group B |
|---|---|---|
| Clinically Significant abnormality - Baseline - No | 46 | 42 |
| Clinically Significant abnormality - Baseline - Yes | 14 | 14 |
| Clinically Significant abnormality - Endpoint - No | 36 | 34 |
| Clinically Significant abnormality - Endpoint - Yes | 13 | 9 |
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.
| Participants | Group A | Group B |
|---|---|---|
| Systolic blood pressure [mmHg] - Baseline - CS high | 1 | 3 |
| Diastolic blood pressure [mmHg] - Baseline - CS low | 0 | 0 |
| Diastolic blood pressure [mmHg] - Baseline - CS high | 0 | 1 |
| Systolic blood pressure [mmHg] - Endpoint - CS high | 1 | 1 |
| Diastolic blood pressure [mmHg] - Endpoint - CS low | 0 | 1 |
| Diastolic blood pressure [mmHg] - Endpoint - CS high | 0 | 0 |
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.
| Participants | Group A | Group B |
|---|---|---|
| Pulse rate [bpm] - Baseline - CS high | 0 | 0 |
| Pulse rate [bpm] - Endpoint - CS high | 0 | 1 |
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.
| Participants | Group A | Group B |
|---|---|---|
| Baseline - Clinically Significant abnormal | 9 | 8 |
| V2 - Clinically Significant abnormal | 4 | 3 |
| V3 - Clinically Significant abnormal | 4 | 3 |
| Early discontinuation visit - Clinically Significant abnormal | 0 | 0 |
| Endpoint | 4 | 3 |
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.
| Score on a scale | Group A | Group B |
|---|---|---|
| Baseline - Observed Value | 3.7 ± 3.34 | 3.4 ± 4.43 |
| V3 - Observed Value | 5.0 ± 5.57 | 4.5 ± 5.12 |
| V5 - Observed Value | 5.0 ± 4.72 | 5.5 ± 5.91 |
| V7 - Observed Value | 3.9 ± 4.08 | 4.4 ± 5.12 |
| Early discontinuation visit - Observed Value | 2.0 ± 0.82 | 3.8 ± 4.35 |
| End of trial visit - Observed Value | 3.8 ± 3.85 | 3.9 ± 5.50 |
| Endpoint - Observed Value | 4.1 ± 3.96 | 4.3 ± 5.25 |
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.
| Participants | Group A | Group B |
|---|---|---|
| EEG recordings of V1a - Patients with seizures | 16 | 24 |
| EEG recordings of EoT - Patients without seizures | 5 | 10 |
| Differences between EoT-V1a - Patients with seizures | 3 | 0 |
| Differences between EoT-V1a - Patients without seizures | 0 | 7 |
Collected over The period of monitored/assessed for the collection of AEs started with the first onset or worsening after the first investigational medicinal product (IMP) intake at V1b until 14 days after the last IMP intake, up to 18 months per participant.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Group A | 6/61 (9.8%) | 12/61 (19.7%) | 50/61 (82%) |
| Group B | 0/62 (0%) | 13/62 (21%) | 48/62 (77.4%) |
| Event | Group A | Group B |
|---|---|---|
| Status epilepticusNervous system disorders | 1/61 | 1/62 |
| SeizureNervous system disorders | 1/61 | 0/62 |
| Thalamic infarctionNervous system disorders | 1/61 | 0/62 |
| Acute respiratory failureRespiratory, thoracic and mediastinal disorders | 1/61 | 0/62 |
| Pneumonia aspirationRespiratory, thoracic and mediastinal disorders | 1/61 | 0/62 |
| Cardiac valve diseaseCardiac disorders | 1/61 | 0/62 |
| Nodal arrhythmiaCardiac disorders | 1/61 | 0/62 |
| EndocarditisInfections and infestations | 1/61 | 0/62 |
| Pulmonary sepsisInfections and infestations | 1/61 | 0/62 |
| Benign neoplasm of bladderNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/61 | 0/62 |
| Event | Group A | Group B |
|---|---|---|
| HypertensionVascular disorders | 10/61 | 13/62 |
| HeadacheNervous system disorders | 4/61 | 8/62 |
| HyponatraemiaMetabolism and nutrition disorders | 6/61 | 1/62 |
| ConstipationGastrointestinal disorders | 3/61 | 6/62 |
| InsomniaPsychiatric disorders | 4/61 | 5/62 |
| Urinary tract infectionInfections and infestations | 4/61 | 5/62 |
| DizzinessNervous system disorders | 4/61 | 0/62 |
| HypokalaemiaMetabolism and nutrition disorders | 4/61 | 3/62 |
| Atrial fibrillationCardiac disorders | 4/61 | 3/62 |
| DepressionPsychiatric disorders | 3/61 | 4/62 |
| Age, Categorical(Participants) | Group A | Group B | Total |
|---|---|---|---|
| <=18 years | 30 | 27 | 57 |
| Between 18 and 65 years | 25 | 33 | 58 |
| >=65 years | 6 | 2 | 8 |
| Sex: Female, Male(Participants) | Group A | Group B | Total |
|---|---|---|---|
| Female | 23 | 22 | 45 |
| Male | 38 | 40 | 78 |
| Race (NIH/OMB)(Participants) | Group A | Group B | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 3 | 1 | 4 |
| White | 57 | 60 | 117 |
| More than one race | 0 | 1 | 1 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Female of childbearing potential(Participants) | Group A | Group B | Total |
|---|---|---|---|
| Yes | 5 | 3 | 8 |
| No | 18 | 19 | 37 |
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Bial - Portela C S.A.