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.

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

Number of ASSs will be summarised by means of descriptive statistics

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.

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.

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.

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

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".

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

Total of all reporting groups

The percentage for females of childbearing potential is based on number of females

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

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

Number of ASSs will be summarised by means of descriptive statistics

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.

The time is related to 6, 12 and 18 months and the percentage means the estimated probability to experience a first US in that specific time.

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.

Omitted with statistical analysis plan (SAP), Final version 1.0, 22-11-2023. 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.

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.

Omitted with statistical analysis plan [SAP], Final version 1.0, 22-NOV-2023. 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.

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

The total BI score (possible range 0 - 100) will be calculated as the sum of the individual scores from each item.

General ranges of BI describe patients' disability as follows:

80-100 - patient should be able to live independently 60-79 - minimally dependent 40-59 - partially dependent 20-39 - very dependent <20 - total dependence

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".

Stroke severity will be stratified based on NIHSS total score as follows:

<11 - mild and moderately severe

≥11 - severe

For each patient, the total NIHSS score at baseline and each post-baseline visit will be calculated adding the individual scores from each item.

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.

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.

Patients censored are all patients who discontinued the study due to any reason including death before study day 548.

The time is related to 6, 12 and 18 months and the percentage means the probability to experience a first US in that specific time.

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

TEAE: Adverse Event with onset or worsening after first IMP intake until 14 days after last IMP intake.

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.

Shifts of Haematology Parameters from Normal or Abnormal to Clinically Significant (CS) Abnormal at Endpoint

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.

Shifts of Biochemistry Parameters from Normal or Abnormal to Clinically Significant Abnormal at Endpoint

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.

The number analyzed are patients with data available

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.

Incidence of Clinically Significant Vital Sign Abnormalities at Baseline or Endpoint

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.

Incidence of Clinically Significant Vital Sign Abnormalities at Baseline or Endpoint

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.

The number analyzed are patients with data available

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.

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 PHQ-9 total score will be categorised as follows:

≤4 - minimal depression >4 - mild to severe depression

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.

The preprocessed EEG data was then analysed in two different ways; (i) we performed a power analyses and (ii) we calculated multivariate autoregressive models to investigate connectivity between channels. For both analyses the following frequency bands were defined and used to group the results: delta (1 - 3.9 Hz), theta (4 - 7.9 Hz), alpha (8 - 12.9 Hz), beta (13 - 39.9 Hz), gamma (>40Hz).

Placebo

Placebo: 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.