Conditions: Post Stroke Epilepsy
Keywords: Prophylaxis Post-stroke Epilepsy BIA 2-093 Unprovoked seizures Eslicarbazepine acetate Anti-epileptogenic Bial - Portela & Ca, S.A.
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 129
Healthy volunteers: no

Brief summary:
This study aims to assess if eslicarbazepine acetate (ESL) treatment (started within 96 hours after stroke occurrence and continued for 30 days) changes the incidence of unprovoked seizures (USs) within the first 6 months after randomisation as compared to placebo

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

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

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

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

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

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

Arms:
arm 1: ESL 800 mg arm 2: Placebo

Interventions: intervention 1: ESL 800 mg intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 1 of 11 
Bial - Portela & Ca, S.A 
 
CLINICAL TRIAL PROTOCOL  
Synopsis 
Prevention of epilepsy in stroke patients at high risk of developing unprovoked seizures: 
anti-epileptogenic effects of eslicarbazepine acetate  
 
Protocol Number 
BIA-2093-213 
EudraCT Number 
2018-002747-29 
Phase 
IIa 
Version 
Final Version 2.0 
Date 
24-OCT-2018 
Product Name 
Eslicarbazepine acetate (BIA 2-093) 
Indication 
Prophylaxis of post-stroke epilepsy  
Sponsor 
Bial - Portela & Ca, S.A. 
À Av. da Siderurgia Nacional  
4745-457 Coronado (S. Romão e S. Mamede) 
Portugal 
Phone: +351 229866100 
Fax:     +351 229866192 
http://www.bial.com 
24/7 Medical Contact 
SCOPE International Medical Monitoring 
Phone: +370 52 360 336 
Central SAE Fax: +370 52 327 903 
safety@scope-international.com 
 
The information contained in this document is the property of Bial and may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without prior written consent of Bial. 
Throughout this document, symbols indicating proprietary names (®, ™) are not 
displayed. Hence the appearance of product names without these symbols does not imply 
that these names are not protected. 
This trial will be performed in compliance with the protocol, Good Clinical Practices 
(GCP) and applicable regulatory requirements, including the archiving of essential 
documents. 
 
 
 


Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 2 of 11 
PROTOCOL SYNOPSIS 
Name of Sponsor/company: Bial - Portela & Ca, S.A., À Av. da Siderurgia Nacional, 
4745-457 Coronado (S. Romão e S. Mamede), Portugal 
Name of active ingredient: Eslicarbazepine acetate (BIA 2-093) 
Title of trial: Prevention of epilepsy in stroke patients at high risk of developing unprovoked 
seizures: anti-epileptogenic effects of eslicarbazepine acetate 
Trial number: BIA-2093-213  
EudraCT number: 2018-002747-29 
Steering Committee:  
Prof. Matthias Koepp, MD PhD FRCP, UCL Institute of Neurology, National Hospital for 
Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom  
Prim. Univ. Prof. Dr. Mag. Eugen Trinka, MD, MSc, FRCP, Universitätsklinik für 
Neurologie, Christian-Doppler-Klinik, Ignaz-Harrer-Str. 79, 5020 Salzburg, Austria 
Trial centres: Up to 22 sites in 7 European countries (Austria, France, Germany, Italy, 
Spain, Sweden and United Kingdom) and Israel. Other sites and other countries may be added 
as needed. 
Planned duration of the trial: 
 First patient first visit: 
Q1 2019 
 Last patient last visit: 
Q2 2021 
Phase of development: IIa 
Objectives: 
Primary: 
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. 
Secondary: 
1. To assess if ESL treatment (started within 96 hours after stroke occurrence and continued 
for 30 days) changes the incidence of USs within the first 12 months after randomisation 
as compared to placebo  
2. To assess if ESL treatment (started within 96 hours after stroke occurrence and continued 
for 30 days) 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 (ASs) 
To assess the effect of ESL treatment over 18 months follow-up period on: 
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 (BI) 
8. Functional outcome, assessed by National Institutes of Health Stroke Scale (NIHSS) 
9. Post-stroke depression, assessed by Patient Health Questionnaire (PHQ-9) 
10. Overall survival 


Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 3 of 11 
Safety: 
To assess the effect of ESL treatment on: 
11. Treatment emergent adverse events (TEAEs) incl. findings from physical and 
neurological examinations 
12. Laboratory parameters 
13. Vital signs 
14. Electrocardiogram (ECG) 
15. Suicidal ideation and behaviour, assessed by PHQ-9 (question 9) 
Exploratory:  
16. Electroencephalogram (EEG), optional 
Methods/trial design:  
The following definitions will be applied for this trial: 
Acute symptomatic seizure (AS): Epileptic seizure or status epilepticus (of any type) 
occurring within 7 days (≤ 7 days) after primary stroke. 
Unprovoked seizure (US): Epileptic seizure or status epilepticus (of any type) occurring later 
than 7 days (> 7 days) after primary stroke. 
Re-stroke: If an additional stroke occurs within the first 7 days after the primary stroke, this 
will be considered as one stroke event and will not lead to withdrawal of the patient. 
Post-stroke epilepsy: One unprovoked (or reflex) seizure with a probability of further 
seizures similar to the general recurrence risk (at least 60%) after 2 USs, occurring over the 
next 10 years. 
This is a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial in 
patients with acute intracerebral haemorrhage with a 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 can receive therapies for stroke treatment according to local clinical practice at any 
time during the trial. 
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, down-
titration 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. Patients 


Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 4 of 11 
who discontinue trial participation prematurely will be asked to come to the site for an early 
discontinuation visit (EDV). Unscheduled visits (UNS) will be performed at the discretion 
of the investigator, as necessary.  
Patients or their caregivers (as applicable) will be instructed to contact the site immediately 
after a seizure has occurred and to document seizure information in the patient diary. 
Number of patients (planned):  
Screened: 
220 
Randomised: 
200 
Indication and main criteria for inclusion and exclusion:  
Indication: Prophylaxis of post-stroke epilepsy 
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 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 96 hours after stroke occurrence. 


Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 5 of 11 
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:  
(as per patient interview, medical records or reported by family members) 
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. 
Duration of treatment for the individual patient: Patients will receive IMP for 30 days. 
Afterwards, they will be tapered-off for 7 days before stopping the intake.  


Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 6 of 11 
Test product, dose and mode of administration (Group A): 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.  
Placebo, dose and mode of administration (Group B): 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. 
IMP dosing schedule: IMP treatment will start at V1b (i.e. within 96 hours after primary 
stroke) and will be continued for 30 days. Thereafter, the IMP will be tapered off. The dosing 
will be as follows: Patients with an eGFR > 60 mL/min/1.73 m² will receive one tablet once 
daily, i.e. 800 mg ESL or placebo. Patients with moderate renal impairment at V1a, defined 
as eGFR 30 - 60 mL/min/1.73 m², will receive half a tablet once daily, i.e. 400 mg ESL or 
placebo. As soon as eGFR has improved to > 60 mL/min/1.73 m², the dose will be increased 
to one tablet once daily (800 mg ESL or placebo). Patients developing moderate renal 
impairment during IMP intake should be adjusted to 400 mg, if applicable. 
If one or more AS(s) occur(s) within 7 days after primary stroke, this will not result in change 
of IMP dose.In case a patient has an US, IMP has to be discontinued and the patient will be 
treated at the discretion of the investigator, except with commercially available ESL. 
Criteria for evaluation:  
Primary efficacy endpoint: 
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. 
Secondary efficacy endpoints: 
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) 


Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 7 of 11 
Exploratory endpoint: 
16. EEG, optional 
Statistical methods: 
Analysis sets: 
• Enrolled set (ES): All patients enrolled into this trial. 
• Safety set (SS): All patients who were randomised and were treated with at least one dose 
of IMP (ESL or placebo). Patients will be assigned to treatment groups as treated. 
• Full analysis set (FAS): All patients who were randomised and were treated with at least 
one dose of IMP (ESL or placebo). Patients will be assigned to treatment groups as 
randomised. 
• Per protocol set (PPS): All patients of the FAS without major protocol deviations. 
Patients will be assigned to treatment groups as treated. 
• EEG analysis subset: All patients in the FAS with a baseline and a post-baseline EEG 
recording available. 
The primary hypotheses will be assessed in the FAS by means of a chi-square test with 
continuity correction on the significance level of 5% (two-sided). 
Secondary efficacy analysis includes an analysis of the proportion of patients who experience 
the first US within the first 12 and within 18 months after randomisation (12 months and 18 
months failure rate, respectively), time to first US after randomisation as well as time to first 
US after stroke by means of Kaplan-Meier estimate, and cause-specific cumulative incidence 
curves to evaluate the competing risk in case of deaths before the first US, as well as 
descriptive statistics for number of ASs, number and 4-week rate of USs, the BI, the NIHSS 
score, the PHQ-9. 
EEG parameters will be evaluated exploratively using descriptive statistics. 
Safety analysis will focus on the presentation of TEAEs by system organ class (SOC) and 
preferred term (PT), and the analysis of vital signs, safety laboratory data, ECG, physical and 
neurological examination, and suicidal behaviours assessed using PHQ-9. 
Sample size estimation: Based on historical data, 26% of patients are expected to experience 
the first US within the first 6 months after stroke (i.e. failure rate) with standard of care. As 
this is a pilot trial, no empirical estimate of the treatment effect in patients randomised to 
ESL is available. For the purpose of sample size estimation, the trial is planned to have at 
least 80% power to demonstrate a significantly lower failure rate under ESL (Group A) 
compared to placebo (Group B) under the following assumptions:  
• An expected failure rate (including death before the first US) of 26% under placebo 
within the first 6 months after stroke. 
• An expected failure rate (including death before the first US) of 8% under ESL within 
the first 6 months after stroke. 
• In order to account for a missing data rate of 5% for reasons other than death before the 
first US, in each treatment arm, the sample size calculated on adjusted failure rates 
(including missing data) of 29.7% under placebo and 12.6% under ESL, respectively.  
Under these assumptions 100 randomised patients per treatment arm will ensure a power of 
the trial of at least 80% to demonstrate a significantly lower failure rate under ESL compared 


Clinical Trial Protocol BIA-2093-213, Synopsis 
Bial - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
CONFIDENTIAL  
Page 8 of 11 
to placebo by means of a two-sided chi-square test with continuity correction on a 5%-level 
of significance. 
Assuming that the failure rate in missing observations equals the failure rate with placebo for 
both treatment groups, the power of the trial is 87%. Based on the expected failure rates 
without adjustment for missing data, the power of the trial is 89%. 


Clinical Trial Protocol BIA-2093-213, Synopsis 
 
BIAL - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
 
CONFIDENTIAL  
 
Page 9 of 11 
Schedule of trial procedures 
Visits 
V1a2 
V1b2 
V215 
V315 
V4 
V5 
V6 
V7 
V8 
EoT12 
EDV3 
UNS1 
Days / Weeks after V1b 
 
 
+7 
days  
+37 
days  
+12 
weeks  
+26 
weeks  
+38 
weeks 
+52 
weeks  
+ 64 
weeks 
+ 78 
weeks 
 
 
On-site visit ⊗/telephone contact  
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
 
⊗ 
 
⊗ 
⊗ 
⊗/ 
Day 
-3 to -1 
1 (within 
96 h after 
stroke) 
8±2 
38+4 
85±10 
183±10 267±10 365±10 449±10 547±10 
 
 
Initiation procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
9 
 
10 
 
 
 
 
 
 
 
 
()14 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
10 
 
 
 
 
 
 
 
 
()14 
Prior medication 
 
 
10 
 
 
 
 
 
 
 
 
()14 
Concomitant medication 
 
 
 
 
 
 
 
 
 
 
 
 
SeLECT score/CAVE score11 
4 
 
 
 
 
 
 
 
 
 
 
 
Modified Rankin Scale (mRS) 
4 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
10 
 
 
 
 
 
 
 
 
 
Randomisation (1:1)  
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
 
 
 
 
 
 
 
 
 
 
 
 
First investigational medicinal product (IMP) 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IMP 
 
 
 
 
 
 
 
 
 
 
 
() 
IMP accountability 
 
 
 
 
 
 
 
 
 
 
13 
() 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
Issue diary (seizures)  
 
 
 
 
 
 
 
 
 
 
 
() 
Review and collect diary 
 
8 
 
 
 
 
 
 
 
 
 
() 
Seizure screening questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
Record seizures (diary/questionnaire)16 
 
 
 
 
 
 
 
 
 
 
 
 
Barthel Index (BI) 
 
 
 
 
 
 
 
 
 
 
 
() 
National Institutes of Health Stroke Scale (NIHSS) 
4 
 
 
 
 
 
 
 
 
 
 
() 
Patient Health Questionnaire (PHQ-9) 
 
 
 
 
 
 
 
 
 
 
 
() 
Electroencephalogram (EEG, optional)5 
(4) 
 
 
 
 
 
 
 
 
() 
 
() 


Clinical Trial Protocol BIA-2093-213, Synopsis 
 
BIAL - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
 
CONFIDENTIAL  
 
Page 10 of 11 
Visits 
V1a2 
V1b2 
V215 
V315 
V4 
V5 
V6 
V7 
V8 
EoT12 
EDV3 
UNS1 
Days / Weeks after V1b 
 
 
+7 
days  
+37 
days  
+12 
weeks  
+26 
weeks  
+38 
weeks 
+52 
weeks  
+ 64 
weeks 
+ 78 
weeks 
 
 
On-site visit ⊗/telephone contact  
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
 
⊗ 
 
⊗ 
⊗ 
⊗/ 
Day 
-3 to -1 
1 (within 
96 h after 
stroke) 
8±2 
38+4 
85±10 
183±10 267±10 365±10 449±10 547±10 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events (AEs) 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
(blood pressure, heart rate, tympanic body temperature)  
 
 
 
 
 
 
 
 
 
 
 
() 
Blood withdrawal (haematology and biochemistry)6 
 
 
 
 
 
 
 
 
 
 
13 
() 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
13 
() 
12-lead electrocardiogram (ECG) 
4 
 
 
 
 
 
 
 
 
 
13 
() 
Physical and neurological examination 
 
 
 
 
 
 
 
 
 
 
 
() 
Serum pregnancy test7 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 7 
 
 
 
 
 
 
 
 
 
 
13 
() 
1. 
Unscheduled visits (UNSs) will be performed at the discretion of the investigator. Assessments in brackets are optional and can be performed at the 
discretion of the investigator. 
2. 
If all conditions for V1a and V1b are fulfilled, V1a and V1b can be performed on the same day. 
3. 
An early discontinuation visit (EDV) should be performed within 10 days, if possible, on withdrawal. 
4. 
If examination was done after primary stroke, the results should be used and the examination does not need to be repeated at V1a. 
5. 
EEGs are optional assessments and will be performed at the discretion of the investigator. 
6. 
Including eGFR and coagulation. At V1a also thyroid function.  
7. 
Only in women of childbearing potential. Frequency may be adapted to meet specific country-specific/local requirements. 
8. 
The diary will only be reviewed but not be collected at V1b. 
9. 
If a patient is unable to give written or verbal consent at V1a, patient consent can be deferred or the patient’s legal representative must provide written 
informed consent (according to country specific requirements). Written or verbal witnessed informed consent from the patient must be obtained until 
V2. 
10. Only applicable for patients who were unable to give informed consent at V1a. 
11. The scores for “Severity of stroke, Large-artery atherosclerotic aetiology, Early seizures, Cortical involvement, Territory of middle cerebral artery” 
(SeLECT score) in patients with an acute ischaemic stroke and for “Cortical involvement, Age < 65 years, Volume of intracerebral haemorrhage 
> 10 mL and Early seizure within 7 days after intracerebral haemorrhage” (CAVE score) in patients with acute intracerebral haemorrhage. 


Clinical Trial Protocol BIA-2093-213, Synopsis 
 
BIAL - Portela & Ca, S.A. 
Final Version 2.0, 24-OCT-2018 
 
CONFIDENTIAL  
 
Page 11 of 11 
12. EoT: End of Trial visit 
13. Only applicable, if EDV is performed before V3. 
14. Only applicable if performed prior to V2 and only for patients who were unable to give informed consent at V1a. 
15. The patients will be reminded via phone call on the working day before Day 30 to either take the last tablet on Day 30 (those with ESL 400 mg) or to 
take half a tablet from Day 31 to Day 37 (those with ESL 800 mg) and (if applicable) to start the down-titration of AED/benzodiazepines according to 
the respective SmPC on Day 31, if not already discontinued before. 
16. Seizure records based on diary entries may be applicable in case of on-site visits, only. 

SAP_001.pdf: 
 
I-DM-011SAP 
Page 1 of 58 
Effective date: 15.09.2020 
 
Prevention of epilepsy in stroke patients at high risk of developing unprovoked seizures: anti-
epileptogenic effects of eslicarbazepine acetate 
 
 
 
Sponsor Project Code: BIA-2093-213 
Scope Project Code: 0229BI29.MPB 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Sponsor:  
Bial - Portela & Ca, S.A. 
À Av. da Siderurgia Nacional  
4745-457 Coronado (S. Romão e S. Mamede), Portugal 
Phone: +351 229866100 
Fax: 
+351 229866192 
 
Author: 
Nicole Dauzenroth 
Statistician 
Scope International AG 
Konrad-Zuse Ring 18 
68163 Mannheim, Germany 
E-mail: contact@scope-international.com 
Fax:  
+49 621 42939 40 
 
 
Version: 
Final 1.0 (22-NOV-2023) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of Bial - 
Portela & Ca, S.A. or a nominated representative. 
 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 2 of 58 
Effective date: 15.09.2020 
DOCUMENT REVISION HISTORY 
 
Version Draft 0.1 (30-SEP-2022):  Document was created. 
 
Version Draft 0.2 (21-MAR-2023): Document was updated after sponsor’s review: 
• 
2.2.1 / 2.2.2 Definition of ‘failure rate’ was specified 
• 
3.1 Definition of ‘Per-protocol set’ was adapted 
• 
3.2 Subgroups were defined 
• 
4.5 Definition for ‘visit slots’ was added if a visit was not scheduled (e.g. vital signs) 
• 
4.8 Baseline definition for NIHSS was changed to ‘post-stroke until V1b’ 
• 
5.5.1 p-value for Fisher’s test was added 
• 
5.5.2.3 Tables 15.2.5.2.1 and 15.2.5.2.2 and figures 15.2.1.2.3 and 15.2.1.2.4 were deleted 
• 
5.4.1.1 Definition of treatment duration was changed: treatment interruptions are incorporated 
 
Version Draft 0.3 (11-AUG-2023): Document was updated after sponsor’s review: 
• 
Secondary objective  and endpoint “Time to first US after stroke occurrence” was deleted as it 
is closely related to the forth secondary endpoint “Time to first US after randomisation” 
• 
Subgroup analysis “NIHSS 4-10 versus NIHSS g11” was deleted 
• 
Definition of study periods was updated 
• 
Definition of the EEG analysis set was changed 
 
Version Draft 0.4 (17-OCT-2023): Document was updated after sponsor’s review: 
• 
Secondary objective  and endpoint “4-week rate of USs” was deleted as this information will 
not be meaningful for this trial 
• 
Table 15.3.2.2.4 was deleted as this parameter was only collected at V1a 
 
Version Draft 0.5 (14-NOV-2023): Document was updated after sponsor’s review and Blind Data 
Review Meeting: 
• 
Subgroup Analysis was changed (subgroup analysis now only for unprovoked seizures after 
18 months) 
• 
General Definition: it was included that all p-values are two-sided and no multiplicity 
adjustments are performed. 
• 
Visit Slotting: new definition included if V1b was not scheduled 
• 
Table 15.2.1.5.3 – Table 15.2.1.5.8 were included 
• 
5.5.1 Included: In case of a re-stroke, the date of re-stroke will be used as ‘Date of 
withdrawal’ 
• 
FAS definition updated 
• 
Study period definitions were added for 1, 3, 9 and 15 months 
• 
15.1.2 Explanation regarding COVID-19 pandemic deviation added 
• 
Per-protocol set: new rule was added 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 3 of 58 
Effective date: 15.09.2020 
TABLE OF CONTENTS 
DOCUMENT REVISION HISTORY ................................................................................................. 2 
LIST OF ABBREVIATIONS AND KEY TERMS ............................................................................ 5 
INTRODUCTION ................................................................................................................................. 7 
1. 
SCHEDULE OF TRIAL PROCEDURES ................................................................................. 8 
2. 
OBJECTIVES AND DESIGN ................................................................................................... 11 
2.1 
STUDY OBJECTIVES ............................................................................................................. 11 
2.1.1 
Primary Objective ....................................................................................................... 11 
2.1.2 
Secondary Objectives .................................................................................................. 11 
2.1.3 
Safety Objectives ......................................................................................................... 11 
2.1.4 
Exploratory Objectives ............................................................................................... 11 
2.2 
STUDY ENDPOINTS .............................................................................................................. 11 
2.2.1 
Primary Efficacy Endpoints ........................................................................................ 11 
2.2.2 
Secondary Efficacy Endpoints .................................................................................... 12 
2.2.3 
Safety Endpoints ......................................................................................................... 12 
2.2.4 
Exploratory Endpoint ................................................................................................. 12 
2.3 
OVERALL STUDY DESIGN .................................................................................................... 12 
2.4 
RANDOMISATION ................................................................................................................. 12 
2.5 
TREATMENTS ....................................................................................................................... 13 
2.6 
SAMPLE SIZE ........................................................................................................................ 13 
2.7 
BLINDING ............................................................................................................................. 13 
3. 
ANALYSIS SETS AND SUBGROUPS .................................................................................... 14 
3.1 
ANALYSIS SETS .................................................................................................................... 14 
3.2 
SUBGROUPS ......................................................................................................................... 14 
4. 
GENERAL DEFINITIONS AND NAMING CONVENTIONS ............................................ 15 
4.1 
GENERAL METHODOLOGY AND PRESENTATION OF THE RESULTS ...................................... 15 
4.2 
STATISTICAL OUTPUT LAYOUT ........................................................................................... 15 
4.3 
TREATMENT GROUP NAMES AND LABELS .......................................................................... 15 
4.4 
VISIT NAMES AND LABELS .................................................................................................. 16 
4.5 
VISIT SLOTTING ................................................................................................................... 16 
4.6 
STUDY DAY NUMBERING .................................................................................................... 17 
4.7 
STUDY PERIODS FOR PRIMARY AND SECONDARY EFFICACY ANALYSIS .............................. 17 
4.8 
BASELINE AND ENDPOINT VALUE ....................................................................................... 17 
4.9 
CODING SYSTEMS AND CONVENTIONS ................................................................................ 18 
4.9.1 
Coding of adverse events and medical history............................................................ 18 
4.9.2 
Coding of medications ................................................................................................ 18 
4.10 
HANDLING OF MISSING DATA ............................................................................................. 18 
5. 
STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY ..................................................................................................................... 19 
5.1 
PATIENT DISPOSITION .......................................................................................................... 19 
5.1.1 
Disposition and Withdrawals ...................................................................................... 19 
5.1.2 
Protocol Deviations .................................................................................................... 20 
5.1.3 
Inclusion/Exclusion ..................................................................................................... 21 
5.2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................ 21 
5.2.1 
Demographics ............................................................................................................. 21 
5.2.2 
Primary Stroke Characteristics .................................................................................. 21 
5.2.3 
Medical History .......................................................................................................... 24 
5.3 
PREVIOUS AND CONCOMITANT MEDICATIONS AND THERAPIES ......................................... 25 
5.4 
EXPOSURE TO IMP AND COMPLIANCE ................................................................................ 26 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 4 of 58 
Effective date: 15.09.2020 
5.4.1 
Exposure to IMP ......................................................................................................... 26 
5.4.2 
Compliance ................................................................................................................. 27 
5.5 
EFFICACY ANALYSIS ........................................................................................................... 27 
5.5.1 
Primary Efficacy Analysis........................................................................................... 27 
5.5.1.1 
Sensitivity Analyses ..................................................................................................... 28 
5.5.2 
Analysis of Secondary Efficacy Variables .................................................................. 30 
5.5.2.1 
Twelve- and Eighteen-Month Failure Rates ............................................................... 30 
5.5.2.2 
Number of Acute Symptomatic Seizures ..................................................................... 31 
5.5.2.3 
Time to First Unprovoked Seizure after Randomisation ............................................ 31 
5.5.2.4 
Number of Unprovoked Seizure .................................................................................. 32 
5.5.2.5 
Barthel Index ............................................................................................................... 32 
5.5.2.6 
National Institutes of Health Stroke Scale .................................................................. 33 
5.5.2.7 
Patient Health Questionnaire ..................................................................................... 35 
5.5.2.8 
Overall Survival .......................................................................................................... 36 
5.6 
SAFETY ANALYSIS ............................................................................................................... 36 
5.6.1 
Adverse Events ............................................................................................................ 37 
5.6.2 
Clinical Laboratory Evaluation .................................................................................. 39 
5.6.3 
Vital Signs ................................................................................................................... 41 
5.6.4 
12-Lead Electrocardiogram Data ............................................................................... 41 
5.6.5 
Physical and Neurological Examination Findings ..................................................... 42 
5.6.6 
Analysis of Exploratory Endpoint ............................................................................... 42 
6. 
BLIND DATA REVIEW ........................................................................................................... 43 
7. 
INTERIM ANALYSIS ............................................................................................................... 47 
8. 
CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
MODIFICATIONS .................................................................................................................... 48 
9. 
REFERENCES ........................................................................................................................... 49 
10. APPENDICES ............................................................................................................................ 50 
10.1 
TABLES ................................................................................................................................ 50 
10.2 
LISTINGS .............................................................................................................................. 55 
10.3 
FIGURES ............................................................................................................................... 57 
11. SIGNATURES ............................................................................................................................ 58 
  


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 5 of 58 
Effective date: 15.09.2020 
LIST OF ABBREVIATIONS AND KEY TERMS 
Abbreviation Description of Abbreviation 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALT 
Alanine transaminase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical 
BI 
Barthel Index original 
BDR 
Blind data review 
β-hCG 
β-human chorionic gonadotropin 
CAVE 
Cortical involvement, Age < 65 years, Volume of intracerebral haemorrhage > 10 
mL and Early seizure within 7 days after intracerebral haemorrhage 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CT 
Computed tomography 
CTP 
Clinical trial protocol 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDV 
Early discontinuation visit 
EEG 
Electroencephalogram 
eGFR 
Estimated glomerular filtration rate 
EoT 
End of Trial 
ES 
Enrolled set 
ESL 
Eslicarbazepine acetate 
FAS 
Full analysis set 
GGT 
Gamma-glutamyl transferase 
HLGT 
High level group term 
HLT 
High level term 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
LDH 
Lactate dehydrogenase 
LLT 
Lowest level term 
MCA 
Middle cerebral artery 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes of Health Stroke Scale 
PDF 
Planned first treatment date 
PHQ 
Patient Health Questionnaire 
PLD 
Planned last treatment date 
PPS 
Per protocol set 
PT 
Preferred term 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 6 of 58 
Effective date: 15.09.2020 
PTD 
Planned total dose 
RBC 
Red blood cell  
RD 
Risk Difference 
RS 
Randomised set 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System 
SCr 
Standardised serum creatinine 
SeLECT 
Severity of stroke, Large-artery atherosclerotic aetiology, Early seizures, Cortical 
involvement, Territory of MCA 
SOC 
System organ class 
SS 
Safety set 
TEAE 
Treatment emergent adverse event 
TDTT 
Total Down Titration Time 
UNS 
Unscheduled visit 
US 
Unprovoked seizure 
V 
Visit 
WBC 
White blood cell  
WHO 
World Health Organization 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 7 of 58 
Effective date: 15.09.2020 
INTRODUCTION 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the clinical trial protocol (CTP) and its modifications: 
Final Protocol Version and Date: 
Final Version 2.0, 24-OCT-2018 
 
Version 1.0_AT, 12-Jul-2019 
 
Version 1.0_DE, 21-Jan-2019 
 
Version 1.0_SE, 27-May-2019 
 
Version 1.0_UK, 15-Jul-2019 
 
 
Protocol Amendment Version and Date: 
 
Implementation of Global Amendment #1, 
20-JAN-2020 for all countries: . 
Final Version 3.0, 20-JAN-2020 
Final Version 2.0_AT, 30-JAN-2020 
Final Version 2.0_DE, 30-JAN-2020 
Final Version 2.0_DE_2001, 30-JAN-2020 
Final Version 2.0_PT, 31-MAR-2020 
Final Version 2.0_SE, 30-JAN-2020 
Final Version 2.0_UK, 30-JAN-2020 
 
 
The SAP includes detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data, and it is structured according to different data types. The SAP is finalised and 
signed-off prior to unblinding the trial. The statistical considerations described in the SAP amend the 
considerations in the CTP.  
All analysis datasets and statistical output will be produced by the statistics department of Scope 
International AG using SAS® for Windows (SAS Institute Inc., Cary, NC, USA) [1] version 9.4 or 
higher. The actual version used will be documented in the Validation Plan for Statistical Programming. 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 8 of 58 
Effective date: 15.09.2020 
1. SCHEDULE OF TRIAL PROCEDURES 
Visits 
V1a2 
V1b2 
V215 V315 
V4 
V5 
V6 
V7 
V8 
EoT12 EDV3 UNS1 
Days / Weeks after V1b 
 
 
+7 
days  
+37 
days  
+12 
weeks  
+26 
weeks  
+38 
weeks 
+52 
weeks  
+ 64 
weeks 
+ 78 
weeks 
 
 
On-site visit ⊗/telephone contact  
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
 
⊗ 
 
⊗ 
⊗ 
⊗/ 
Day (CTP Final Version 3.0) 
(within 120 h after 
stroke)  
1 (within 120 h after 
stroke) 
8±2 38+4 85±10 183±10 267±10 365±10 449±10 547±10 
 
 
Day (CTP Final Version 2.0) 
-3 to -1 
1 
(within 96 h after 
stroke) 
Initiation procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
9 
 
10 
 
 
 
 
 
 
 
 
()14 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
10 
 
 
 
 
 
 
 
 
()14 
Prior medication 
 
 
10 
 
 
 
 
 
 
 
 
()14 
Concomitant medication 
 
 
 
 
 
 
 
 
 
 
 
 
SeLECT score/CAVE score11 (CTP Final 
Version 3.0) 
 
 
17 (17) 
 
 
 
 
 
 
 
 
SeLECT score/CAVE score11 (CTP Final 
Version 2.0) 
4 
 
 
 
 
 
 
 
 
 
 
 
Modified Rankin Scale (mRS) 
4 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
10 
 
 
 
 
 
 
 
 
 
Randomisation (1:1)  
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
 
 
 
 
 
 
 
 
 
 
 
 
First investigational medicinal product (IMP) 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IMP 
 
 
 
 
 
 
 
 
 
 
 
() 
IMP accountability 
 
 
 
 
 
 
 
 
 
 
13 
() 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
Issue diary (seizures)  
 
 
 
 
 
 
 
 
 
 
 
() 
Review and collect diary 
 
8 
 
 
 
 
 
 
 
 
 
() 
Seizure screening questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 9 of 58 
Effective date: 15.09.2020 
Visits 
V1a2 
V1b2 
V215 V315 
V4 
V5 
V6 
V7 
V8 
EoT12 EDV3 UNS1 
Days / Weeks after V1b 
 
 
+7 
days  
+37 
days  
+12 
weeks  
+26 
weeks  
+38 
weeks 
+52 
weeks  
+ 64 
weeks 
+ 78 
weeks 
 
 
On-site visit ⊗/telephone contact  
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
 
⊗ 
 
⊗ 
⊗ 
⊗/ 
Day (CTP Final Version 3.0) 
(within 120 h after 
stroke)  
1 (within 120 h after 
stroke) 
8±2 38+4 85±10 183±10 267±10 365±10 449±10 547±10 
 
 
Day (CTP Final Version 2.0) 
-3 to -1 
1 
(within 96 h after 
stroke) 
Record seizures (diary/questionnaire)16 
 
 
 
 
 
 
 
 
 
 
 
 
Barthel Index (BI) 
 
 
 
 
 
 
 
 
 
 
 
() 
National Institutes of Health Stroke Scale 
(NIHSS) 
4 
 
 
 
 
 
 
 
 
 
 
() 
Patient Health Questionnaire (PHQ-9) 
 
 
 
 
 
 
 
 
 
 
 
() 
Electroencephalogram (EEG, optional)5 
(4) 
 
 
 
 
 
 
 
 
() 
 
() 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events (AEs) 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
(blood pressure, heart rate, tympanic body 
temperature)  
 
 
 
 
 
 
 
 
 
 
 
() 
Blood withdrawal (haematology and 
biochemistry)6 
 
 
 
 
 
 
 
 
 
 
13 
() 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
13 
() 
12-lead electrocardiogram (ECG) 
4 
 
 
 
 
 
 
 
 
 
13 
() 
Physical and neurological examination 
 
 
 
 
 
 
 
 
 
 
 
() 
Serum pregnancy test7 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 7 
 
 
 
 
 
 
 
 
 
 
13 
() 
1. 
Unscheduled visits (UNSs) will be performed at the discretion of the investigator. Assessments in brackets are optional and can be performed at the 
discretion of the investigator. 
2. 
If all conditions for V1a and V1b are fulfilled, V1a and V1b can be performed on the same day. 
3. 
An early discontinuation visit (EDV) should be performed within 10 days, if possible, on withdrawal. 
4. 
If examination was done after primary stroke, the results should be used and the examination does not need to be repeated at V1a. 
5. 
EEGs are optional assessments and will be performed at the discretion of the investigator. 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
 
Page 10 of 58 
Effective date: 15.09.2020 
6. 
Including eGFR and coagulation. At V1a also thyroid function.  
7. 
Only in women of childbearing potential. Frequency may be adapted to meet specific country-specific/local requirements. 
8. 
The diary will only be reviewed but not be collected at V1b. 
9. 
If a patient is unable to give written or verbal consent at V1a, patient consent can be deferred or the patient’s legal representative must provide written 
informed consent (according to country specific requirements). Written or verbal witnessed informed consent from the patient must be obtained until 
V2. 
10. Only applicable for patients who were unable to give informed consent at V1a. 
11. The scores for “Severity of stroke, Large-artery atherosclerotic aetiology, Early seizures, Cortical involvement, Territory of middle cerebral artery” 
(SeLECT score) in patients with an acute ischaemic stroke and for “Cortical involvement, Age < 65 years, Volume of intracerebral haemorrhage 
> 10 mL and Early seizure within 7 days after intracerebral haemorrhage” (CAVE score) in patients with acute intracerebral haemorrhagic stroke. 
12. EoT: End of Trial visit 
13. Only applicable, if EDV is performed before V3. 
14. Only applicable if performed prior to V2 and only for patients who were unable to give informed consent at V1a. 
15. The patients will be reminded via phone call on the working day before Day 30 to either take the last tablet on Day 30 (those with ESL 400 mg) or to 
take half a tablet from Day 31 to Day 37 (those with ESL 800 mg) and (if applicable) to start the down-titration of AED/benzodiazepines according to 
the respective SmPC on Day 31, if not already discontinued before. 
16. Seizure records based on diary entries may be applicable in case of on-site visits, only. 
17. In case V2 is scheduled earlier than 7 days post stroke, the assessment of early seizures after stroke will be done at V3. 
 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Draft 0.3 
11-AUG-2023 
 
I-DM-011SAP 
Page 11 of 58 
Effective date: 15.09.2020 
 
2. OBJECTIVES AND DESIGN 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of this trial is 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. 
2.1.2 
Secondary Objectives 
The secondary objectives of this trial are: 
1. To assess if ESL treatment (started within 120 hours after stroke occurrence and continued for 
30 days) changes the incidence of USs – within the first 12 months after randomisation as 
compared to placebo  
2. To assess if ESL treatment (started within 120 hours after stroke occurrence and continued for 
30 days) 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 (Ass) 
To assess the effect of ESL treatment over 18 months follow-up period on: 
4. Time to first US after randomisation 
5. Number of Uss 
6. Functional outcome, assessed by Barthel Index original 10-item version (BI) 
7. Functional outcome, assessed by National Institutes of Health Stroke Scale (NIHSS) 
8. Post-stroke depression, assessed by Patient Health Questionnaire (PHQ-9) 
9. Overall survival  
2.1.3 
Safety Objectives 
The safety objectives of this trial are to assess the effect of ESL treatment on: 
10. Treatment emergent adverse events (TEAEs) incl. findings from physical and neurological 
examinations 
11. Laboratory parameters 
12. Vital signs 
13. Electrocardiogram (ECG) 
14. Suicidal ideation and behaviour, assessed by PHQ-9 (question 9) 
2.1.4 
Exploratory Objectives 
The exploratory objective of the trial is the evaluation of electroencephalogram (EEG) (optional). 
2.2 
Study Endpoints 
2.2.1 
Primary Efficacy Endpoints 
The primary endpoint of this trial is the proportion of patients who experience the first US within the 
first 6 months after randomisation. Deaths before the first US or patients without evaluable assessment 
of the primary endpoint (i.e. drop-outs independently of the reason) will be counted as treatment failures 
(failure rate). 


Sponsor: Bial - Portela & Ca, S.A. 
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Effective date: 15.09.2020 
2.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this trial are: 
1. Proportion of patients (same criteria for failure rate as in 2.2.1) who experience the first US 
during the first 12 months after randomisation (12 months failure rate)  
2. Proportion of patients (same criteria for failure rate as in 2.2.1) 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. Number of Uss 
6. BI 
7. NIHSS 
8. PHQ-9 
9. Overall survival 
2.2.3 
Safety Endpoints 
The safety endpoints of this trial are: 
10. TEAEs incl. findings from physical and neurological examinations 
11. Laboratory parameters (haematology and biochemistry, including eGFR and coagulation, 
urinalysis) 
12. Vital signs 
13. ECG 
14. Suicidal ideation and behaviour (as per PHQ-9, question 9) 
2.2.4 
Exploratory Endpoint 
The exploratory endpoint of this trial is EEG (optional assessment). 
2.3 
Overall Study Design 
This is a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial in patients at 
high risk of developing unprovoked seizures after acute intracerebral haemorrhage or an acute 
ischaemic stroke. 
At the first visit (screening/baseline, V1a), patients will undergo several examinations to check 
eligibility. The next visit (V1b) has to be performed within 120 hours after primary stroke occurrence 
or since last time seen well. After eligibility has been confirmed, patients will be randomised to 
treatment with ESL 800 mg or placebo. 
Patients will start treatment with the investigational medicinal product (IMP) i.e. ESL or placebo within 
120 hours after primary stroke occurrence, or since last time seen well 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. 
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.  
2.4 
Randomisation 
After confirmed eligibility at V1b, patients will be randomised (randomisation ratio 1:1) to treatment 
with ESL 800 mg or placebo. 
 


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2.5 
Treatments 
Treatment name 
Dosage Form 
Active ingredient 
Strength/concentration 
ESL 
Tablet 
Eslicarbazepine acetate (ESL) 
800 mg 
Placebo 
Tablet 
None 
Not applicable 
Treatment with IMP will start at V1b (i.e. within 120 hours after primary stroke, or since last time seen 
well) and will be continued for 30 days. Thereafter, the IMP will be tapered off, as applicable. The 
dosing will be as follows:  
Patients with an eGFR > 60 mL/min/1.73 m2 will take one tablet once daily (800 mg ESL or placebo). 
Patients with moderate renal impairment at V1a, defined as eGFR 30 – 60 mL/min/1.73 m2, will take 
half a tablet once daily (400 mg ESL or placebo). As soon as eGFR has improved to 
> 60 mL/min/1.73 m2, the dose will be increased to one tablet once daily (800 mg ESL or placebo). 
Patients developing moderate renal impairment during IMP intake should be adjusted to 400 mg, if 
applicable. Worsening of renal function with an eGFR < 30 mL/min/1.73 m2 must lead to 
discontinuation of IMP intake (dose independent) without down-titration. 
Patients taking one tablet once daily (800 mg ESL or placebo) must be down-titrated for 7 days before 
stopping intake of IMP i.e. those patients will take half a tablet (400 mg ESL or placebo) from Day 31 
to Day 37. Patients taking half a tablet once daily (400 mg ESL or placebo) on Day 30 do not require 
down-titration i.e. they will take the last IMP on Day 30. 
2.6 
Sample Size 
Based on retrospective historical data, 26% of patients are expected to experience the first US (i.e. 
failure rate) within the first 6 months after stroke with standard of care. As this is a pilot trial, no 
empirical estimate of the treatment effect in patients randomised to ESL is available. For the purpose 
of sample size estimation, the trial is planned to have at least 80% power to demonstrate a significantly 
lower failure rate under ESL compared to placebo under the following assumptions:  
• 
An expected failure rate (including death and other reasons of missing data before the first US) 
of 26% under placebo within the first 6 months after stroke  
• 
An expected failure rate (including death and other reasons of missing data before the first US) 
of 8% under ESL within the first 6 months after stroke 
Under these assumptions 100 randomised patients per treatment arm will ensure a power of the trial of 
at least 80% to demonstrate a significantly lower failure rate under ESL compared to placebo by means 
of a two-sided chi-square test on a 5%-level of significance. 
Recruitment was terminated before reaching the estimated sample size. 
2.7 
Blinding 
ESL and placebo tablets will be identical in size, colour, taste and appearance. The packaging and 
labelling will not allow for any distinction between test drug and placebo. 
No person involved in conducting the trial may have access to the randomisation code before the blind 
is officially broken. 


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3. ANALYSIS SETS AND SUBGROUPS 
3.1 
Analysis Sets 
The Enrolled Set (ES) will be defined as all patients who have been enrolled in the trial (i.e. informed 
consent form (ICF) signed by patient, by witness in case of verbal consent or by patient´s legal 
representative or deferral of informed consent adequately documented and signed by the investigator). 
The Randomised Set (RS) will be defined as all patients who were randomised. 
The Safety Set (SS) will be defined as all patients who were randomised and were treated with at least 
one dose of IMP (ESL or placebo). Patients will be assigned to treatment groups as treated. 
The Full Analysis Set (FAS) will be defined as all patients who were randomised and were treated with 
at least one dose of IMP (ESL or placebo). Patients will be assigned to treatment groups as randomised.  
The Per-Protocol Set (PPS) will be defined as all patients of the FAS without any major protocol 
deviations and with verbal witnessed or signed written consent. Patients will be assigned to treatment 
groups as randomised.  
The EEG analysis subset will be defined and described in the separate EEG report. 
3.2 
Subgroups 
For analysis of efficacy endpoints the following subgroups will be defined based on: 
1. Acute intracerebral haemorrhagic stroke versus acute ischemic stroke 
2. Time of treatment start (treatment start within the first 72 hours after primary stroke vs. 
treatment start after 72 hours after primary stroke). In case of unknown start time of IMP, it 
will assumed that first IMP intake was at 23:59. 
Exploratory subgroup analysis of unprovoked seizures only at 18 months will performed in the FAS. 
 
Final decision concerning subgroup analyses and definitions were made during Blind Data Review 
(BDR). 
 


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4. GENERAL DEFINITIONS AND NAMING CONVENTIONS   
In order to avoid ambiguity during the analysis, a number of definitions and conventions for data 
handling are described here. 
4.1 
General Methodology and Presentation of the Results 
The default summary statistics for quantitative (continuous) variables will be  
- 
the number of patients with data at the visit (n), 
- 
number of patients with missing data (nmiss), 
- 
mean, 
- 
standard deviation (SD),  
- 
median, 
- 
first quartile (Q1) and third quartile (Q3) 
- 
minimum (min) and maximum (max) 
for patients with data. 
Mean, median, and the quartiles will be presented to one more decimal place than the raw value. The 
minimum and maximum values will be presented with the same decimal precision as the raw value. SD 
will be reported to two decimal places greater than the original value. 
For qualitative (categorical) variables, the number (n) and percentage (%) of patients with non-missing 
data per category will be the default frequency tabulations. Where appropriate and present, the number 
of missing values will be displayed as “Missing” category. 
Percentage values are to be presented to one decimal place, for example, 52.3%. 
The denominator used for calculation of the percentages will be specified in a footnote to the tables for 
clarification. 
All reported p-values will be two-sided. No adjustment for multiplicity will be performed. 
4.2 
Statistical Output Layout 
All titles and column headers (consisting of one or several words) will be capitalised; articles, 
prepositions, and conjunctions, and “to” in infinitives will not be capitalised, except they are at the 
beginning of titles or headers. 
All pages will be numbered according to the table/listing/figure to which the page belongs to. Every 
table/listing/figure will be numbered from page 1, “Page X of Y” at the bottom of each page. 
The definition of baseline and endpoint value will be described in a footnote in every TLF where 
applicable. Other important definitions will also be presented if necessary. 
Dates will be listed in the format: yyyy-mm-dd (e.g. 2003-11-20). Times will be listed in the format: 
hh:mm (e.g. 13:15) or in the format hh:mm:ss if seconds are collected. When date and time are collected, 
these are listed in the format: yyyy-mm-ddThh:mm (e.g. 2003-11-20T09:15), yyyy-mm-ddThh, or 
yyyy-mm-ddThh:mm:ss. 
Partial missing dates will be listed in the format yyyy-mm (e.g. 2013-11) if only day is missing or in 
the format yyyy (e.g. 2013) if month and day are missing. 
Missing data including missing dates or times will be displayed in listings as blank fields, unless 
otherwise specified. 
Listings will be sorted by treatment group, patient number and visit number where applicable, unless 
specified otherwise. 
4.3 
Treatment Group Names and Labels 
Statistical output will be presented by treatment group and the treatment labels to be used in the tables, 
listings and figures are defined in Table 1 below. 


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Table 1: Treatment Group Labels 
Number 
Description 
Label in TLFs 
1 
One or half of 800 mg ESL tablet once daily 
ESL 
2 
One or half of placebo tablet once daily 
Placebo 
4.4 
Visit Names and Labels 
The names to be used in the analysis datasets and the labels to be used in the tables, listings and figures 
for the different study visits are defined in Table 2 below. 
Table 2: Visit Labels 
Name 
Description 
Label in TLFs 
Visit 1a 
Screening/baseline, within 120 hours after stroke, or since last 
time seen well 
V1a 
Visit 1b 
Day 1, within 120 hours after stroke, or since last time seen well 
V1b 
Visit 2 
Day 8 ± 2 
V2 
Visit 3 
Day 38 + 4 
V3 
Visit 4 
Day 85 ± 10 
V4 
Visit 5 
Day 183 ± 10 
V5 
Visit 6 
Day 267 ± 10 
V6 
Visit 7 
Day 365 ± 10 
V7 
Visit 8 
Day 449 ± 10 
V8 
EoT 
Day 547 ± 10 
EOT 
EDV 
Early discontinuation visit 
EDV 
UNS 
Unscheduled visits 
USV X.X 
 
4.5 
Visit Slotting 
Due to COVID-19 pandemic visits might be delayed. Therefore, visit slots will be used for the analysis 
of efficacy (where applicable) and safety variables (where applicable). For a visit slot the closest non-
missing assessment in time (scheduled or unscheduled) to the target day will be used (see Table 3). 
 
Table 3: Visit Slotting 
Visit Slot/ 
Label 
Target Day 
Description 
V1a 
- 
Screening/baseline, within 120 hours after stroke, or since last 
time seen well 
V1b 
1 
Day 1, within 120 hours after stroke, or since last time seen well 
V2 
8 
Closest non missing assessment to target day between study day 
2 and 31 
V3 
38 
Closest non missing assessment to target day between study day 
32 and 71 
V4 
85 
Closest non missing assessment to target day between study day 
72 and 171 
V5 
183 
Closest non missing assessment to target day between study day 
172 and 242 
V6 
267 
Closest non missing assessment to target day between study day 
243 and 353 
V7 
365 
Closest non missing assessment to target day between study day 
354 and 437 
V8 
449 
Closest non missing assessment to target day between study day 
438 and 533 
EOT 
547 
Closest non missing assessment to target day between study day 
534 and >547 


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EDV 
EDV 
Early discontinuation visit 
 
If, for any variable, a visit was not scheduled (e.g. V4 for vital signs), the respective measurement will 
be assigned to the visit slot with the closest target day where a visit was scheduled. If two measurements 
fall into that slot, the closest one to target day will be used. 
 
If, for any safety variable, V1b is not scheduled and a measurement is taken on Study Day 1, this 
measurement will be slotted to V2 if the assessment was done after first IMP intake. 
4.6 
Study Day Numbering 
All assessment dates will be related to the date of first IMP intake. The date of first IMP intake is 
referred to as Day 1. Day –1 is the day preceding Day 1 and Day 0 will not be defined. The numbering 
is such that Day –2 is the day before Day -1, Day 2 is the day after the first IMP intake, etc.  
4.7 
Study Periods for primary and secondary efficacy analysis 
Treatment Period 
The period from Day 1 to Day of last IMP intake will be defined as the treatment period. 
1-month-period! 
The period from Day 1 to Day 30 (Day 30 included) is defined as the 1-month-period. 
3-month-period 
The period from Day 1 to Day 91 (Day 91 included) is defined as the 3-month-period. 
6-month-period 
The period from Day 1 to Day 182 (Day 182 included) is defined as the 6-month-period. 
9-month-period 
The period from Day 1 to Day 273 (Day 273 included) is defined as the 9-month-period. 
12-month-period 
The period from Day 1 to Day 365 (Day 365 included) is defined as the 12-month-period. 
15-month-period 
The period from Day 1 to Day 456 (Day 456 included) is defined as the 15-month-period. 
18-month-period 
The period from Day 1 to Day 547 (Day 547 included) or EOT (scheduled visit) is defined as the 18-
month-period. 
 
4.8 
Baseline and Endpoint Value 
Baseline value 
The baseline value for efficacy variables (BI, PHQ-9) is defined as value collected at visit V1a (within 
120h after stroke). For the NIHSS score the worst value post-stroke until V1b will be defined as 
baseline. 
The baseline value for all other variables is defined as the last non-missing value collected before the 
first IMP intake.  
 
For EEG subgroup, the baseline values and the exploratory analysis will be defined in a separate report.  


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Endpoint value 
The endpoint value for an efficacy variable is defined as the last non-missing value collected after first 
intake of IMP before or at the respective endpoint (within the time window of interest i.e. 6 month-
period, 12 month-period and 18 month-period). 
The endpoint for a safety variable is defined as the last non-missing value collected after first intake of 
IMP that is no baseline value. 
Absolute change from baseline will be calculated as 
ൂ䋛ൂ䋛ൂ䋛ൂ䋛ൂ䋛ൂ䋛ൂ䋛ൂ䋛 ൂ䋻ℎൂ䉼ൂ䉼ൂ䉼ൂ䋛 ൂ䋍ൂ䋍ൂ䋛ൂ䋍 ൂ䋫ൂ䉼ൂ䋛ൂ䋛ൂ䋛ൂ䋫ൂ䉼ൂ䋛 ൂ䉼ൂ䋛 ൂ䈬ൂ䋫ൂ䋛ൂ䋫ൂ䋛 ൂ䉌= ൂ䈬ൂ䉼ൂ䋛ൂ䋛ൂ䋛 ൂ䉼ൂ䋛 ൂ䈬ൂ䋫ൂ䋛ൂ䋫ൂ䋛 ൂ䉌−ൂ䋫ൂ䉼ൂ䋛ൂ䋛ൂ䋛ൂ䋫ൂ䉼ൂ䋛 ൂ䈬ൂ䉼ൂ䋛ൂ䋛ൂ䋛 
Relative change from baseline (%) will be calculated as 
ൂ䋬ൂ䋛ൂ䋛ൂ䉼ൂ䋛ൂ䋫ൂ䋬ൂ䋛 ൂ䋻ℎൂ䉼ൂ䉼ൂ䉼ൂ䋛 ൂ䋍ൂ䋍ൂ䋛ൂ䋍 ൂ䋫ൂ䉼ൂ䋛ൂ䋛ൂ䋛ൂ䋫ൂ䉼ൂ䋛 ൂ䉼ൂ䋛 ൂ䈬ൂ䋫ൂ䋛ൂ䋫ൂ䋛 ൂ䉌= ൂ䈬ൂ䉼ൂ䋛ൂ䋛ൂ䋛 ൂ䉼ൂ䋛 ൂ䈬ൂ䋫ൂ䋛ൂ䋫ൂ䋛 ൂ䉌−ൂ䋫ൂ䉼ൂ䋛ൂ䋛ൂ䋛ൂ䋫ൂ䉼ൂ䋛 ൂ䈬ൂ䉼ൂ䋛ൂ䋛ൂ䋛
ൂ䋫ൂ䉼ൂ䋛ൂ䋛ൂ䋛ൂ䋫ൂ䉼ൂ䋛 ൂ䈬ൂ䉼ൂ䋛ൂ䋛ൂ䋛
× 100 
Note: Patients with a baseline value of ‘0’ will be excluded from the calculation of relative change. 
 
See section 5.4.1  for the definition of first and last IMP intakes. 
4.9 
Coding Systems and Conventions 
4.9.1 
Coding of adverse events and medical history 
Adverse event and medical history investigator terms are assigned to a lowest level term (LLT) and a 
preferred term (PT) and will be classified by high level term (HLT), high level group term (HLGT) and 
system organ class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA), 
in the version as specified in the Data Management Plan (DMP) [2]. 
4.9.2 
Coding of medications 
Medications are classified according to active drug substance using the World Health Organization-
(WHO) drug dictionary WHODrug Global, version as specified in the DMP [3]. The WHO drug code 
has 11 digits. The generic name is defined by the first 6 of the 11 digits. In addition, the Anatomical 
Therapeutic Chemical (ATC) classes are assigned to the drug code. In this study, ATC codes are defined 
to the 4th level. 
4.9.3 Coding of therapies 
Therapies investigator terms are assigned to preferred term (PT) and System Organ Class (SOC) using 
the Medical Dictionary for Regulatory Activities (MedDRA), in the version as specified in the Data 
Management Plan (DMP) [2]. 
 
4.10 Handling of Missing Data 
The analysis of missing data impact on the primary efficacy endpoint is described in the Section 5.5.1.1. 
All other data will be analysed as reported and missing data will not be imputed. 
 


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5. STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY 
5.1 
Patient Disposition 
5.1.1 
Disposition and Withdrawals 
The following disposition data will be collected: 
- 
Did the patient give his/her informed consent? 
• if Yes, date of written informed consent or date of verbal witnessed informed consent  
• if No, reasons for IC absence: 
a) the patient refused to give his/her consent or  
b) the patient died or 
c) the patient did not regain the ability to give consent. 
d) Only applicable for Portugal: a legal representative gave his/her informed 
consent at V1a 
- 
deferred consent date or date of legal representative’s consent (if patient was unable to 
give written or verbal consent at V1a) 
- 
date and time of first IMP intake 
- 
time (h) of first IMP intake after primary stroke 
- 
date of last IMP intake 
- 
date of trial termination 
- 
did the patient complete the 6/ 12/ 18 month period (yes,no) 
- 
did the patient complete the trial as scheduled (yes, no) 
- 
primary reason for premature trial termination, including specification 
 
Screening failures will be all patients who have been enrolled in the trial (i.e. ICF signed by patient, 
by witness in case of verbal consent or by patient´s legal representative or deferral of informed consent 
adequately documented and signed by the investigator), but discontinue the trial prior to randomisation 
at V1b due to whatever reason (withdrawal of consent by patient or legal representative, do not fulfil 
criteria, by decision of investigator, etc.). 
Withdrawals will be all patients who have been enrolled and, for whatever reason, discontinue the trial 
after randomisation at V1b. Patients may be withdrawn from the trial at any time, either on their own 
or upon legal representative request or at the discretion of the investigator.  
The following statistical outputs will be provided: 
Table 15.1.1.1 Analysis Sets – Enrolled Set 
The number and percentage of patients included in the enrolled, randomised, safety, full analysis, per-
protocol and EEG analysis sets will be provided by treatment group and in total. Percentages will be 
based on the number of patients in the enrolled set. Date of first patient first visit and date of last patient 
last visit will be displayed. 
Table 15.1.1.2 Reasons for Exclusions from Analysis Sets – Randomised Set 
The number and percentage of patients excluded from the safety, full analysis and per-protocol sets will 
be provided by treatment group and in total. Percentages will be based on the number of patients in the 
randomised set. The reasons of exclusion from the analysis sets will be incorporated into the table. 
Table 15.1.2 Screening Failures – Enrolled Set 
Counts and percentages of patients who discontinued the study during the screening phase prior to 
randomisation to treatment will be summarised by reasons associated with the discontinuation. 
Percentages will be based on the number of patients in the enrolled set. 
Table 15.1.3 Patient Disposition – Safety Set 
Counts and percentages of patients who completed the 6-month-period, the 12-month-period, the 18-
month-period (= patients who completed the trial as scheduled) and patients who prematurely 


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terminated the trial will be summarised by treatment group and in total. Reasons for discontinuation 
will be included. Percentages will be based on the number of patients in the safety set. 
Table 15.1.4.1.1 Number of Patients by Country and Site – Enrolled Set 
Counts and percentages of patients in each country and site in total. Percentages will be based on the 
number of patients in the enrolled set. 
Table 15.1.4.1.2 Number of Patients by Country and Site – Safety Set 
Counts and percentages of patients in each country and site by treatment group and in total. Percentages 
will be based on the number of patients in the safety set. 
Table 15.1.4.2.1 Number of Patients by Visit – Safety Set 
Counts and percentages of patients attending each scheduled visit will be presented by treatment and in 
total. Percentages will be based on the number of patients in the respective set. 
Figure 15.1.1 Flow Chart of Patient Disposition – Enrolled Set 
The number of patients with the occurrence of each protocol milestone (Enrolment, Randomisation, 
Completion) will be displayed. The number of screening failures and discontinuations as well as their 
reasons will also be summarised. 
Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled Set 
The number of patients in each analysis set will be displayed. 
Listing 16.2.1.1 Patient Disposition – Randomised Set 
The disposition data including the informed consent date and type, first and last IMP intake date, trial 
termination date, if the patient completed the trial as scheduled (yes/no) and reasons for premature 
termination (if applicable) will be listed by treatment group. 
Listing 16.2.1.2 Screening Failures – Enrolled Set 
Patients who discontinued the study prior to the randomisation to treatment will be listed. Informed 
consent data and type, reason in case of informed consent absence and reasons for premature trial 
termination will be displayed. 
Listing 16.2.1.3 Patient Visits – Enrolled Set 
All patient visits and visit dates and the respective study day will be listed by patient. 
Listing 16.2.1.4 Exclusions from Analysis Sets – Randomised Set 
Patients excluded from the safety, full analysis and per-protocol set and corresponding reasons for 
exclusion will be listed. 
Listing 16.2.1.5 Patient Randomisation to Treatments – Randomised Set 
Randomisation numbers and treatment assignments will be listed for all randomised patients. 
5.1.2 
Protocol Deviations 
Protocol deviations are deviations from the procedures outlined in the clinical study protocol or from 
subsequent protocol-related instructions like missed evaluations, incorrect timing of evaluations, non-
compliance with IMP and intake of prohibited medications or any non-adherence to the clinical study 
protocol that impacts patient’s rights, safety or welfare. 
Major protocol deviations will be summarised. Protocol deviations (including COVID-19 pandemic 
related protocol deviations) will be evaluated as major or minor during BDR (See Section 6). 
Patients will be excluded from the PPS for the following reasons:  
• 
No acute intracerebral haemorrhage or acute ischaemic stroke confirmed by Magnetic 
resonance imaging (MRI)/ Computed tomography (CT). 
• 
First administration of IMP was more than 96/120 hours after stroke occurrence respective to 
the protocol version, or since last time seen well. 
• 
Brain scanning has not excluded structural brain lesions that can mimic stroke, e.g. cerebral 
tumor or brain abscess, etc. 


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• 
Use of prohibited medication or treatments 
• 
Other events occur that may have a relevant impact on the efficacy evaluations. Such trial 
conditions, which may or may not represent a protocol deviation or violation, will be identified 
during the data review meeting. 
COVID-19 pandemic related protocol deviations will be taken from Global-PD-Log (PD category 13: 
COVID-19 pandemic). 
The following statistical outputs will be provided: 
Table 15.1.5.1 Major Protocol Deviations – Safety Set 
The number and percentage of patients with major protocol deviations will be summarised by treatment 
group and in total. The categories of major protocol deviations will be included. Percentages will be 
based on the number of patients in the respective analysis set. 
Listing 16.2.1.6.1 Major Protocol Deviations – Safety Set 
Patients with major protocol deviations will be listed by treatment group. 
Listing 16.2.1.6.2 Protocol Deviations related to COVID-19 – Enrolled Set 
Minor and major deviations related to COVID-19 will be listed by patient by treatment group (ESL, 
placebo and Screening Failures). 
5.1.3 
Inclusion/Exclusion 
For each inclusion/exclusion criterion, as appropriate, a response of “Yes/No” is to be obtained at V1a 
and V1b. Inclusion criteria at V2 are checked only for patients who were unable to give informed 
consent at V1a except for Portugal. 
The following statistical output will be provided: 
Listing 16.2.1.7 Inclusion Criteria Not Met and Exclusion Criteria Met – Enrolled Set 
Inclusion criteria which were not met and exclusion criteria which were met will be listed by treatment 
group. 
5.2 
Demographic and Other Baseline Characteristics 
5.2.1 
Demographics 
The following demographic characteristics will be presented: 
• 
Age 
• 
Year of birth 
• 
Gender  
• 
Childbearing potential (yes/no), if patient is female 
• 
Race 
 
The following statistical outputs will be presented: 
Table 15.1.6.1 Demographics – Safety Set 
Table 15.1.6.2 Demographics – Per-Protocol Set 
Demographic data will be summarised for each treatment group and in total in the respective set. Overall 
summary will also be included. Percentage of females of childbearing potential will be based on the 
number of females while all other percentages will be based on the number of patients in the respective 
analysis set. 
Listing 16.2.1.8 Demographics– Enrolled Set 
Demographic data will be listed for patients in the enrolled set. 
5.2.2 
Primary Stroke Characteristics 
Information concerning the primary stroke will be collected: 
• 
mRS 


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• 
total NIHSS (worst score post-stroke until V1b) 
• 
(Total) SeLECT/CAVE score  
• 
Primary stroke and brain imaging details 
• 
For acute ischemic stroke only: Development of a secondary haemorrhage details  
The Modified Rankin Scale (mRS) is a single item, global outcomes rating scale which was designed 
to measure post-stroke recovery. However, in the present trial the scale is used to measure pre-stroke 
disability and confirm patient eligibility. 
Modified Rankin Scale Description 
Grade 
No symptoms at all 
0 
No significant disability despite symptoms; able to carry out all usual duties and activities 
1 
Slight disability; unable to carry out all previous activities, but able to look after own affairs 
without assistance 
2 
Moderate disability; requiring some help, but able to walk without assistance 
3 
Moderately severe disability; unable to walk without assistance, and unable to attend to own 
bodily needs without assistance 
4 
Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 
5 
The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool that provides 
a quantitative measure of stroke-related neurologic deficits (see also section 5.5.2.6 below). The worst 
total NIHSS score post-stroke until V1b will collected.  
To calculate the CAVE score or SeLECT score, brain scanning results (MRI/CT) will be used. The 
assessment will be performed at V2 (V1a in the CTP Final Version 2.0). In case V2 is scheduled earlier 
than 7 days post stroke the assessment of early seizures after stroke will be done at V3.  
For patients included according to the CTP Final Version 2.0 or respective country-specific protocol 
versions, the initial CAVE score and initial SeLECT score were assessed by the investigators at V1a 
(less than 7 days after the primary stroke). Due to the fact that acute seizures can occur within 7 days 
after the primary stroke, the total CAVE score or total SeLECT score after 7 days could theoretically 
be higher than respective scores documented at V1a. It was confirmed (for patients included according 
to the CTP Final Version 2.0 or respective country-specific protocol versions) that no acute seizures 
have occurred after V1a. For patients with ischaemic stroke also the total worst NIHSS score was 
compared to NIHSS documented within the SeLECT score and total scoring was confirmed to be correct 
for all patients. The total CAVE and total SeLECT score are therefore identical to the initial scores for 
all patients and comparable to the scores collected for patients included according to the CTP Final 
Version 3.0 or respective country-specific protocol versions. A manual correction of the total CAVE or 
total SeLECT scores was therefore not applicable.  
The SeLECT score was developed to calculate the patient’s individual risks of having a seizure after 
an acute ischemic stroke. The patient’s individual total SeLECT score will be calculated by adding the 
points associated with each predictor [4]:  


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Predictors of SeLECT Score: 
Category 
Points 
(Se) Severity of stroke 
NIHSS f 3 
0  
 
NIHSS 4 to 10 
1  
 
NIHSS g 11 
2  
(L) Large-artery atherosclerosis 
No 
0  
 
Yes 
1  
(E) Early seizure (f 7 days) 
No 
0  
 
Yes 
3  
(C) Cortical involvement 
No 
0  
 
Yes 
2  
(T) Territory of MCA 
No 
0  
 
Yes 
1  
The CAVE score was developed to calculate the patient’s individual risks of having a seizure after 
intracerebral haemorrhage. To calculate an individual’s CAVE score, the points associated with each 
predictor will be added to obtain the total risk score: [5]. 
Predictors of CAVE Score 
Points 
Cortical involvement of intracerebral haemorrhage 
1  
Age < 65 years 
1  
Volume of intracerebral haemorrhage > 10 mL 
1  
Early seizure within 7 days of intracerebral haemorrhage 
1  
The following details for the primary stroke will be collected: 
- 
Date/time of primary stroke 
- 
Type of primary stroke (acute intracerebral haemorrhagic stroke or acute ischaemic stroke) 
- 
If type is acute intracerebral haemorrhagic stroke: 
o Cortical involvement of intracerebral haemorrhage (yes/no) 
o Age <65 years (yes/no) 
o Volume of intracerebral haemorrhage >10 m (yes/no) 
o Early seizure within 7 days of intracerebral haemorrhage (yes/no) 
o CAVE Score 
- 
If type is acute ischaemic stroke: 
o Severity of stroke (NIHSS f 3, NIHSS 4 to 10, NIHSS g 11) 
o Large-artery atherosclerosis (yes/no) 
o Early seizure (f 7 days) (yes/no) 
o Cortical involvement (yes/no) 
o Territory of middle cerebral artery (MCA) (yes/no) 
o SeLECT Score 
- 
mRS 
The brain imaging (MRI/CT) details include:  
- 
Type of procedure (MRI or CT) 
- 
Date of procedure 
- 
Scan conclusion 
If the type of primary stroke is “acute ischaemic stroke”, the details about the development of a 
secondary haemorrhage will be collected: 
- 
Development of a secondary haemorrhage (yes / no / unknown) 
- 
If yes, then: 
o Date/time identified after primary acute ischaemic stroke 
o Volume of the haemorrhage > 10mL (yes/no) 
o Involvement of the cerebral cortex, even if the origin of the bleeding was in deep 
structures (yes/no) 


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The following statistical outputs will be provided: 
Table 15.1.7.1 Summary of Primary Stroke Characteristics – Safety Set 
Table 15.1.7.2 Summary of Primary Stroke Characteristics – Per-Protocol SetPrimary Stoke 
characteristics will be summarised for the SS, FAS and PPS by treatment group and in total. Counts 
and percentages of patients by the type of stroke (acute ischaemic stroke or acute intracerebral 
haemorrhagic stroke) will be presented. Total SeLECT and total CAVE scores as well as mRS will be 
summarised by means of descriptive statistics. The number of patients that developed a secondary 
haemorrhage will be summarised. 
Listing 16.2.1.9 (Primary) Stroke and Brain Imaging Details – Enrolled Set 
Date, time and type of primary stroke, brain imaging details, worst total NIHSS and mRS will be listed 
for the ES by treatment group. Data about the development of a secondary haemorrhage will be 
included, if applicable. 
Listing 16.2.1.10 SeLECT and CAVE Scores – Enrolled Set 
Total SeLECT and CAVE scores will be listed by treatment group including points for each predictor 
and if a correction was necessary, type of stroke will be indicated for each patient. 
5.2.3 
Medical History 
Medical history encompasses relevant (former 6 month) previous or ongoing relevant diseases, 
conditions, hospitalisation and surgical procedures except the primary stroke. Medical history records 
are collected at V1a. If the patient was unable to give informed consent at V1a, medical history is 
collected at V2. 
A stroke occurring within 7 days after the primary stroke will be considered as re-stroke and 
documented in the medical history if occurred before patient enrolment.  
Medical history of the patients includes: 
- Diagnosis 
- Start date 
- Ongoing (yes/no)  
- Stop date, if applicable 
- Medication taken (at the time of patient’s enrolment)? (yes/no) 
Medical history is classified as: 
- Previous medical conditions are the conditions which started and ended prior to V1a. 
- Ongoing medical conditions are the conditions which are marked as ongoing at V1a or with 
a stop date at or after V1a. 
If the stop date of a medical history condition is incomplete or missing, it will be assumed to be 
ongoing except if the incomplete stop date indicates that the condition stopped prior to the V1a. 
The following statistical output will be provided: 
Table 15.1.8.1.1 Previous Medical Conditions – Safety Set 
Table 15.1.8.2.1 Ongoing Medical Conditions – Safety Set 
Medical history except for the primary stroke will be summarised by treatment group and in total 
displaying counts and percentages of patients having at least one medical condition and will be 
presented by Primary System Organ Class (SOC) and by Preferred Term (PT) within SOC. SOCs and 
PT within SOC are to be sorted by descending order of overall incidence. Patients with two or more 
occurrences of the same condition (as qualified by its PTs) will be counted only once for the respective 
PT. Percentages will be based on the number of patients in the respective analysis set.  
Listing 16.2.1.11 Medical History – Enrolled Set 
Medical history conditions will be listed for patients in the enrolled set by treatment group. 


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5.3 
Previous and Concomitant Medications and Therapies 
The following information is documented about previous and concomitant medications and 
concomitant therapies in the eCRF: 
- Medication / therapy name 
- Indication 
- Total Daily Dose 
- Units 
- Route 
- Frequency 
- Start date of medication/ therapy 
- Ongoing (yes, no) 
- Stop date of medication, if applicable 
Total daily dose, units and route will be collected as NA for concomitant therapies. 
Medications will be classified as ‘previous’, ‘concomitant’ or ‘post’ based on start/stop dates: 
- Previous medications are defined as those medications starting and ending prior to the first 
IMP intake. 
- Concomitant medications are defined as medications started at or after first IMP intake and 
at or before the last IMP intake. It also includes medications that started prior to the first IMP 
intake but continued after the first IMP intake. 
- Post-treatment [subsequent] medications are defined as medications which started after the 
last IMP intake. 
- Therapies related to primary stroke are defined as therapies (preferred terms) that are 
related to the primary stroke according to the indication provided by the investigator (primary 
stroke or related post-stroke rehabilitations). The indications of therapies were manually 
reviewed and evaluated by the Medical Monitor to select “Therapies related to primary 
stroke”. 
 
If the start or stop date of a medication is incomplete or missing, it will be assumed to be concomitant 
except if the incomplete start or stop date indicates that the medication stopped prior to the first IMP 
intake or started after the last IMP intake. 
The following statistical output will be provided: 
Table 15.1.9.1 Previous Medications – Safety Set 
Table 15.1.9.2 Concomitant Medications – Safety Set 
The number and percentage of patients with at least one previous or concomitant medication within 
each ATC 2nd level subgroup and substance name (or combination of substances) will be presented by 
treatment and in total for the respective analysis set. The ATC 2nd level subgroups and substance names 
within ATC 2nd level subgroup will be ordered by descending overall incidence. 
Table 15.1.9.3.1 Therapies Related to Primary Stroke – Safety Set 
Table 15.1.9.3.2 Therapies Related to Primary Stroke – Per-Protocol Set 
The number and percentage of patients with at least one therapy related to indication “primary stroke 
or related post-stroke rehabilitation” will be presented by therapy name (PT) and in total for the 
respective analysis set. The PT will be ordered by descending overall incidence. 
Table 15.1.9.4.1 Concomitant Anti-Epileptic Drugs – Safety Set 
Table 15.1.9.4.2 Concomitant Anti-Epileptic Drugs – Per-Protocol Set 
Number and percentages of patients receiving Anti-epileptic drugs (AEDs) as concomitant therapy will 
be presented by treatment group and in total, including substance name, for the respective set. 


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Listing 16.2.1.12 Medications – Enrolled Set 
All medications, previous, concomitant and post [subsequent], will be listed for patients in the enrolled 
set by treatment group. Anti-epileptic drugs will be marked. 
Listing 16.2.1.13 Therapies – Enrolled Set 
All therapies (all indications) will be listed for patients in the enrolled set by treatment group. 
5.4 
Exposure to IMP and Compliance 
5.4.1 
Exposure to IMP 
IMP will be taken from V1b (Day 1) to Day 30 by all patients. Patients taking once daily one tablet will 
take in addition half a tablet from Day 31 to Day 37. 
At V3, patients will bring back their IMP bottle including all unused tablets and drug accountability 
will be performed. 
Exposure data from eCRF include:  
- 
Date and time of first IMP intake 
- 
Prescribed dose of IMP (mg) 
- 
Prescribed from (date) 
- 
Prescribed until (date) 
- 
This is tampering-off dose (tick) 
- 
Reason for change 
- 
Number of IMP tablets 
- 
Date of last IMP intake 
- 
Total number of IMP tablets patient should have taken according to prescription 
- 
Bottle number of dispensed IMP 
- 
Bottle number of returned IMP 
- 
Number of tablets returned 
- 
Reason of IMP accountability discrepancy. 
The treatment duration (while on treatment) in days will be calculated as follows: 
- 
treatment duration (days) = (date of last IMP intake – date of first IMP intake + 1) – (end 
date of interruption – start date of interruption +1) 
The total dose of IMP taken will be calculated in tablets as follows: 
Total dose (tablets)
=  40 ×  Number of bottles dispensed 3  Total number of IMP tablets returned 
Note: Each IMP bottle is a monthly pack containing 40 tablets. 
The mean daily dose of IMP in mg will be calculated as follows: 
Mean daily dose (mg) = 
Total dose (tablets) × Tablet strength 
Treatment duration (while on treatment) (days)  
Note: Tablet strength for patients who received ESL will be 800 mg. For patients who received placebo 
the mean daily dose will not be available (n.a.). 
The following statistical output will be provided: 
Table 15.1.10.1.1 Exposure to IMP – Safety Set 
Table 15.1.10.1.2 Exposure to IMP – Per-Protocol Set 
The default summary statistics of treatment duration, total dose of IMP (tablets) and the mean daily 
dose (mg) will be presented by treatment group and overall. The prescribed number and percentages of 
tablets will be summarised. The number of patient with a treatment duration f 4 days will be displayed. 


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Listing 16.2.2.1 Exposure to IMP– Safety Set 
Exposure to treatment data will be displayed for each patient in the safety set. 
5.4.2 
Compliance 
Overall treatment compliance will be calculated as: 
ൂ䊼ൂ䋬ൂ䋛ൂ䋍ൂ䉼ൂ䋛ൂ䋛 ൂ䊝ൂ䋛ൂ䋍ൂ䊝ൂ䋛ൂ䋫ൂ䉼ൂ䉼ൂ䊝ൂ䋛 (%) = 
ൂ䊬ൂ䋛ൂ䋍ൂ䋛ൂ䋛ൂ䋍 ൂ䋛ൂ䋍 ൂ䉛ൂ䉛ൂ䉛 ൂ䋛ൂ䉼ൂ䋛ൂ䋛ൂ䋛ൂ䋛ൂ䋛 ൂ䋛ൂ䉼ൂ䊮ൂ䋛ൂ䉼
ൂ䊬ൂ䋛ൂ䋍ൂ䋛ൂ䋛ൂ䋍 ൂ䋛ൂ䋍 ൂ䉛ൂ䉛ൂ䉛 ൂ䋛ൂ䉼ൂ䋛ൂ䋛ൂ䋛ൂ䋛ൂ䋛 ൂ䋛ℎൂ䋛 ൂ䊝ൂ䉼ൂ䋛ൂ䋫ൂ䋛ൂ䉼ൂ䋛 ൂ䋛ℎൂ䋛ൂ䋛ൂ䋛ൂ䉝 ℎൂ䉼ൂ䋬ൂ䋛 ൂ䋛ൂ䉼ൂ䊮ൂ䋛ൂ䉼× 100 
The number of IMP tablets taken and the number of IMP tablets the patient should have taken will be 
collected in eCRF. The “Number of IMP tablets taken” will be calculated by “Dispensed Amount of 
Tablets” – “Returned Amount of Tablets”. 
In case an IMP bottle is not returned, the overall compliance will be considered as missing. 
All patients with a compliance <80% and >120% will be discussed at BDRM. It was decided during 
BDRM that all patients with a treatment duration > 4 days are compliant, as this is the very minimum 
amount of intakes to reach steady state serum level of ESL. Patients with missing compliance were 
discussed at BDRM and compliance was assessed on a case-by-case basis. 
The following statistical output will be provided: 
Table 15.1.10.2.1 Treatment Compliance (%) – Safety Set 
Table 15.1.10.2.2 Treatment Compliance (%) – Per-Protocol Set 
The default summary statistics of compliance will be presented by treatment group and overall. The 
number and percentage of patients within each compliance category (< 80%, g 80% and f 120%, 
>120%) will also be summarised. Percentages will be based on the number of patients in the 
corresponding analysis set. 
Listing 16.2.2.2 Treatment Duration and Compliance– Safety Set 
Treatment duration as well as the total dose of IMP, mean daily dose of IMP, planned total dose of 
IMP and overall compliance will be displayed for each patient in the safety set. 
Listing 16.2.2.3 IMP Accountability– Safety Set 
IMP accountability data will be displayed for each patient in the safety set. 
5.5 
Efficacy Analysis 
5.5.1 
Primary Efficacy Analysis 
The FAS and the PPS will be used for the analysis of the primary efficacy analysis. 
The primary endpoint is the proportion of patients who experience the first US within the first 6 months 
(until Day 182) after randomisation (failure rate). First US within the first 6 month, deaths before the 
first US and patients without evaluable assessment of the primary endpoint will be counted as treatment 
failures. The first occurring event will be used for this analysis e.g. if a patient experiences an US and 
dies later, this patient will be included as a patient with an US. If a patient experienced a re-stroke, the 
patient will be counted as a withdrawal with the date of re-stroke as ‘Date of withdrawal’. 
To show that ESL is different to placebo, the primary null hypothesis  
 
H0: pESL g pplacebo 
will be tested against the alternative hypothesis  
 
H1: pESL < pplacebo 
where pESL and pplacebo denote the proportions of patients with the first US within 6 months after 
randomisation in ESL and placebo patients, respectively. 
The primary hypotheses will be assessed in the FAS by means of a chi-square test with continuity 
correction on the significance level of 5% (two-sided, which corresponds to the significance level of 


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2.5% one-sided). The Odds Ratio for Placebo vs. ESL and the corresponding 95% score CI will be 
provided. The Risk Difference (RD) of failing between Placebo and ESL with corresponding 95% 
continuity-corrected Newcombe Confidence Interval (CI) for the risk difference Placebo – ESL will be 
calculated. Additionally, the p-value of Fisher’s exact test will be provided. 
For this purpose, the following SAS code will be used: 
Note: Data should be sorted by descending treatment group (first “ESL” then “Placebo”) and by 
treatment failures (first “Failure” then “Non-failure”). 
PROC FREQ DATA = <dataset> order=data; 
TABLE <Treatment group> * < Treatment Failure>  
/CHISQ RISKDIFF (CL =Newcombe (Corrected)) OR(CL =SCORE) ALPHA=0.05; 
RUN; 
 
PROC FREQ DATA = <dataset> order=data; 
tables <Treatment group> * < Treatment Failure>/ fisher; 
run; 
The following statistical outputs will be created: 
Table 15.2.1.1.1 Analysis of Treatment Failure Rate within 6 Months after Randomisation – Full 
Analysis Set 
Table 15.2.1.1.2 Analysis of Treatment Failure Rate within 6 Months after Randomisation – Per-
Protocol Set 
Number and percentage of failures (overall, US, death, early withdrawal, missing) and non-failures 
6 months after randomisation will be tabulated, including degrees of freedom (DF), value and p-value 
for chi-square test, p-value for Fisher’s exact test, RD of failing between ESL and Placebo with 
corresponding 95% continuity-corrected Newcombe CI as well as ESL vs. PlaceboOR with 95% score 
confidence interval.  
Listing 16.2.3.1 Seizure Screening Questionnaire – Enrolled Set 
Seizure screening questionnaire data will be listed. 
Listing 16.2.3.2 Seizure Information after the Primary Stroke Occurrence – Enrolled Set 
Seizure information after the primary stroke occurrence will be listed. 
5.5.1.1 
Sensitivity Analyses 
For the primary analysis, patients withdrawing early during the trial will be considered as non-seizure 
free (treatment failure). This replacement strategy is defined under the assumption that it cannot be 
excluded that “missingness” is related to treatment failure and thus not at random. In order to assess the 
effect of missing data, the following sensitivity analyses will be performed:  
The primary analysis will be repeated by imputing the missing values (patient withdrew from study 
before primary endpoint was reached) in both groups (ESL and Placebo) multiple times assuming the 
rate of treatment failures among the missing data follows the observed rate of treatment failures in the 
placebo group. 
The following SAS code will be used: 
Note: Treatment Failure will be 1 if a patient had an US or died, 0 if not and ‘.’ if the data is missing 
(patient withdrew). A dummy baseline variable that consists only 0 will be created. Treatment group 
will be 1, if the patient received ESL and 2 if the patient received placebo. n will be the number of 
patients that experienced at least one US until 6 months. 
proc mi data=<data> seed=14823 nimpute=&n. out=<out> noprint; 
 
class <Treatment group> <Treatment Failure>; 
 
var <Baseline Dummy> <Treatment Failure>; 
 
monotone logistic(<Treatment Failure> /detail); 
 
mnar model(<Treatment Failure> / modelobs=(trt='2')); 
 
run; 


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The chi-square test as described in 5.5.1 will be applied to each of the imputed datasets. The results will 
be pooled by Rubin’s rule. For the Odds Ratio, the logarithm will be applied before pooling and 
afterwards the exponential function will be applied: 
 
DATA lgsodds_t;  
SET < DATA ODDS>; 
log_or_lr_value=LOG(ODDSRATIO); 
log_or_lr_se=(LOG(UPPERCL)-LOG(LOWERCL))/(2*1.96); 
RUN; 
*** Combine transformed estimates; 
PROC MIANALYZE DATA=lgsodds_t; 
 
ODS OUTPUT PARAMETERESTIMATES=mian_lgsodds_t; 
 
MODELEFFECTS log_or_lr_value; 
 
STDERR log_or_lr_se; 
RUN; 
*** Back-transform combined values; 
DATA mian_lgsodds_bt; SET mian_lgsodds_t; 
Estimate_back = EXP(ESTIMATE); *Pooled odds ratio; 
LCL_back=Estimate_back*EXP(-1.96*STDERR); *Pooled lower limit; 
UCL_back=Estimate_back*EXP(+1.96*STDERR); *Pooled upper limit; 
RUN; 
 
A tipping point analysis based on multiple imputation relating the outcome of the primary efficacy 
analysis to the assumed rate of treatment failure among missing data under ESL and placebo, 
respectively, will be performed. In the primary analysis, patients with missing data will be classified as 
‘treatment failure’. By contrast, the tipping point analysis proceeds as follows: Assuming there will be 
ൂ䊬= 1, … , ൂ䉼 missing values for patients in the treatment group and ൂ䉛= 1, … , ൂ䋍 missing values for the 
patients in the placebo group. ൂ䊬∗ൂ䉛 datasets will be created, one for each possible combination of 
imputation for the missing values (‘treatment failure’ or ‘treatment success’). 
The chi-square test presented in the primary analysis 5.5.1 will be conducted for each of the datasets. 
Results will be tabulated and p-values will be presented via a heatmap where significant and non-
significant p-values will be differently colored. . 
 
Another sensitivity analysis will be conducted based on observed Unprovoked Seizures only as Failure 
Rate. Death, Withdrawals or patients with missing  data will not be counted as a Failure but as a Non-
Failure. The primary efficacy analysis will be repeated for this scenario. 
 
The following statistical outputs will be presented: 
Table 15.2.1.3.1 Sensitivity Analysis of Treatment Failure Rate within 6 Months after Randomisation 
Using Multiple Imputation for Missing Data – Full Analysis Set 
Table 15.2.1.3.2 Sensitivity Analysis of Treatment Failure Rate within 6 Months after Randomisation 
Using Multiple Imputation for Missing Data – Per-Protocol Set 
Degrees of freedom (DF), value and p-value for chi-square test, RD of failing between ESL and Placebo 
with corresponding 95% continuity-corrected Newcombe CI as well as ESL vs Placebo OR with 95% 
score confidence interval for the multiple imputed datasets that are combined by Rubin’s Rule will be 
presented. 


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Table 15.2.1.4.1 Tipping Point Analysis of Treatment Failure Rate within 6 Months after 
Randomisation – Full Analysis Set 
Table 15.2.1.4.2 Tipping Point Analysis of Treatment Failure Rate within 6 Months after 
Randomisation – Per-Protocol Set 
Degrees of freedom (DF), value and p-value for chi-square test, RD of failing between ESL and Placebo 
with corresponding 95% continuity-corrected Newcombe CI as well as ESL vs Placebo OR with 95% 
score confidence interval will be presented for all possible combinations of imputed non-failures in ESL 
and Placebo arm. 
 
Table 15.2.1.5.1 Sensitivity Analysis of Unprovoked Seizures within 6 Months after Randomisation– 
Full Analysis Set 
Table 15.2.1.5.2 Sensitivity Analysis of Unprovoked Seizures within 6 Months after Randomisation– 
Per-Protocol Set 
Table 15.2.1.5.3 Sensitivity Analysis of Unprovoked Seizures within 12 Months after Randomisation – 
Full Analysis Set 
Table 15.2.1.5.4 Sensitivity Analysis of Unprovoked Seizures within 12 Months after Randomisation – 
Per-Protocol Set 
Table 15.2.1.5.5 Sensitivity Analysis of Unprovoked Seizures within 18 Months after Randomisation – 
Full Analysis Set 
Table 15.2.1.5.6 Sensitivity Analysis of Unprovoked Seizures within 18 Months after Randomisation – 
Per-Protocol Set 
Table 15.2.1.5.7 Sensitivity Analysis of Unprovoked Seizures within 18 Months after Randomisation 
(Subgroup 1) – Full Analysis Set 
Table 15.2.1.5.8 Sensitivity Analysis of Unprovoked Seizures within 18 Months after Randomisation 
(Subgroup 2) – Full Analysis Set 
Number and percentage of unprovoked seizures and non-failures 6, 12 or 18 months after randomisation 
will be tabulated, including degrees of freedom (DF), value and p-value for chi-square test, p-value for 
Fisher’s exact test, RD of failing between ESL and Placebo with corresponding 95% continuity-
corrected Newcombe CI as well as ESL vs Placebo OR with 95% score confidence interval.  
 
Figure 15.2.1.1.1 Tipping Point Analysis of Treatment Failure Rate within 6 Months after 
Randomisation – Full Analysis Set 
Figure 15.2.1.1.2 Tipping Point Analysis of Treatment Failure Rate within 6 Months after 
Randomisation – Per-Protocol Set 
Results (p-values) of the tipping point analysis will be presented via heatmap. 
 
5.5.2 
Analysis of Secondary Efficacy Variables  
The FAS and the PPS will be used for the analysis of secondary efficacy variables. 
All data will be analysed as reported and missing data will not be imputed. 
5.5.2.1 
Twelve- and Eighteen-Month Failure Rates  
The same approach employed for the primary analysis will be used for the analyses of the twelve-month 
failure rate (until Day 365) and the eighteen-month failure rate (until Day 547 or scheduled EoT). 
The following statistical outputs will be presented: 


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Table 15.2.2.1 Analysis of Treatment Failure Rate within 12 Months after Randomisation – Full 
Analysis Set 
Table 15.2.2.2 Analysis of Treatment Failure Rate within 12 Months after Randomisation – Per-
Protocol Set 
Table 15.2.3.1 Analysis of Treatment Failure Rate within 18 Months after Randomisation – Full 
Analysis Set 
Table 15.2.3.2 Analysis of Treatment Failure Rate within 18 Months after Randomisation – Per-
Protocol Set 
Number and percentage of failures (overall, US, death, early withdrawal, missing) and non-failures 12 
or 18 months after randomisation will be tabulated, including degrees of freedom (DF), value and p-
value for chi-square test, p-value for fisher’s exact test, RD of failing between ESL and Placebo with 
corresponding 95% continuity-corrected Newcombe CI as well as ESL vs Placebo OR with 95% score 
confidence interval.  
 
5.5.2.2 
Number of Acute Symptomatic Seizures 
The number of patients that experience at least one AS will be analysed. 
The following statistical outputs will be created: 
Table 15.2.4.1 Summary of Acute Symptomatic Seizures – Full Analysis Set 
Table 15.2.4.2 Summary of Acute Symptomatic Seizures – Per-Protocol Set 
The number of ASs will be summarised by means of descriptive statistics for patients with at least one 
AS (FAS and PPS) by treatment group and in total. The number and percentage of patients without and 
with AS(s) will be incorporated into the table. 
5.5.2.3 
Time to First Unprovoked Seizure after Randomisation 
For the following analyses, patients will be censored at their last day in the trial. 
The time to first US after randomisation will be analysed and presented by means of the Kaplan-Meier 
estimate (including censored data e.g. withdrawals) after 6, 12 and 18 months for the failure time and 
corresponding simultaneous CI, a log-rank test (p-value) as well as estimates for 25% percentile, 
median, and 75% percentile failure time and corresponding CI. The time to first US will be analysed 
from the day of randomisation.  
For this purpose, the following SAS code will be used: 
ODS OUTPUT Quartiles=quartiles; 
ODS OUTPUT ProductLimitEstimates=limit; 
ODS OUTPUT HomTests= tests; 
PROC LIFETEST DATA=<dataset> METHOD=KM CONFBAND=EP TIMELIST= 182 365 547; 
TIME <Time to first US>*<Status> (0); 
STRATA <Treatment group> /TEST=LOGRANK; 
RUN; 
The Kaplan-Meier product limit estimate and simultaneous equal precision 95% confidence bands will 
be graphed.  
In case of deaths before the first US, the competing risk of deaths and US will be evaluated exploratively 
using cause-specific cumulative incidence function and Gray’s test for homogeneity in addition.  
The following SAS code will be used: 
Note: the status will be 0 for censored observations, 1 if US occurred and 2 if the patient died before 
experiencing an US. 
ODS OUTPUT GrayTest= graytest; 


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PROC LIFETEST DATA=<dataset>; 
TIME <Time to first US or death>*<Status> (0) /eventcode=1; 
STRATA <Treatment group> / order=internal; 
RUN; 
 
The following statistical outputs will be presented: 
Table 15.2.5.1.1 Time to First Unprovoked Seizure after Randomisation– Full Analysis Set 
Table 15.2.5.1.2 Time to First Unprovoked Seizure after Randomisation – Per-Protocol Set 
The time to first US after randomisation will be presented by estimates for 25% percentile, median, and 
75% percentile failure time and corresponding CI; means of the Kaplan-Meier estimate after 6, 12 and 
18 months for the failure time and corresponding simultaneous CI (equal precision bands) and the p-
value of a log-rank test  
Figure 15.2.1.2.1 Time to First Unprovoked Seizure after Randomisation – Full Analysis Set 
Figure 15.2.1.2.2 Time to First Unprovoked Seizure after Randomisation – Per-Protocol Set 
The Kaplan Meier Product Limit Estimate and simultaneous equal precision 95% confidence bands will 
be presented for the treatment groups. 
5.5.2.4 
Number of Unprovoked Seizure  
The total number in all patients and in patients with US(s) only will be summarised by means of 
descriptive statistics.  
The following statistical output will be presented: 
Table 15.2.5.4.1 Summary of Unprovoked Seizures– Full Analysis Set 
Table 15.2.5.4.2 Summary of Unprovoked Seizures – Per-Protocol Set 
Number and percentage of patients with and without US(s) will be presented. The total number of USs  
will be summarised by means of descriptive statistics for all patients and for patients that experienced 
US(s). 
5.5.2.5 
Barthel Index 
BI data is collected at V1a, V3, V5, V7 and EOT or EDV and, if applicable, UNS. 
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) 
Items are weighted according to the level of nursing care required and are rated in terms of whether 
individuals can perform activities independently, with some assistance, or are dependent (scored as 0, 
5, 10 or 15). 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 


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40-59 – partially dependent 
20-39 – very dependent 
<20 – total dependence. 
The BI can be used to determine a baseline level of function and to monitor improvements in activities 
of daily living over time [4]. 
The BI total score at baseline and post-baseline visits of each patient will be calculated adding the 
individual scores from each item.  
The BI total score and its change from baseline at each time of examination will be summarised by 
means of descriptive statistics. Differences between the treatment groups (ESL-Placebo) will be 
evaluated exploratively using multiple exact Wilcoxon-Mann-Whitney Test and exact Hodge-Lehmann 
CIs at each time of examination.  
The following SAS Code will be used: 
Note: Data should be sorted by treatment group (first “ESL” then “Placebo”)  
proc npar1way hl correct=no alpha=.05 data=<dataset>; 
   class <treatment_group>; 
   var <change from baseline of BI_total_score at specific timepoint>; 
   exact wilcoxon; 
   exact hl; 
   ods select WilcoxonScores WilcoxonTest HodgesLehmann; 
run; 
If this SAS code runs for more than 10 minutes, maxtime=50 will be used and the normal approximate 
result will be tabulated. A higher maxtime does not lead to a change of the result. 
Cumulative incidence of USs will be illustrated using Kaplan-Meier curves by the BI Baseline 
categories (<=79, 80-100) and treatment group. Patients without an event or lost to follow-up will be 
censored at their last visit or termination date. Time to event will be calculated from time of 
randomisation to first US. 
The following statistical outputs will be presented: 
Table 15.2.6.1.1 Summary of Barthel Index Total Score – Full Analysis Set 
Table 15.2.6.1.2 Summary of Barthel Index Total Score – Per-Protocol Set 
The default summary statistics for the BI total score will be presented by visit slots by treatment group 
at Baseline, V3, V5, V7, EOT, EDV (if applicable) and Endpoint.  
Table 15.2.6.2.1 Analysis of Barthel Index Total Score Differences – Full Analysis Set 
Table 15.2.6.2.2 Analysis of Barthel Index Total Score Differences – Per-Protocol Set 
The Hodges-Lehmann estimate of location shift and the corresponding 95% CIs including the Wilcoxon 
Mann Whitney test p-value will be presented by visit slots for V3, V5, V7 and Endpoint for ESL-
Placebo. 
Figure 15.2.2.1 Cumulative Incidence Curves of Unprovoked Seizures using Kaplan-Meier Curves by 
Barthel Index Total Score – Full Analysis Set 
Figure 15.2.2.2 Cumulative Incidence Curves of Unprovoked Seizures using Kaplan-Meier Curves by 
Barthel Index Total Score – Per-Protocol Set 
Cumulative incidence curves of USs using Kaplan-Meier curves displayed by time of randomisation 
and treatment group for each category of the BI total score. 
Listing 16.2.3.3 Barthel Index – Enrolled Set 
The BI items and total score data will be listed by treatment group. 
5.5.2.6 
National Institutes of Health Stroke Scale 
NIHSS data is collected at V1a (the worst total NIHSS score post-stroke until V1b is collected), V2, 
V3, V5, V7 and EOT or EDV and, if applicable, UNS. 


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The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related 
neurologic deficits. The stroke scale is valid for predicting lesion size and can serve as a measure of 
stroke severity. A trained investigator or a qualified delegate will record the patient’s ability to answer 
questions and perform activities on the level of consciousness, extraocular movement, visual fields, 
facial muscle function, extremity strength, sensory function, coordination (ataxia), language (aphasia), 
speech (dysarthria), and hemi-inattention (neglect). 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” [5]. 
Stroke severity will be stratified based on NIHSS total score as follows: 
<11 – mild and moderately severe 
g11 – severe. 
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) 
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 NIHSS score and its change from baseline at each time of examination will be summarised by 
means of descriptive statistics. Differences between the treatment groups (ESL-Placebo) will be 
evaluated exploratively using the Wilcoxon-Mann-Whitney Test and exact Hodge-Lehmann CIs at each 
time of examination (if the SAS code runs for more than 10 minutes, maxtime=50 will be used and the 
approximate result will be tabulated. A higher maxtime does not lead to a change of the result). 
Cumulative incidence of USs will be illustrated using Kaplan-Meier curves by the NIHSS baseline 
categories (<11, g11) and treatment group. Patients without an event or lost to follow-up will be 
censored at their last visit or termination date. Time to event will be calculated from time of examination 
since randomisation to first US. 
 
The following statistical outputs will be presented: 
Table 15.2.7.1.1 Summary of NIHSS Total Score – Full Analysis Set 
Table 15.2.7.1.2 Summary of NIHSS Total Score – Per-Protocol Set 
The default summary statistics for the NIHSS total score will be presented by treatment group by visit 
slots at Baseline, V2, V3, V5, V7, EOT, EDV (if applicable) and Endpoint.  
Table 15.2.7.2.1 Analysis of NIHSS Total Score Differences – Full Analysis Set 
Table 15.2.7.2.2 Analysis of NIHSS Total Score Differences – Per-Protocol Set 
The Hodges-Lehmann estimate of location shift and the corresponding 95% CIs including the p-value 
will be presented by visit slots for V3, V5, V7 and Endpoint for ESL-Placebo. 


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Figure 15.2.3.1 Cumulative Incidence Curves of  Unprovoked Seizures using Kaplan-Meier Curves by 
NIHSS Total Score – Full Analysis Set 
Figure 15.2.3.2 Cumulative Incidence Curves of  Unprovoked Seizures using Kaplan-Meier Curves by 
NIHSS Total Score – Per-Protocol Set 
Cumulative incidence curves of USs using Kaplan-Meier curves displayed by time after randomisation 
and treatment group for each category of the NIHSS total score. 
Listing 16.2.3.4 National Institutes of Health Stroke Scale (NIHSS) – Enrolled Set 
The NIHSS items and total score data will be listed by treatment group. 
5.5.2.7 
Patient Health Questionnaire 
The PHQ-9 will be collected at V1a, V3, V5, V7 and EOT or EDV and, if applicable, UNS. 
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. With question 9, the presence and duration of suicide 
ideation will be screened [6]. 
The PHQ-9 consists of the following questions: 
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 PHQ-9 total score will be categorised as follows:  
f4 – minimal depression 
>4 – mild to severe depression 
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 PHQ-9 score and its change from baseline will be summarised by means 
of descriptive statistics and differences between the treatment groups (ESL-Placebo) will be evaluated 
exploratively using the Wilcoxon-Mann-Whitney Test and exact Hodge-Lehmann Cis (if the SAS code 
runs for more than 10 minutes, maxtime=50 will be used and the approximate result will be tabulated. 
A higher maxtime does not lead to a change of the result).  
Cumulative incidence curves of USs vs. the PHQ-9 score (f4, >4) will be displayed graphically by time 
after randomisation and treatment group.  
PHQ-9 question 9 (related to suicidal ideation) will also be evaluated for the safety set.  
 
The following statistical outputs will be presented: 


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Table 15.2.8.1.1 Summary of PHQ-9 Total Score – Full Analysis Set  
Table 15.2.8.1.2 Summary of PHQ-9 Total Score – Per Protocol Set  
The default summary statistics for the PHQ-9 total score will be presented by visit slots by treatment 
group at Baseline, V3, V5, V7, EOT, EDV (if applicable) and Endpoint.  
Table 15.2.8.2 Summary of PHQ-9 Question 9 Score – Safety Set  
The default summary statistics for the PHQ-9 Question 9 score will be presented by visit slots by 
treatment group at Baseline, V3, V5, V7, EOT, EDV (if applicable) and Endpoint.  
Table 15.2.8.3.1 Analysis of PHQ-9 Total Score Differences – Full Analysis Set 
Table 15.2.8.3.2 Analysis of PHQ-9 Total Score Differences – Per-Protocol Set 
The Hodges-Lehmann estimate of location shift and the corresponding 95% CIs including the p-value 
will be presented by visit slots for V3, V5, V7 and Endpoint for ESL-Placebo. 
Figure 15.2.4.1 Cumulative Incidence Curves of Unprovoked Seizures using Kaplan-Meier Curves by 
PHQ-9 Total Score – Full Analysis Set 
Figure 15.2.4.2 Cumulative Incidence Curves of Unprovoked Seizures using Kaplan-Meier Curves by 
PHQ-9 Total Score – Per-Protocol Set 
Cumulative incidence curves of USs using Kaplan-Meier curves displayed by time after randomisation 
and treatment group for each category of the PHQ-9 total score. 
Listing 16.2.3.5 Patient Health Questionnaire (PHQ-9)– Enrolled Set 
The PHQ-9 items and total score data will be listed by treatment group. 
5.5.2.8 
Overall Survival 
Overall survival (time to death relative to the date of randomisation) 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 including pointwise 
CI, log-rank test as well as estimates for 25% percentile, median, and 75% percentile survival time and 
corresponding CI. 
For this purpose, the following SAS code will be used: 
ODS OUTPUT Quartiles=quartiles; 
ODS OUTPUT ProductLimitEstimates=limit; 
ODS OUTPUT HomTests= tests; 
PROC LIFETEST DATA=<dataset> METHOD=KM TIMELIST= 182 365 547; 
TIME <Time to death>*<Status> (0); 
STRATA <Treatment group> /TEST=LOGRANK; 
RUN; 
Kaplan-Meier plot for overall survival will be presented. 
The following statistical outputs will be presented: 
Table 15.2.9.1 Overall Survival – Full Analysis Set  
Table 15.2.9.2 Overall Survival – Per Protocol Set  
Number and percentage of patients who died and patients censored will be tabulated. The time to death 
in days will be presented by estimates for 25% percentile, median, and 75% percentile and 
corresponding CI; means of the Kaplan-Meier estimate after 6, 12 and 18 months for the time to death 
and corresponding pointwise CI and the p-value of a log-rank test will be presented. 
Figure 15.2.5.1 Overall Survival – Full Analysis Set  
Figure 15.2.5.2 Overall Survival – Per Protocol Set  
The Kaplan-Meier Product Limit Estimate and simultaneous equal precision 95%-Confidence bounds 
will be presented. 
5.6 
Safety Analysis 
Safety will be assessed by evaluation of the following variables: 
- TEAEs incl. findings from physical and neurological examinations 


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- Laboratory parameters (haematology and biochemistry, including eGFR and coagulation, 
urinalysis) 
- Vital signs 
- ECG 
- Suicidal ideation and behaviour (as per PHQ-9, question 9) 
The safety set will be used for the analysis of safety data. 
5.6.1 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA®) 
Version as defined in the Data Management Plan. 
Adverse event data includes: 
- adverse event name 
- start date and time 
- ongoing? (yes/no) 
- stop date and time, if applicable 
- severity (mild, moderate, severe) 
- frequency (single event, intermittent, continuous) 
- causal relationship to IMP (not related, unlikely, possible, probable, definite) 
- action taken with IMP (dose increased, dose not changed, dose reduced, drug interrupted, 
drug withdrawn, unknown, not applicable) 
- other action taken (none, medication required, tests required, hospitalisation required or 
prolonged, withdrawn from the trial, other, including specification) 
- outcome (recovered/resolved, recovering/resolving, not recovered/not resolved, 
recovered/resolved with sequelae, fatal, unknown) 
- seriousness (yes/no) 
All AEs will be presented in listings. 
Summaries of adverse events will include AEs defined as treatment-emergent adverse events 
(TEAEs), defined as AEs with the first onset or worsening after the first IMP intake until 14 days after 
the last IMP intake. AEs not considered treatment-emergent according to this definition or with missing 
data will be medically reviewed during the blind data review meeting and will be considered treatment-
emergent if appropriate.  
If the relationship to IMP is missing, the event will be classified as unrelated, if it started before first 
IMP intake. In all other cases it will be assumed to be possibly related. 
If the start date of an AE is incomplete or missing, it will be assumed to be treatment-emergent except 
if the incomplete start date or the stop date indicates that the event started prior to the first IMP intake 
or later than 14 days after last IMP intake. 
Adverse events will be further assigned to the following categories: 
- Serious Adverse Events (SAEs): defined as AEs considered by the investigator as serious, 
including AEs with an unknown or missing seriousness assessment. 
- Related TEAEs: TEAEs with a causal relationship to IMP assessed as “possible” or 
“probable” and “definite”, including events with missing IMP relationship assessment. 
- Unrelated TEAEs: TEAEs with a causal relationship to IMP assessed as “not related” or 
“unlikely”. 
- Severe TEAEs: TEAEs assessed as “severe” in severity, including events with missing 
severity assessments. 
- TEAEs leading to discontinuation of IMP: TEAEs for which “action taken with study 
medication” is indicated as “drug withdrawn”. 


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- TEAEs leading to dose reduction: TEAEs for which “action taken with IMP” is indicated as 
“dose reduced”  
- TEAEs requiring medication: TEAEs for which “action taken with study medication” is 
indicated as “medication required”. 
- TEAEs leading to death: TEAEs documented as having a “fatal” outcome. 
- Ongoing TEAEs at the end of the trial: TEAEs documented without an end date of the 
TEAE. 
The duration of the AE will be calculated from the start date (or onset) to the AE stop date. If the start 
or stop dates of the AE are incomplete or AE is still ongoing at the end of the study, duration of AE will 
not be calculated.  
The following statistical output will be provided:  
Table 15.3.1.1 Overall Summary of TEAEs – Safety Set 
An overview of TEAEs:  
- TEAEs 
- Non-serious TEAEs 
- Serious TEAEs 
- Related TEAEs 
- Related Serious TEAEs 
- Severe TEAEs 
- TEAEs leading to discontinuation of IMP 
- TEAEs leading to dose reduction 
- TEAEs requiring medication 
- TEAEs leading to death  
- Ongoing TEAEs at the end of the trial 
will be displayed by treatment group and in total for the patients in the safety set. 
Table 15.3.1.2.1 Incidence of TEAEs – Safety Set 
Table 15.3.1.2.2 Incidence of Non-Serious TEAEs – Safety Set 
Table 15.3.1.2.3 Incidence of Serious TEAEs – Safety Set 
Table 15.3.1.2.4 Incidence of Related TEAEs – Safety Set 
Table 15.3.1.2.5 Incidence of Related Serious TEAEs – Safety Set 
Table 15.3.1.2.6 Incidence of TEAEs Leading to Discontinuation of IMP – Safety Set 
Table 15.3.1.2.7 Incidence of TEAEs Leading to Dose Reduction – Safety Set 
Table 15.3.1.2.8 Incidence of TEAEs Requiring Medication– Safety Set 
Table 15.3.1.2.9 Incidence of TEAEs Leading to Death – Safety Set 
TEAEs will be summarised by treatment group and in total by displaying the numbers of adverse events, 
as well as counts and percentages of patients having experienced adverse events. Percentages will be 
based on the number of patients in the safety set. SOCs and PTs within each SOC will be ordered by 
descending number of adverse events in the total column.  
Table 15.3.1.3.1 Incidence of TEAEs by Maximum Severity – Safety Set 
Table 15.3.1.3.2 Incidence of Related TEAEs by Maximum Severity – Safety Set 
Table 15.3.1.3.3 Incidence of Serious TEAEs by Maximum Severity – Safety Set 
TEAEs will be summarised as above within each severity category (mild, moderate, severe). 


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Table 15.3.1.4.1 Incidence of Preferred Term: TEAEs– Safety Set 
Table 15.3.1.4.2 Incidence of Preferred Term: Serious TEAEs – Safety Set 
Table 15.3.1.4.3 Incidence of Preferred Term: Related TEAEs – Safety Set 
Table 15.3.1.4.4 Incidence of Preferred Term: Serious Related TEAEs – Safety Set 
Table 15.3.1.4.5 Incidence of Preferred Term: TEAEs Leading to Discontinuation of IMP – Safety Set 
Table 15.3.1.4.6 Incidence of Preferred Term: Most Frequent (g 2% of patients in any treatment group) 
TEAEs  – Safety Set 
Frequency counts and percentages of PTs will be summarised for each treatment group and in total. 
Percentages will be based on the overall number of PTs in the safety set. PTs will be ordered by 
descending percentages in the total column. 
Listing 16.2.4.1.1 Adverse Events: MedDRA Coding 
MedDRA system organ class and preferred terms assigned to each reported AE name will be displayed. 
Listing 16.2.4.2.1 Serious Adverse Events – Enrolled Set 
Listing 16.2.4.2.2 AEs Leading to Discontinuation of IMP – Safety Set 
Listing 16.2.4.2.3 AEs Leading to Death – Enrolled Set 
All AEs will be displayed by patient including the PT of an AE, start and stop dates, date of last IMP 
intake and other characteristics of AEs.  
5.6.2 
Clinical Laboratory Evaluation 
Clinical laboratory values (haematology, biochemistry, including eGRF and coagulation, urinalysis) are 
collected at V1a, V2. V3, EDV (if EDV performed before V3) and, if applicable, UNS for each 
laboratory parameter. Thyroid function will be assessed at V1a. 
A serum pregnancy test at V1a and urine pregnancy tests at V1a, V2, V3, EDV (if EDV performed 
before V3) and, if applicable, UNS will be performed for all females of childbearing potential. 
The following parameters are collected: 
Haematology: Haemoglobin, haematocrit, red blood cell (RBC) count, white blood cell (WBC) count, 
differential - neutrophils, eosinophils, lymphocytes, monocytes and basophils, and platelet count. 
Biochemistry: Sodium, 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 lipoprotein-cholesterol, high-
density lipoprotein-cholesterol, triglycerides, and total bilirubin (bilirubin will be fractionated 
direct/indirect if elevated). 
Sodium levels will be monitored for signs of hyponatraemia. Patients will be classified by their 
minimum post-baseline sodium level according to the following categories: 
 
g 135 mEq/L 
 
130 - < 135 mEq/L 
 
125 - < 130 mEq/L 
 
< 125 mEq/L 
and for any decrease from baseline > 10 mEq/L.  
eGFR will be estimated based on serum creatinine value (see CTP 11.4.3). 
Coagulation: INR and activated partial thromboplastin time (aPTT). 
Thyroid function (at V1a only): total triiodothyronin, free triiodothyronine, total thyroxine, free 
thyroxine, thyroid stimulating hormone. 
Serum pregnancy test (at V1a only): β-hCG in females of childbearing potential. 
Urinalysis:  


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• 
local: pH, specific gravity, protein, blood, glucose, ketones, bilirubin, urobilinogen, leukocytes, 
nitrite (local dipstick). Microscopy and other appropriate tests (as needed) will be performed if 
dipstick indicates any significant abnormality. 
• 
central: U-Casts, U-Crystals, U-Epithelials, U-Erythrocytes quan., U-Leucocytes quan., U-
Others. 
Urine pregnancy tests: in females of childbearing potential. 
All laboratory values will be classified as normal or abnormal according to the laboratories’ normal 
ranges and as clinically significant (yes/no) according to the assessment of the investigator. 
The following statistical outputs will be provided:  
Table 15.3.2.1.1 Summary of Clinical Laboratory Tests: Haematology – Safety Set 
Table 15.3.2.1.2 Summary of Clinical Laboratory Tests: Biochemistry – Safety Set 
Table 15.3.2.1.3 Summary of Clinical Laboratory Tests: Coagulation – Safety Set 
The default summary statistics of clinical laboratory test results for haematology, biochemistry 
(including eGRF) and coagulation will be presented by treatment group and in total by visit slots (if 
applicable) at V1, baseline, V3, EDV (if applicable) and Endpoint. The absolute change from baseline 
will be presented as well.  
Table 15.3.2.2.1 Clinical Laboratory Tests: Incidence of Haematology Abnormalities – Safety Set 
Table 15.3.2.2.2 Clinical Laboratory Tests: Incidence of Biochemistry Abnormalities – Safety Set 
Table 15.3.2.2.3 Clinical Laboratory Tests: Incidence of Coagulation Abnormalities – Safety Set 
The number and percentage of patients with Low, CS Low, Normal, High, and CS High categories of 
each laboratory parameter will be displayed by treatment group and in total. Percentages will be based 
on the number of patients at the specified visit slot. 
Table 15.3.2.3.1 Clinical Laboratory Tests: Shift Table of Haematology Results from Baseline to 
Endpoint – Safety Set 
Table 15.3.2.3.2 Clinical Laboratory Tests: Shift Table of Biochemistry Results to Endpoint– Safety 
Set 
Table 15.3.2.3.3 Clinical Laboratory Tests: Shift Table of Coagulation Results to Endpoint – Safety Set 
Shift tables showing changes in the number and frequency of patients with respect to the normal range 
and clinical significance between baseline and endpoint by treatment will be provided. Patients with 
missing data will be presented as part of a “missing” category. 
Table 15.3.2.4.1 Clinical Laboratory Tests: Shift Table of Haematology Results from Baseline to Worst 
Post Baseline Value – Safety Set 
Table 15.3.2.4.2 Clinical Laboratory Tests: Shift Table of Biochemistry Results from Baseline to Worst 
Post Baseline Value – Safety Set 
Table 15.3.2.4.3 Clinical Laboratory Tests: Shift Table of Coagulation Results from Baseline to Worst 
Post Baseline Value – Safety Set 
Shift tables showing changes in the number and frequency of patients with respect to the normal range 
and clinical significance between baseline and the worst-post-baseline-value by treatment will be 
provided. Patients with missing data will be presented as part of a “missing” category. 
Table 15.3.2.5.1 Clinical Laboratory Tests: Incidence Clinically Significant Urinalysis Results (Local 
Dipstick) – Safety Set 
Clinically significant values of urinalysis parameters (collected using local dipstick) will be summarised 
by visit using default frequency tabulation by treatment group and in total. The number of patients with 
any CS abnormalities will be summarised. Visit Slots will be used. 
Table 15.3.2.5.2 Clinical Laboratory Tests: Incidence of Urinalysis Results (Central Laboratory) – 
Safety Set 
Clinically significant values of urinalysis parameters (provided by central laboratory) will be 
summarised by visit using default frequency tabulation by treatment group and in total. The number of 
patients with any CS abnormalities will be summarised. Visit Slots will be used. 


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Table 15.3.2.6 Signs of Hyponatraemia – Safety Set 
Number and frequency of patients will be presented by sodium level categories and by visit. This table 
will be provided by treatment group and in total. Visit Slots will be used. 
Listing 16.2.4.3.1 Laboratory Data – Haematology – Enrolled Set 
Listing 16.2.4.3.2 Laboratory Data – Biochemistry – Enrolled Set 
Listing 16.2.4.3.3 Laboratory Data – Coagulation – Enrolled Set 
Listing 16.2.4.3.4 Laboratory Data – Thyroid Function – Enrolled Set 
Safety laboratory test results will be listed. 
Listing 16.2.4.3.5 Laboratory Data – Clinically Significant Urinalysis Results (Local Dipstick) – 
Enrolled Set 
All clinically significant urinalysis (local dipstick) data will be listed by treatment group.  
Listing 16.2.4.3.6 Laboratory Data –Signs of Hypontraemia – Enrolled Set 
All patients with signs of hyponatraemia will be listed by treatment group. 
Listing 16.2.4.3.7 Laboratory Data –Urinalysis Results (Central Laboratory) – Enrolled Set 
All urinalysis (provided by central laboratory) data will be listed by treatment group.  
Listing 16.2.4.3.8 Pregnancy Tests– Enrolled Set 
Urine and serum pregnancy test results will be listed by treatment group for female patients, including 
cases when test was not done. 
5.6.3 
Vital Signs 
Vital signs (tympanic body temperature, systolic and diastolic blood pressure and pulse rate) after five 
minutes at rest are collected at V1a, V2, V3, V5, V7, EOT, EDV and, if applicable, UNS. 
Results for tympanic body temperature, systolic and diastolic blood pressure and pulse rate will be 
classified according to whether the value was lower than (L), within (N) or higher than (H) the reference 
range for that parameter. The normal ranges are provided in Table 4. 
Table 4: Normal Ranges for Vital Signs 
Parameter 
Lower Reference Range 
Upper Reference Range 
Tympanic body temperature 
36.0 
38.5 
Systolic blood pressure [mmHg] 
80 
160 
Diastolic blood pressure [mmHg] 
50 
110 
Pulse rate [bpm] 
50 
100 
Clinical significance (not significant/significant) of vital sign abnormalities will be assessed by the 
investigator. 
The following statistical output will be provided:  
Table 15.3.3.1.1 Summary of Vital Signs – Safety Set 
Vital sign parameters will be summarised including change from baseline at each visit slot where 
assessments were made by treatment group and in total. 
Table 15.3.3.1.2 Incidence of Vital Signs Abnormalities – Safety Set 
The number and percentage of patients with Low, Normal and High categories of each vital sign 
parameter will be displayed by treatment group and in total. Percentages will be based on the number 
of patients at the specified visit slot. 
Listing 16.2.4.4 Vital Signs – Enrolled Set 
Vital signs data will be listed. 
5.6.4 
12-Lead Electrocardiogram Data 
A standard 12-lead electrocardiogram (ECG) is performed at V1a, V2, V3, EDV (if EDV performed 
before V3) and, if applicable, UNS. 


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If an ECG was done after primary stroke, the results will be used and the examination does not need to 
be repeated at V1a. ECG assessment after primary stroke, if available, otherwise the last collected value 
before IMP intake will be defined as baseline value. 
ECG results will be assessed by an investigator if normal, abnormal or CS abnormal and assessments 
will be documented in the eCRF. 
The following statistical outputs will be presented: 
Table 15.3.3.2 Summary of ECG Assessments – Safety Set 
The number and percentage of patients with normal, abnormal, and CS abnormal ECG assessments will 
be displayed by treatment group and in total. Percentages will be based on the number of patients at the 
specified visit slot. 
Listing 16.2.4.5 Lead ECG Assessments – Enrolled Set 
12-lead electrocardiogram findings will be listed. 
5.6.5 
Physical and Neurological Examination Findings 
Physical examinations are performed at V1a, V2, V3, V5, V7, EOT, EDV and, if applicable, UNS on 
relevant body systems (appearance, skin, eyes, ears-nose-throat, lungs-chest, heart, abdomen, 
extremities, other).  
Neurological examinations are performed at V1a, V2, V3, V5, V7, EOT, EDV and, if applicable, UNS. 
Complete neurological examination will include mental status, cranial nerves, motor system, sensory 
system, reflexes, co-ordination, gait and station. 
Physical and neurological examination findings will be assessed by an investigator if normal or 
abnormal and if abnormal, clinical significance (significant/not significant) will be assessed. 
The following statistical outputs will be presented: 
Table 15.3.3.3 Summary of Physical Examination Findings – Safety Set 
The number and percentage of patients with normal, abnormal, and CS abnormal physical examinations 
findings will be displayed at all visits by treatment group and in total. Percentages will be based on the 
number of patients at the specified visit slot. 
Table 15.3.3.4 Summary of Neurological Examination Findings – Safety Set 
The number and percentage of patients with normal, abnormal, and CS abnormal neurological 
examinations findings will be displayed at all visits by treatment group and in total. Percentages will be 
based on the number of patients at the specified visit slot. 
Listing 16.2.4.6 Physical Examination Findings – Enrolled Set 
Physical examination findings will be listed. 
Listing 16.2.4.7 Neurological Examination Findings – Enrolled Set 
Physical examination findings will be listed. 
5.6.6 
Analysis of Exploratory Endpoint 
Recording of the Electroencephalogram (EEG) is optional. All EEG analyses will be presented for the 
EEG analysis subset. 
EEG will be performed at V1a, EOT and, if applicable, UNS. If an examination was done after primary 
stroke, the results will be used, and the examination does not need to be repeated at V1a. 
EEG parameters will be evaluated exploratively using descriptive statistics and provided in a separate 
report.  
 


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6. BLIND DATA REVIEW 
A BDR will be performed after data entry and following a database lock. The following goals are 
defined for the BDR: 
- 
to identify major/minor protocol deviations 
- 
to identify patients that are not eligible for the per protocol population 
- 
to identify protocol deviations that may affect the primary endpoint, i.e. patients with 
insufficient IMP compliance, patients with intake of prohibited medications during the 
observation period 
- 
to discuss any open data issues 
All decisions made during the BDR will be documented in the BDR report before the closure of the 
database and the randomisation code release. 
An appropriate clinical study team, including a physician, will review potential protocol deviations and 
relevant information regarding those deviations to determine a possible impact on efficacy endpoints. 
An assessment will be made as to the effect of each of the possible deviations to determine if it is 
considered major or minor. The status, major or minor, of each protocol deviation will be documented 
in the BDR report. A patient may have one or more major protocol deviations resulting in the exclusion 
of that patient from the per-protocol analysis set. 
Protocol deviations will, if possible, be validated against data recorded in the eCRF. Where an answer 
for an inclusion/exclusion tick box differs from the algorithmic check of the criteria, the algorithmic 
check will overrule the tick box. 
Protocol deviations of the following categories will be reviewed during the BDR. 
 
Inclusion Criteria 
No. 
Inclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#01.  1. Male or female patient not aged 18 years and above. 
 


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No. 
Inclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#02.  2a. CTP V3.0: To not have one of the following confirmed by magnetic 
resonance imaging (MRI)/computed tomography (CT): 
• 
Acute ischaemic or intracerebral haemorrhagic stroke with  
- an acute symptomatic seizure until 120 hours post-stroke and  
- cerebral cortex involvement OR 
• 
Acute ischaemic stroke with  
- National Institutes of Stroke Scale (NIHSS) g 11 and 
- cerebral cortex involvement and 
- large-artery atherosclerosis and/or territory of middle cerebral 
artery (MCA) OR 
• 
 Acute ischaemic stroke with 
- NIHSS 4-10 and 
- cerebral cortex involvement and 
- large-artery atherosclerosis and 
- territory of MCA OR 
• 
Acute intracerebral haemorrhagic stroke with 
- cerebral cortex involvement and 
- volume of intracerebral haemorrhage > 10 mL. 
 
2b CTP V2.0: Acute intracerebral haemorrhage with a CAVE score 
g 3or acute ischaemic stroke with a SeLECT score g6, in each case 
confirmed by magnetic resonance imaging computed tomography 
 
 
PD#03.  CTP 2.0: Time of stroke occurrence is known and V1b is not planned 
within 96 hours. 
CTP 3.0. Time of stroke occurrence is known and V1b is not planned 
within 120 hours since the known time of stroke occurrence, or since 
last time seen well. 
 
PD#04.  Brain scan analysis has reliably excluded structural e.g. cerebral tumour 
or brain abscess, etc. brain lesions that can mimic stroke, 
 
 
PD#05. a. Patient is not able to give informed consent and to write and has not 
signed written informed consent OR 
b. Patient is not able to give informed consent, and unable to write and has 
provided verbal witnessed consent OR 
c. Patient is unable to give informed consent, and not likely to regain this 
ability until V2, and the informed consent is not deferred OR 
d. Patient is unable to give informed consent, but likely to regain this 
ability until V2, but patient’s legal representative (according to the 
respective national/local requirements) has noz provided written 
informed consent. 
 


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No. 
Inclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#06.  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. 
 
 
PD#07.  V1b is within 96 hours (CTP 2.0) / 120 hours (CTP 3.0) after stroke 
occurrence. 
 
 
PD#08.  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 
No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#09.  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. 
 
PD#10.  2. Known Han Chinese or Thai ancestry. 
 
PD#11.  3a. CTP 3.0: 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. 
3b. CTP 2.0: History of previous stroke (other than the one described in 
inclusion criteria no. 2 - 3). 
 
PD#12.  4. Sinus venous thrombosis. 
 
PD#13.  5. Spontaneous sub-arachnoid haemorrhage due to e.g. aneurysmatic or 
arteriovenous malformation. 
 
PD#14.  6. History of USs prior to primary (index) stroke. 
 
PD#15.  7. Impaired pre-stroke level of function, i.e. modified Rankin Scale (mRS) 
score > 3 prior to first stroke occurrence. 
 


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No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#16.  8. History of AED use within the last 2 years (CTP V3.0) or last 5 years 
(CTP V2.0) as defined in the list of not allowed AEDs (see CTP). 
 
PD#17.  9. Use of ESL unless provided as IMP of this trial and oxcarbazepine. 
 
PD#18.  10. Severe hepatic impairment 
 
PD#19.  11. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 
(measured at V1a). 
 
PD#20.  12. Known or suspected acute or chronic alcoholism, delirium tremens, or 
toxic psychosis. 
 
PD#21.  13. History of suicidal ideation or suicide attempt within the past 3 years. 
 
PD#22.  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. 
 
PD#23.  15. For women: Pregnancy or breast-feeding 
 
PD#24.  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. 
 
PD#25.  17. Persons committed to an institution by virtue of an order issued either 
by the judicial or other authorities. 
 
PD#26.  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. 
 
 
Additional study conduct deviations 
No. 
Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#27.  IMP treatment compliance according to eCRF or diary <80% or >120%, 
compliance <80% or <120% will not be considered as major PD but patients 
must have at least 4 consecutive treatment days (first IMP intake until last 
IMP intake to reach steady state serum level of ESL 
Case by case 
PD#28.  IMP repeatedly taken not according to schedule 
Case by case 
PD#29.  Intake of prohibited medications or treatments as per CTP 
Case by case 
PD#30.  Visits performed not according to the study protocol schedule 
Case by case 
PD#31.  No acute intracerebral haemorrhage or acute ischaemic stroke confirmed by 
MRI/CT. 
Case by case 
PD#32.  First administration of IMP was more than 120 hours after stroke 
occurrence, or since last time seen well. 
Case by case 
PD#33.  Brain scanning has not excluded structural brain lesions that can mimic 
stroke, e.g. cerebral tumour or brain abscess, etc. 
Case by case 


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No. 
Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#34.  Treated not according to the randomisation plan 
Case by case 
PD#35.  Missing 
efficacy 
assessments 
(seizure 
information 
and 
seizure 
questionnaire) 
Case by case 
PD#36.  PDs from the global Protocol deviations log that may significantly affect 
the primary study objective and are not covered by other listings 
Case by case 
Reference listings will be made available to facilitate the review of the protocol deviations. The specific 
content and format of listings to be reviewed during the BDR meeting (including any additional 
requirements that may be necessary to aid in review) will be determined outside the scope of this SAP. 
7. INTERIM ANALYSIS 
No Interim Analysis will be performed. 


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8. CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
MODIFICATIONS 
The study was considered to be terminated earlier due to sponsor’s decision. Recruitment was 
terminated before reaching the estimated sample size. 
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 secondary objective and endpoint “4-week rate of USs” was decided to be deleted as this 
information will not be meaningful for this trial. 
 


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9. REFERENCES 
 
1. SAS® Institute Inc., Cary, North Carolina, United States of America, Version 9.4. 
2. MedDRA – Medical Dictionary for Regulated Activities. International Federation of 
Pharmaceutical Manufacturers Associations (IFPMA), c/o TRW, VAR1/8A/MSSO, 12011 
Sunset Hills Road, Reston, VA 20190-3285, USA, version as specified in the DMP. 
3. WHO – Drug Dictionary. World Health Organization Collaborating Center for International 
Drug Monitoring, P.O. Box 26, S-751 03 Uppsala, Sweden, version as specified in the DMP. 
4. Mahoney FI, Barthel DW. Functional Evaluation: The Barthel index. Md State Med J 1965 
Feb:1461-65 
5. Brott T et. al. Measurements of acute cerebral infarction: a clinical examination scale, Stroke. 
1989 Jul;20(7):864-70 
6. Kroenke K, Spitzer RL and Williams JBW. The PHQ-9 Validity of a Brief Depression Severity 
Measure. J Gen Intern Med. 2001 Sep; 16(9): 606–613. 
 
 


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10. APPENDICES 
Shells for tables, listings, and figures are available in the following attachments: 
1. BIA-2093-213_Table_Shells_Version_YYYYMMDD.docx 
2. BIA-2093-213_Listing_Shells_Version_YYYYMMDD.docx 
3. BIA-2093-213_Figure_Shells_Version_YYYYMMDD.docx 
10.1 Tables 
Appendix tables defined below will be provided in separate .rtf files for each output. 
No 
Table Identifier, Title 
Output file 
Baseline Characteristics etc.  
1 
Table 15.1.1.1 Analysis Sets – Enrolled Set 
BIA-2093-213-T-1501010100-sets-enr.rtf 
2 
Table 15.1.1.2 Reasons for Exclusion from Analysis 
Sets – Randomised Set 
BIA-2093-213-T-1501010200-reas-excl-
rs.rtf 
3 
Table 15.1.2 Screening Failures – Enrolled Set 
BIA-2093-213-T-1501020000-scrf-enr.rtf 
4 
Table 15.1.3 Patient Disposition – Safety Set 
BIA-2093-213-T-1501030000-disp-ss.rtf 
5 
Table 15.1.4.1.1 Number of Patients by Country and 
Site – Enrolled Set 
BIA-2093-213-T-1501040101-no-pat-by-
cntr-en.rtf 
6 
Table 15.1.4.1.2 Number of Patients by Country and 
Site – Safety Set 
BIA-2093-213-T-1501040102-no-pat-by-
cntr-ss.rtf 
7 
Table 15.1.4.2 Number of Patients by Visit – Safety 
Set 
BIA-2093-213-T-1501040200-no-pat-by-
vis-ss.rtf 
8 
Table 15.1.5 Major Protocol Deviations – Safety Set 
BIA-2093-213-T-1501050000-mp-dev-
enr.rtf 
9 
Table 15.1.6.1 Demographics – Safety Set 
BIA-2093-213-T-1501060100-dm-ss.rtf 
10 
Table 15.1.6.2 Demographics – Per-protocol Set 
BIA-2093-213-T-1501060200-dm-pps.rtf 
11 
Table 15.1.7.1 Summary of Primary Stroke 
Characteristics - Safety Set 
BIA-2093-213-T-1501070100-pr-stoke-
ss.rtf 
12 
Table 15.1.7.2 Summary of Primary Stroke 
Characteristics - Per-protocol Set 
BIA-2093-213-T-1501070200-pr-stoke-
pps.rtf 
13 
Table 15.1.8.1 Previous Medical Conditions – Safety 
Set 
BIA-2093-213-T-1501080100-mh-prev-
med-ss.rtf 
14 
Table 15.1.8.2 Ongoing Medical Conditions – Safety 
Set 
BIA-2093-213-T-1501080200-mh-conc-
med-ss.rtf 
15 
Table 15.1.9.1 Previous Medications – Safety Set 
BIA-2093-213-T-1501090100-prev-med-
ss.rtf 
16 
Table 15.1.9.2 Concomitant Medications – Safety Set 
BIA-2093-213-T-1501090201-conmed-
ss.rtf 
17 
Table 15.1.9.3.1 Therapies Related to Primary Stroke 
– Safety Set 
BIA-2093-213-T-1501090301-th-rps-ss.rtf 
18 
Table 15.1.9.3.2 Therapies Related to Primary Stroke 
– Per-protocol Set 
BIA-2093-213-T-1501090302-th-rps-pps.rtf 
19 
Table 15.1.9.4.1 Concomitant Anti-Epileptic Drugs – 
Safety Set 
BIA-2093-213-T-1501090401-con-aed-
ss.rtf 
20 
Table 15.1.9.4.2 Concomitant Anti-Epileptic Drugs – 
Per-protocol Set 
BIA-2093-213-T-1501090402-con-aed-
pps.rtf 
21 
Table 15.1.10.1.1 Exposure to IMP - Safety Set 
BIA-2093-213-T-1501100101-exp-ss.rtf 
22 
Table 15.1.10.1.2 Exposure to IMP - Per-protocol Set 
BIA-2093-213-T-1501100102-exp-pps.rtf 
23 
Table 15.1.10.2.1 Treatment Compliance (%) - Safety 
Set 
BIA-2093-213-T-1501100201-compl-ss.rtf 
24 
Table 15.1.10.2.2 Treatment Compliance (%) - Per-
protocol Set 
BIA-2093-213-T-1501100202-compl-
pps.rtf 


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No 
Table Identifier, Title 
Output file 
Efficacy Data 
25 
Table 15.2.1.1.1 Analysis of Treatment Failure Rate 
within 6 Months after Randomisation – Full Analysis 
Set 
BIA-2093-213-T-1502010101-treat-fail-
6m-fas.rtf 
26 
Table 15.2.1.1.2 Analysis of Treatment Failure Rate 
within 6 Months after Randomisation – Per Protocol 
Set 
BIA-2093-213-T-1502010102-treat-fail-
6m-pps.rtf 
27 
Table 15.2.1.3.1 Sensitivity Analysis of Treatment 
Failure within 6 Months after Randomisation Using 
Multiple Imputation for Missing Data–Full Analysis 
Set 
BIA-2093-213-T-1502010301-sens-treat-
fail-6m-fas.rtf 
28 
Table 15.2.1.3.2 Sensitivity Analysis of Treatment 
Failure within 6 Months after Randomisation Using 
Multiple Imputation for Missing Data– Per Protocol 
Set 
BIA-2093-213-T-1502010302-sens-treat-
fail-6m-pps.rtf 
29 
Table 15.2.1.4.1 Tipping Point Analysis of Treatment 
Failure Rate within 6 Months after Randomisation – 
Full Analysis Set 
BIA-2093-213-T-1502010401-sens-tipp-
fas.rtf 
30 
Table 15.2.1.4.1 Tipping Point Analysis of Treatment 
Failure Rate within 6 Months after Randomisation – 
Per-Protocol Set 
BIA-2093-213-T-1502010402-sens-tipp-
pps.rtf 
30 
Table 15.2.1.5.1 Sensitivity Analysis of Unprovoked 
Seizures within 6 Months after Randomisation – Full 
Analysis Set 
BIA-2093-213-T-1502010501-us-6m-fas.rtf 
31 
Table 15.2.1.5.2 Sensitivity Analysis of Unprovoked 
Seizures within 6 Months after Randomisation – Per 
Protocol Set 
BIA-2093-213-T-1502010502-us-6m-
pps.rtf 
32 
Table 15.2.1.5.3 Sensitivity Analysis of Unprovoked 
Seizures within 12 Months after Randomisation – Full 
Analysis Set 
BIA-2093-213-T-1502010503-us-12m-
fas.rtf 
33 
Table 15.2.1.5.4 Sensitivity Analysis of Unprovoked 
Seizures within 12 Months after Randomisation – 
Per Protocol Set 
BIA-2093-213-T-1502010504-us-12m-
pps.rtf 
34 
Table 15.2.1.5.5 Sensitivity Analysis of Unprovoked 
Seizures within 18 Months after Randomisation – Full 
Analysis Set 
BIA-2093-213-T-1502010505-us-18m-
fas.rtf 
35 
Table 15.2.1.5.6 Sensitivity Analysis of Unprovoked 
Seizures within 18 Months after Randomisation – 
Per Protocol Set 
BIA-2093-213-T-1502010506-us-18m-
pps.rtf 
36 
Table 15.2.1.5.7 Sensitivity Analysis of Unprovoked 
Seizures within 18 Months after Randomisation 
(Subgroup 1)– Full Analysis Set 
BIA-2093-213-T-1502010507-us-18m-
sgr1-fas.rtf 
37 
Table 15.2.1.5.8 Sensitivity Analysis of Unprovoked 
Seizures within 18 Months after Randomisation 
(Subgroup 2) – Full Analysis Set 
BIA-2093-213-T-1502010508-us-18m-
sgr2-fas.rtf 
38 
Table 15.2.2.1 Analysis of Treatment Failure Rate 
within 12 Months after Randomisation – Full Analysis 
Set 
BIA-2093-213-T-1502020100-treat-fail-
12m-fas.rtf 
39 
Table 15.2.2.2 Analysis of Treatment Failure Rate 
within 12 Months after Randomisation – Per Protocol 
Set 
BIA-2093-213-T-1502020200-treat-fail-
12m-pps.rtf 
40 
Table 15.2.3.1 Analysis of Treatment Failure Rate 
within 18 Months after Randomisation – Full Analysis 
Set 
BIA-2093-213-T-1502030100-treat-fail-
18m-fas.rtf 
41 
Table 15.2.3.2 Analysis of Treatment Failure Rate 
within 18 Months after Randomisation – Per Protocol 
Set 
BIA-2093-213-T-1502030200-treat-fail-
18m-pps.rtf 
42 
Table 15.2.4.1 Summary of Acute Symptomatic 
Seizures – Full Analysis Set 
BIA-2093-213-T-1502020301-sum-stat-as-
us-fas.rtf 
43 
Table 15.2.4.2 Summary of Acute Symptomatic 
Seizures – Per Protocol Set 
BIA-2093-213-T-1502040200-ac-seiz-
pps.rtf 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
Page 52 of 58 
Effective date: 15.09.2020 
No 
Table Identifier, Title 
Output file 
44 
Table 15.2.5.1.1 Time to First Unprovoked Seizure 
after Randomisation – Full Analysis Set 
BIA-2093-213-T-1502050101-unpr-seiz-
fas.rtf 
45 
Table 15.2.5.1.2 Time to First Unprovoked Seizure 
after Randomisation – Per Protocol Set 
BIA-2093-213-T-1502050102-unpr-seiz-
pps.rtf 
46 
Table 15.2.5.4.1 Summary of Unprovoked Seizures – 
Full Analysis Set 
BIA-2093-213-T-1502050401-sum-us-
fas.rtf 
47 
Table 15.2.5.4.2 Summary of Unprovoked Seizures – 
Per Protocol Set 
BIA-2093-213-T-1502050402-sum-us-
pps.rtf 
48 
Table 15.2.6.1.1 Summary of Barthel Index Total 
Score – Full Analysis Set 
BIA-2093-213-T-1502060101-sum-stat-bi-
fas.rtf 
49 
Table 15.2.6.1.2 Summary of Barthel Index Total 
Score – Per Protocol Set 
BIA-2093-213-T-1502060102-sum-stat-bi-
pps.rtf 
50 
Table 15.2.6.2.1 Analysis of Barthel Index Total 
Score Differences – Full Analysis Set 
BIA-2093-213-T-1502060201-bi-diff-fas.rtf 
51 
Table 15.2.6.2.2 Analysis of Barthel Index Total 
Score Differences – Per Protocol Set 
BIA-2093-213-T-1502060202-bi-diff-
pps.rtf 
52 
Table 15.2.7.1.1 Summary of NIHSS Total Score – 
Full Analysis Set 
BIA-2093-213-T-1502070101-sum-stat-
nihss-fas.rtf 
53 
Table 15.2.7.1.2 Summary of NIHSS Total Score – 
Per Protocol Set 
BIA-2093-213-T-1502070102-sum-stat-
nihss-pps.rtf 
54 
Table 15.2.7.2.1 Analysis of NIHSS Total Score 
Differences – Full Analysis Set 
BIA-2093-213-T-1502070201-nihss-diff-
fas.rtf 
55 
Table 15.2.7.2.2 Analysis of NIHSS Total Score 
Differences – Per Protocol Set 
BIA-2093-213-T-1502070202-nihss-diff-
pps.rtf 
56 
Table 15.2.8.1.1 Summary of PHQ-9 Total Score – 
Full Analysis Set 
BIA-2093-213-T-1502080101-sum-stat-
phq9-fas.rtf 
57 
Table 15.2.8.1.2 Summary of PHQ-9 Total Score – 
Per Protocol Set 
BIA-2093-213-T-1502080102-sum-stat-
phq9-pps.rtf 
58 
Table 15.2.8.2 Summary of PHQ-9 Question 9 Score 
– Safety Set 
BIA-2093-213-T-1502080200-sum-phq9-
q9-score-ss.rtf 
59 
Table 15.2.8.3.1 Analysis of PHQ-9 Total Score 
Differences – Full Analysis Set 
BIA-2093-213-T-1502080301-ph9q-diff-
fas.rtf 
60 
Table 15.2.8.3.2 Analysis of PHQ-9 Total Score 
Differences – Per Protocol Set 
BIA-2093-213-T-1502080302-ph9q-diff-
pps.rtf 
61 
Table 15.2.9.1 Overall Survival – Full Analysis Set 
BIA-2093-213-T-1502090100-ovr-surv-
fas.rtf 
62 
Table 15.2.9.2 Overall Survival – Per Protocol Set 
BIA-2093-213-T-1502090200-ovr-surv-
pps.rtf 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
Page 53 of 58 
Effective date: 15.09.2020 
No 
Table Identifier, Title 
Output file 
Safety Data 
63 
Table 15.3.1.1 Overall Summary of TEAEs – Safety 
Set 
BIA-2093-213-T-1503010100-sum-teae-
ss.rtf 
64 
Table 15.3.1.2.1 Incidence of TEAEs – Safety Set 
BIA-2093-213-T-1503010201-teae-ss.rtf 
65 
Table 15.3.1.2.2 Incidence of Non-Serious TEAEs– 
Safety Set 
BIA-2093-213-T-1503010202-nser-teae-
ss.rtf 
66 
Table 15.3.1.2.3 Incidence of Serious TEAEs – Safety 
Set 
BIA-2093-213-T-1503010203-ser-teae-
ss.rtf 
67 
Table 15.3.1.2.4 Incidence of Related TEAEs – Safety 
Set 
BIA-2093-213-T-1503010204-rel-teae-ss.rtf 
68 
Table 15.3.1.2.5 Incidence of Serious Related TEAEs 
– Safety Set 
BIA-2093-213-T-1503010205-rel-ser-teae-
ss.rtf 
69 
Table 15.3.1.2.6 Incidence of TEAEs Leading to 
Discontinuation of IMP – Safety Set 
BIA-2093-213-T-1503010206-teae-disc-
ss.rtf 
70 
Table 15.3.1.2.7 Incidence of TEAEs Leading to Dose 
Reduction– Safety Set 
BIA-2093-213-T-1503010207-teae-dose-
ss.rtf 
71 
Table 15.3.1.2.8 Incidence of TEAEs Requiring 
Medication – Safety Set 
BIA-2093-213-T-1503010208-teae-med-
ss.rtf 
72 
Table 15.3.1.2.9 Incidence of TEAEs Leading to 
Death – Safety Set 
BIA-2093-213-T-1503010209-teae-death-
ss.rtf 
73 
Table 15.3.1.3.1 Incidence of TEAEs by Maximum 
Severity – Safety Set 
BIA-2093-213-T-1503010301-teae-max-
sev-ss.rtf 
74 
Table 15.3.1.3.2 Incidence of Related TEAEs by 
Maximum Severity – Safety Set 
BIA-2093-213-T-1503010302-teae-rel-
max-sev-ss.rtf 
75 
Table 15.3.1.3.3 Incidence of Serious TEAEs by 
Maximum Severity – Safety Set 
BIA-2093-213-T-1503010303-teae-ser-
max-sev-ss.rtf 
76 
Table 15.3.1.4.1 Incidence of Preferred Terms: 
TEAEs – Safety Set 
BIA-2093-213-T-1503010401-teae-pt-ss.rtf 
77 
Table 15.3.1.4.2 Incidence of Preferred Terms: 
Serious TEAEs – Safety Set 
BIA-2093-213-T-1503010402-ser-teae-pt-
ss.rtf 
78 
Table 15.3.1.4.3 Incidence of Preferred Terms: 
Related TEAEs – Safety Set 
BIA-2093-213-T-1503010403-rel-teae-pt-
ss.rtf 
79 
Table 15.3.1.4.4 Incidence of Preferred Terms: 
Serious Related TEAEs– Safety Set 
BIA-2093-213-T-1503010404-rel-ser-teae-
pt-ss.rtf 
80 
Table 15.3.1.4.5 Incidence of Preferred Terms: 
TEAEs Leading to Discontinuation of IMP – Safety 
Set 
BIA-2093-213-T-1503010405-teae-disc-pt-
ss.rtf 
81 
Table 15.3.1.4.6 Incidence of Preferred Terms: (g 2% 
of patients in any treatment group) TEAEs – Safety 
Set 
BIA-2093-213-T-1503010406-teae-2perc-
pt-ss.rtf 
82 
Table 15.3.2.1.1 Summary of Clinical Laboratory 
Tests: Haematology – Safety Set 
BIA-2093-213-T-1503020101-lbh-sum-
ss.rtf 
83 
Table 15.3.2.1.2 Summary of Clinical Laboratory 
Tests: Biochemistry – Safety Set 
BIA-2093-213-T-1503020102-lbb-sum-
ss.rtf 
84 
Table 15.3.2.1.3 Summary of Clinical Laboratory 
Tests: Coagulation – Safety Set 
BIA-2093-213-T-1503020103-lbc-sum-
ss.rtf 
85 
Table 15.3.2.2.1 Clinical Laboratory Tests: Incidence 
of Haematology Abnormalities – Safety Set 
BIA-2093-213-T-1503020201-lbh-abnorm-
ss.rtf 
86 
Table 15.3.2.2.2 Clinical Laboratory Tests: Incidence 
of Biochemistry Abnormalities – Safety Set 
BIA-2093-213-T-1503020202-lbb-abnorm-
ss.rtf 
87 
Table 15.3.2.2.2 Clinical Laboratory Tests: Incidence 
of Coagulation Abnormalities – Safety Set 
BIA-2093-213-T-1503020203-lbc-abnorm-
ss.rtf 
88 
Table 15.3.2.2.4 Clinical Laboratory Tests: Incidence 
of Thyroid Function Abnormalities – Safety Set 
BIA-2093-213-T-1503020204-lbth-abnorm-
ss.rtf 
89 
Table 15.3.2.3.1 Clinical Laboratory Tests: Shift 
Table of Haematology Results from Baseline to 
Endpoint – Safety Set 
BIA-2093-213-T-1503020301-lbh-shift-
ss.rtf 
90 
Table 15.3.2.3.2 Clinical Laboratory Tests: Shift 
Table of Biochemistry Results from Baseline to 
Endpoint– Safety Set 
BIA-2093-213-T-1503020302-lbb-shift-
ss.rtf 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
Page 54 of 58 
Effective date: 15.09.2020 
No 
Table Identifier, Title 
Output file 
91 
Table 15.3.2.3.3 Clinical Laboratory Tests: Shift 
Table of Coagulation Results from Baseline to 
Endpoint – Safety Set 
BIA-2093-213-T-1503020303-lbc-shift-
ss.rtf 
92 
Table 15.3.2.4.1 Clinical Laboratory Tests: Shift 
Table of Haematology Results from Baseline to Worst 
Post-Baseline Value – Safety Set 
BIA-2093-213-T-1503020401-lbh-shift-
wpb-ss.rtf 
93 
Table 15.3.2.4.2 Clinical Laboratory Tests: Shift 
Table of Biochemistry Results from Baseline to Worst 
Post-Baseline Value – Safety Set 
BIA-2093-213-T-1503020402-lbb-shift-
wpb-ss.rtf 
94 
Table 15.3.2.4.3 Clinical Laboratory Tests: Shift 
Table of Coagulation Results from Baseline to Worst 
Post-Baseline Value – Safety Set 
BIA-2093-213-T-1503020403-lbc-shift-
wpb-ss.rtf 
95 
Table 15.3.2.5.1 Clinical Laboratory Tests: Incidence 
Clinically Significant Urinalysis Results (Local 
Dipstick) – Safety Set 
BIA-2093-213-T-1503020501-lbu-local-
ss.rtf 
96 
Table 15.3.2.5.2 Clinical Laboratory Tests: Incidence 
of Urinalysis Results (Central Laboratory) – Safety 
Set 
BIA-2093-213-T-1503020502-lbu-central-
ss.rtf 
97 
Table 15.3.2.6 Signs of Hyponatraemia – Safety Set 
BIA-2093-213-T-1503020600-hyp-ss.rtf 
98 
Table 15.3.3.1.1 Summary of Vital Signs – Safety Set 
BIA-2093-213-T-1503030101-vs-sum-ss.rtf 
99 
Table 15.3.3.1.2 Incidence of Vital Signs 
Abnormalities – Safety Set 
BIA-2093-213-T-1503030102-vs-abnorm-
ss.rtf 
100 
Table 15.3.3.2 Summary ECG Assessments – Safety 
Set 
BIA-2093-213-T-1503030200-ecg-sum-
ss.rtf 
101 
Table 15.3.3.3 Summary of Physical Examination 
Findings – Safety Set 
BIA-2093-213-T-1503030300-pe-sum-ss.rtf 
102 
Table 15.3.3.4 Summary of Neurological Examination 
Findings – Safety Set 
BIA-2093-213-T-1503030400-neuro-sum-
ss.rtf 
103 
Table 15.3.3.5 Summary of EEG Assessments – EEG 
Analysis Subset 
BIA-2093-213-T-1503030500-eeg-sum-
ss.rtf 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
Page 55 of 58 
Effective date: 15.09.2020 
10.2 Listings 
Appendix listings defined below will be provided in separate .rtf files for each output.  
No 
Listing Identifier, Title 
Output file 
Demographic and Study Population Data 
1 
Listing 16.2.1.1 Patient Disposition – Randomised Set 
BIA-2093-213-L-1602010100-disp-rs.rtf 
2 
Listing 16.2.1.2 Screening Failures – Enrolled Set 
BIA-2093-213-L-1602010200-scr-fail-es.rtf 
3 
Listing 16.2.1.3 Patient Visits – Enrolled Set 
BIA-2093-213-L-1602010300-visit-es.rtf 
4 
Listing 16.2.1.4 Exclusions from Analysis Sets – 
Randomised Set 
BIA-2093-213-L-1602010400-excl-sets-
rs.rtf 
5 
Listing 16.2.1.5 Patient Randomisation to Treatments – 
Randomised Set 
BIA-2093-213-L-1602010500-rand-rs.rtf 
6 
Listing 16.2.1.6.1 Major Protocol Deviations – Full 
Analysis Set 
BIA-2093-213-L-1602010601-dev-fas.rtf 
7 
Listing 16.2.1.6.2 Protocol Deviations related to 
COVID-19 – Enrolled Set 
BIA-2093-213-L-1602010602-dev-covid-
es.rtf 
8 
Listing 16.2.1.7 Inclusion Criteria Not Met and 
Exclusion Criteria Met – Enrolled Set 
BIA-2093-213-L-1602010700-incl-excl-
es.rtf 
9 
Listing 16.2.1.8 Demographics – Enrolled Set 
BIA-2093-213-L-1602010800-demo-es.rtf 
10 
Listing 16.2.1.9 (Primary) Stroke and Brain Imaging 
Details – Enrolled Set 
BIA-2093-213-L-1602010900-stroke-brain-
es.rtf 
11 
Listing 16.2.1.10 SeLECT and CAVE Scores – 
Enrolled Set 
BIA-2093-213-L-1602011000-select-cave-
es.rtf 
12 
Listing 16.2.1.11 Medical History – Enrolled Set 
BIA-2093-213-L-1602011100-med-h-es.rtf 
13 
Listing 16.2.1.12 Medications – Enrolled Set  
BIA-2093-213-L-1602011200-med-es.rtf 
14 
Listing 16.2.1.13 Therapies – Enrolled Set  
BIA-2093-213-L-1602011300-ther-es.rtf 
15 
Listing 16.2.2.1 Exposure to IMP – Safety Set 
BIA-2093-213-L-1602020100-exp-ss.rtf 
16 
Listing 16.2.2.2 Treatment Duration and Compliance – 
Safety Set 
BIA-2093-213-L-1602020200-dur-compl-
ss.rtf 
17 
Listing 16.2.2.3 IMP Accountability – Safety Set 
BIA-2093-213-L-1602020300-acc-ss.rtf 
Efficacy Data 
18 
Listing 16.2.3.1 Seizure Screening Questionnaire – 
Enrolled Set 
BIA-2093-213-L-1602030100-ques-seiz-
es.rtf 
19 
Listing 16.2.3.2 Seizure Information after the Primary 
Stroke Occurrence – Enrolled Set 
BIA-2093-213-L-1602030200-inf-seiz-
es.rtf 
20 
Listing 16.2.3.3 Barthel Index – Enrolled Set 
BIA-2093-213-L-1602030300-barthel-es.rtf 
21 
Listing 16.2.3.4 National Institutes of Health Stroke 
Scale (NIHSS)– Enrolled Set 
BIA-2093-213-L-1602030400-nihss-es.rtf 
22 
Listing 16.2.3.5 Patient Health Questionnaire (PHQ-9) 
– Enrolled Set 
BIA-2093-213-L-1602030500-phq9-es.rtf 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
Page 56 of 58 
Effective date: 15.09.2020 
No 
Listing Identifier, Title 
Output file 
Safety Data 
23 
Listing 16.2.4.1.1 Adverse Events: MedDRA Coding 
BIA-2093-213-L-1602040101-ae-cod-es.rtf 
24 
Listing 16.2.4.1.2 Adverse Events: General – Enrolled 
Set 
BIA-2093-213-L-1602040102-ae-es.rtf 
25 
Listing 16.2.4.2.1 Serious Adverse Events – Enrolled 
Set 
BIA-2093-213-L-1602040102-ser-ae-es.rtf 
26 
Listing 16.2.4.2.2 AEs Leading to Discontinuation of 
IMP – Safety Set 
BIA-2093-213-L-1602040102-disc-ae-es.rtf 
27 
Listing 16.2.4.2.3 AEs Leading to Death – Enrolled Set 
BIA-2093-213-L-1602040203-death-ae-
es.rtf 
28 
Listing 16.2.4.3.1 Laboratory Data - Haematology– 
Enrolled Set 
BIA-2093-213-L-1602040301-lbh-es.rtf 
29 
Listing 16.2.4.3.2 Laboratory Data - Biochemistry– 
Enrolled Set 
BIA-2093-213-L-1602040302-lbb-es.rtf 
30 
Listing 16.2.4.3.3 Laboratory Data - Coagulation– 
Enrolled Set 
BIA-2093-213-L-1602040303-lbc-es.rtf 
31 
Listing 16.2.4.3.4 Laboratory Data - Thyroid 
Function– Enrolled Set 
BIA-2093-213-L-1602040304-lbth-es.rtf 
32 
Listing 16.2.4.3.5 Laboratory Data - Clinically 
Significant Urinalysis Results (Local Dipstick) – 
Enrolled Set 
BIA-2093-213-L-1602040305-lbu-local-
es.rtf 
33 
Listing 16.2.4.3.6 Signs of Hyponatraemia – Enrolled 
Set 
BIA-2093-213-L-1602040306-hyp-es.rtf 
34 
Listing 16.2.4.3.7 Laboratory Data - Urinalysis 
Parameters (Central Laboratory) – Enrolled Set 
BIA-2093-213-L-1602040307-lbu-central-
es.rtf 
35 
Listing 16.2.4.3.8 Pregnancy Tests – Enrolled Set 
BIA-2093-213-L-1602040308-preg-es.rtf 
36 
Listing 16.2.4.4 Vital Signs – Enrolled Set 
BIA-2093-213-L-1602040400-vs-es.rtf 
37 
Listing 16.2.4.5 Lead ECG Assessments – Enrolled Set 
BIA-2093-213-L-1602040500-ecg-es.rtf 
38 
Listing 16.2.4.6 Physical Examination Findings – 
Enrolled Set 
BIA-2093-213-L-1602040600-pe-es.rtf 
39 
Listing 16.2.4.7 Neurological Examination Findings – 
Enrolled Set 
BIA-2093-213-L-1602040700-ne-es.rtf 
 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
Page 57 of 58 
Effective date: 15.09.2020 
10.3 Figures  
Appendix figures defined below will be provided in separate .rtf files for each output.  
 
No 
Figure Identifier, Title 
Output file 
Demographic and Study Population Data 
1 
Figure 15.1.1 Flow Chart of Patient Disposition – 
Enrolled Set 
BIA-2093-213-F-1501010000-
disp-es.rtf 
2 
Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled 
Set 
BIA-2093-213-F-1501020000-
asets-es.rtf 
Efficacy Data 
3 
Figure 15.2.1.1.1 Tipping Point Analysis of Treatment 
Failure Rate within 6 Months after Randomisation – 
Full Analysis Set 
BIA-2093-213-F-1502010101-
tipp-fas.rtf 
4 
Figure 15.2.1.1.2 Tipping Point Analysis of Treatment 
Failure Rate within 6 Months after Randomisation – 
Per Protocol Set 
BIA-2093-213-F-1502010102-
tipp-pps.rtf 
5 
Figure 15.2.1.2.1 Time to First US after Randomisation 
– Full Analysis Set 
BIA-2093-213-F-1502010201-
time-us-fas.rtf 
6 
Figure 15.2.1.2.2 Time to First US after Randomisation 
– Per Protocol Set 
BIA-2093-213-F-1502010202-
time-us-pps.rtf 
7 
Figure 15.2.2.1 Cumulative Incidence Curves of USs 
using Kaplan-Meier Curves by Barthel Index Total 
Score – Full Analysis Set 
BIA-2093-213-F-1502020100-
cum-inc-barthel-fas.rtf 
8 
Figure 15.2.2.2 Cumulative Incidence Curves of USs 
using Kaplan-Meier Curves by Barthel Index Total 
Score – Per-Protocol Set 
BIA-2093-213-F-1502020200-
cum-inc-barthel-pps.rtf 
9 
Figure 15.2.3.1 Cumulative Incidence Curves of USs 
using Kaplan-Meier Curves by NIHSS Total Score – 
Full Analysis Set 
BIA-2093-213-F-1502030100-
cum-inc-nihss-fas.rtf 
10 
Figure 15.2.3.2 Cumulative Incidence Curves of USs 
using Kaplan-Meier Curves by NIHSS Total Score – 
Per Protocol Set 
BIA-2093-213-F-1502030200-
cum-inc-nihss-pps.rtf 
11 
Figure 15.2.4.1 Cumulative Incidence Curves of USs 
using Kaplan-Meier Curves by PHQ-9 Total Score– 
Full Analysis Set 
BIA-2093-213-F-1502040100-
cum-inc-phq9-fas.rtf 
12 
Figure 15.2.4.2 Cumulative Incidence Curves of USs 
using Kaplan-Meier Curves by PHQ-9 Total Score– 
Per Protocol Set 
BIA-2093-213-F-1502040200-
cum-inc-phq9-pps.rtf 
13 
Figure 15.2.5.1 Overall Survival – Full Analysis Set 
BIA-2093-213-F-1502050100-
surv-fas.rtf 
14 
Figure 15.2.5.2 Overall Survival – Per Protocol Set 
BIA-2093-213-F-1502050200-
surv-pps.rtf 
 


Sponsor: Bial - Portela & Ca, S.A. 
Protocol no. BIA-2093-213 
Statistical Analysis Plan, Version Final 1.0 
22-NOV-2023 
I-DM-011SAP 
Page 58 of 58 
Effective date: 15.09.2020 
11. SIGNATURES 
 
 
 
_______________________________  ______________________ 
Signature 
 
 
 
 
Date 
Author: 
Nicole Dauzenroth 
Statistician, Scope International AG 
 
 
 
_______________________________  ______________________ 
Signature 
 
 
 
 
Date 
Reviewer: 
Björn Bosse 
Head of Statistics, Scope International AG 
 
 
 
_______________________________  ______________________ 
Signature 
 
 
 
 
Date 
Reviewer: 
Angelika Seedorf 
Medical Writer, Scope International AG 
 
 
 
_______________________________  ______________________ 
Signature 
 
 
 
 
Date 
Reviewer: 
Angelika Kippert 
Project Manager, Scope International AG 
 
 
 
_______________________________  ______________________ 
Signature  
 
 
 
 
Date 
Sponsor: 
Guillermo Castilla 
Position, Bial - Portela & Ca, S.A.  
 
 
22/NOV/2023


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Hash algorithm: SHA256
Name: Angelika Seedorf
User Name: sc\aseedorf
Date: Wed, 22 Nov 2023 11:19:26 UTC
Number of signed pages: 58
Document hash code: 3BB4CD069A55773495993A99024643247034F2DF97F1F34D543D99F0512152F8
Hash algorithm: SHA256
0229_SAP_final_1.0
Scope International Electronic Signature Page 1 of 1.