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    Clinical Trial Results:
    Prevention of epilepsy in stroke patients at high risk of developing unprovoked seizures: anti-epileptogenic effects of eslicarbazepine acetate

    Summary
    EudraCT number
    		 2018-002747-29
    Trial protocol
    		 ES   SE   GB   PT   IT  
    Global end of trial date
    11 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2025
    First version publication date
    18 Jan 2025
    Other versions
    Summary report(s)
    		 BIA-2093-213_Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    BIA-2093-213
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT06597084
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bial - Portela & Ca, S.A.
    Sponsor organisation address
    À Av. da Siderurgia Nacional, Trofa, Portugal, 4745-457
    Public contact
    Sponsor, Bial - Portela & Ca, S.A., 00351 22 98661 00, info@bial.com
    Scientific contact
    Head of Clinical Operations, Bial - Portela & Ca, S.A., 00351 229866100, clinical.trials@bial.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    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.
    Protection of trial subjects
    This trial was performed in compliance with Good Clinical Practices (GCP) and applicable regulatory requirements, including the archiving of essential documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Italy: 27
    Worldwide total number of subjects
    125
    EEA total number of subjects
    93
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    58
    From 65 to 84 years
    59
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 129 patients were enrolled at 19 active trial centres in Europe and Israel. Following sponsor’s decision, recruitment was closed by the end of February 2022, since due to the unforeseen COVID-19 pandemic circumstances. The recruitment termination was not related to safety issues or other circumstances related to the IMP.

    Pre-assignment
    Screening details
    		 4 patients failed screening, 125 patients were randomised. Two did not take the IMP due to withdrawal of consent (patient or patient’s family decision). Overall, of 125 patients randomised, 92 (73.6%) patients completed the 6-month period, 86 (68.8%) patients completed the 12-month period, and 84 (667.2%) patients completed the 18 month period.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A - ESL
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eslicarbazepine acetate
    Investigational medicinal product code
    BIA 2093
    Other name
    Zebinix
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Arm title
    		 Group B - Placebo
    Arm description
    		 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.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    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.

    Number of subjects in period 1
    		Group A - ESL Group B - Placebo
    Started
    62
    63
    Completed
    43
    41
    Not completed
    19
    22
         Stroke more than 7 days after primary stroke
    2
    6
         Adverse event, serious fatal
    4
    -
         Consent withdrawn by subject
    4
    9
         Physician decision
    1
    -
         Adverse event, non-fatal
    3
    2
         Consent was not given by the patient until V2
    -
    3
         Other
    1
    -
         Lost to follow-up
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A - ESL
    Reporting group description
    		 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.

    Reporting group title
    Group B - Placebo
    Reporting group description
    		 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.

    Reporting group values
    		 Group A - ESL Group B - Placebo Total
    Number of subjects
    		 62 63 125
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 31 28 59
        From 65-84 years
    		 25 33 58
        85 years and over
    		 6 2 8
        Not recorded
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.1 ( 14.47 ) 65.3 ( 13.94 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 22 45
        Male
    		 39 41 80
    Race
    Units: Subjects
        White
    		 58 61 119
        Black or African American
    		 3 1 4
        Asian
    		 1 0 1
        Multiple
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Group A - ESL
    Reporting group description
    		 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.

    Reporting group title
    Group B - Placebo
    Reporting group description
    		 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.

    Primary: Proportion of Patients Who Experience the First Unprovoked Seizures (US) Within the First 6 Months After Randomisation (Failure Rate)

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    End point title
    		 Proportion of Patients Who Experience the First Unprovoked Seizures (US) Within the First 6 Months After Randomisation (Failure Rate)
    End point description
    Deaths before the first US or patients without evaluable assessment of the primary endpoint will be counted as treatment failures. To show that ESL (Group A) is superior to placebo (Group B), the primary null hypothesis will be tested against the alternative hypothesis
    End point type
    Primary
    End point timeframe
    First 6 months after randomisation
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Failures - Unprovoked seizure
    2
    7
        Failures - Death
    3
    0
        Failures - Withdrawn
    12
    16
        Non-failures
    44
    39
    Statistical analysis title
    		 U within 6 Months after Randomis
    Comparison groups
    Group A - ESL v Group B - Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1739 [1]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.0801
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1953
         upper limit
    		 0.0301
    Notes
    [1] - p-value from chi-square test with continuity correction

    Secondary: Measure Title Proportion of Patients Who Experience the First US During the First 12 Months After Randomisation

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    End point title
    		 Measure Title Proportion of Patients Who Experience the First US During the First 12 Months After Randomisation
    End point description
    Deaths before the first US or patients without evaluable assessment of the primary endpoint will be counted as treatment failures. To show that ESL (Group A) is superior to placebo (Group B), the primary null hypothesis will be tested against the alternative hypothesis
    End point type
    Secondary
    End point timeframe
    First 12 months after randomisation
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Failures - Unprovoked seizure
    3
    8
        Failures - Death
    3
    0
        Failures - Withdrawn
    13
    18
        Non-failures
    42
    36
    No statistical analyses for this end point

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

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    End point title
    		 Proportion of Patients Who Experience the First US During the Course of the Trial
    End point description
    Deaths before the first US or patients without evaluable assessment of the primary endpoint will be counted as treatment failures. To show that ESL (Group A) is superior to placebo (Group B), the primary null hypothesis will be tested against the alternative hypothesis
    End point type
    Secondary
    End point timeframe
    Until 18 months after randomisation
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Failures - Unprovoked seizure
    5
    9
        Failures - Death
    4
    0
        Failures - Withdrawn
    14
    18
        Non-failures
    38
    35
    No statistical analyses for this end point

    Secondary: Number of Acute Symptomatic Seizure (ASS)

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    End point title
    		 Number of Acute Symptomatic Seizure (ASS)
    End point description
    Number of ASSs will be summarised by means of descriptive statistics
    End point type
    Secondary
    End point timeframe
    During the first 7 days after stroke
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Patients without an ASS
    51
    47
        Patients with at least one ASS
    10
    15
    No statistical analyses for this end point

    Secondary: Time to First US After Randomisation

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    End point title
    		 Time to First US After Randomisation
    End point description
    The time to first US will be analysed and presented by means of the Kaplan-Meier estimate for the failure time and corresponding simultaneous confidence interval (CI), logrank test as well as estimates for 25% percentile, median, and 75% percentile failure time and corresponding CI.
    End point type
    Secondary
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Percentage
    number (not applicable)
        KM failure probability estimate at Month 6 (D 182)
    0.0350
    0.1455
        KM failure probability estimate at Month 12 (D365)
    0.0574
    0.1686
        KM failure probability estimate at Month 18 (D547)
    0.1034
    0.1917
    Statistical analysis title
    		 Time to First US After Randomisation
    Comparison groups
    Group A - ESL v Group B - Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.2081
    Method
    		 Logrank
    Parameter type
    		 Percentiles of time to first US
    Point estimate
    92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25
         upper limit
    		 95
    Notes
    [2] - The primary efficacy endpoint was assessed in the FAS by using a Chi-square test with continuity correction on the significance level of 5% (two-sided), which corresponds to one-sided 2.5% to compare the proportion of treatment failures between both arms. The odds ratio for ESL vs. placebo and corresponding 95% Confidence Interval (CI) were provided. The risk difference between ESL and placebo with corresponding 95% continuity-corrected Newcombe CI was also calculated. Additionally, the p-value

    Secondary: Barthel Index (BI) Original 10-item Version

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    End point title
    		 Barthel Index (BI) Original 10-item Version
    End point description
    The BI at baseline and post-baseline visits of each patient will be calculated adding the individual scores from each item. Baseline is the value assessed before first IMP intake. Endpoint is the last non-missing value collected after the first IMP intake.
    End point type
    Secondary
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Points
    median (full range (min-max))
        Baseline - Observed Value
    85.0 (0 to 100)
    72.5 (0 to 100)
        Endpoint - Observed Value
    100.0 (0 to 100)
    100.0 (0 to 100)
        Endpoint - Change from Baseline
    5.0 (0 to 100)
    7.5 (0 to 100)
    No statistical analyses for this end point

    Secondary: National Institutes of Health Stroke Scale (NIHSS)

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    End point title
    		 National Institutes of Health Stroke Scale (NIHSS)
    End point description
    The NIHSS is a systematic assessment tool that provides a quantitative measure of strokerelated neurologic deficits. The stroke scale is valid for predicting lesion size and can serve as a measure of stroke severity 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”. For each patient, the total NIHSS score at baseline and each post-baseline visit will be calculated adding the individual scores from each item.
    End point type
    Secondary
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Points
    median (confidence interval 42%)
        Baseline - Observed Value
    22 (0 to 42)
    24 (0 to 42)
        Endpoint - Observed Value
    15 (0 to 42)
    16 (0 to 42)
        Endpoint - Change from Baseline
    5 (0 to 42)
    1 (0 to 42)
    No statistical analyses for this end point

    Secondary: Patient Health Questionnaire (PHQ-9)

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    End point title
    		 Patient Health Questionnaire (PHQ-9)
    End point description
    The PHQ-9 can be used for screening, diagnosing and measuring the severity of depression in stroke patients. The patient will rate on a scale from 0 (not at all) to 3 (nearly every day) how often each of the 9 symptoms occurred during the past 2 weeks. The individual scores from each item of the PHQ-9 will be added to calculate the total PHQ-9 score for each time of examination.
    End point type
    Secondary
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Point
    log mean (standard deviation)
        Baseline - Observed Value
    3.7 ( 3.34 )
    3.4 ( 4.43 )
        Endpoint - Observed Value
    4.1 ( 3.96 )
    4.3 ( 5.25 )
        Endpoint - Change from Baseline
    0.5 ( 4.61 )
    0.7 ( 6.13 )
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival will be analysed and presented by means of the Kaplan-Meier estimates for the survival rates including pointwise CI, logrank test as well as estimates for 25% percentile, median, and 75% percentile survival time and corresponding CI
    End point type
    Secondary
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Percentage
    number (not applicable)
        KM death probability estimate at Month 6 (Day 182)
    0.0564
    0.000
        KM death probability estimate at Month 12 (Day365)
    0.0564
    0.000
        KM death probability estimate at Month 18 (Day547)
    0.0774
    0.000
    No statistical analyses for this end point

    Secondary: Electrocardiogram (ECG)

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    End point title
    		 Electrocardiogram (ECG)
    End point description
    Safety endpoint: The ECG equipment is to be calibrated to 1 cm/mV and recording is to be done at 25 mm/sec and performed for a minimum of 10 sec. At V1a the investigator should examine the ECG for signs of cardiac disease that should exclude the patient from the trial. An assessment of normal or abnormal will be recorded and if the ECG abnormality is considered clinically significant, the abnormality will be documented in the eCRF. If an ECG was done after primary stroke, the results should be used and the examination does not need to be repeated at V1a. After each recording of a simultaneous 12-lead resting ECG, a copy of the originally printed ECG records will be printed, assessed and filed by the investigator, in order to ensure that maintenance of the data will not be affected by thermolability of the paper.
    End point type
    Secondary
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61 [3]
    62 [4]
    Units: Participants
    number (not applicable)
        Baseline - Clinically Significant abnormal
    9
    8
        V2 - Clinically Significant abnormal
    4
    3
        V3 - Clinically Significant abnormal
    4
    3
        Early disconti. visit - Clinically Signific abnorm
    0
    0
        Endpoint
    4
    3
    Notes
    [3] - 1ª Category: Group A - 60 participan. 2ª Cat: A - 43 3ª Cat: A - 34 4ª Cat: A - 4 4ª Cat: A - 47
    [4] - 1ª Category: Group B - 62 participan. 2ª Cat: B - 37 3ª Cat: B - 32 4ª Cat: B - 1 4ª Cat: B - 41
    No statistical analyses for this end point

    Other pre-specified: Treatment Emergent Adverse Events (TEAEs) Incl. Findings From Physical and Neurological Examinations

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    End point title
    		 Treatment Emergent Adverse Events (TEAEs) Incl. Findings From Physical and Neurological Examinations
    End point description
    Safety endpoint: AEs not considered treatment-emergent according to this definition or with missing data will be medically reviewed during the data review meeting and will be considered treatment emergent if appropriate. TEAE: Adverse Event with onset or worsening after first IMP intake until 14 days after last IMP intake.
    End point type
    Other pre-specified
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        TEAE
    50
    51
        Non-serious TEAE
    50
    48
        Serious TEAE
    12
    13
        Related TEAE
    23
    12
        Serious related TEAE
    3
    0
        Severe TEAE
    9
    8
        TEAE leading to discontinuation of IMP
    16
    6
        TEAE leading to dose reduction
    0
    2
        TEAE requiring medication
    36
    46
        TEAE leading to death
    2
    0
        Ongoing TEAE at the end of the trial
    31
    30
        TEAE leading to study discontinuation
    4
    4
    No statistical analyses for this end point

    Other pre-specified: Clinically Significant Haematology Abnormalities

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    End point title
    		 Clinically Significant Haematology Abnormalities
    End point description
    Safety endpoint: Based on haemoglobin, haematocrit, red blood cell count (RBC), white blood cell count (WBC), differential - neutrophils, eosinophils, lymphocytes, monocytes and basophils, and platelet count. All laboratory values will be classified as normal or abnormal according to the laboratories normal ranges and as clinically significant according to the assessment of the investigator. For these tests, approximately 12 mL of blood will be collected at each blood withdrawal. Shifts of Haematology Parameters from Normal or Abnormal to Clinically Significant Abnormal at Endpoint
    End point type
    Other pre-specified
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Eosinophils - Low to CS high
    1
    0
        Eosinophils abs. - Low to CS high
    1
    0
        Lymphocytes - Low to CS low
    1
    0
        Lymphocytes abs - Low to CS low
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Clinically Significant Biochemistry Abnormalities, Including eGFR (Estimated Glomerular Filtration Rate) and Coagulation

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    End point title
    		 Clinically Significant Biochemistry Abnormalities, Including eGFR (Estimated Glomerular Filtration Rate) and Coagulation
    End point description
    Safety endpoint The biochemistry analysis is based on sodium (will be monitored for signs of hyponatraemia), potassium, chloride, calcium, phosphate, blood urea nitrogen, aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase, creatine phosphokinase (CPK), creatinine, glucose, C-reactive protein, albumin, total protein, total cholesterol, low-density lipoproteincholesterol, high-density lipoprotein-cholesterol, triglycerides, and total bilirubin (bilirubin will be fractionated direct/indirect if elevated). eGFR will be estimated based on serum creatinine value using the according CKD-EPI formula using age, sex and race. Coagulation is based on international normalised ratio and activated partial thromboplastin time (aPTT). All laboratory values will be classified as normal or abnormal according to the laboratories normal ranges and as clinically significant according to the assessment of the invest
    End point type
    Other pre-specified
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Sodium - Normal to CS low
    1
    0
        Potassium - Normal to CS low
    1
    0
        Potassium - Normal to CS high
    1
    0
        Potassium - Missing to CS high
    1
    0
        Blood urea nitrogen - Missing to CS high
    1
    0
        Aspartate transaminase - Normal to CS high
    1
    0
        Alanine transaminase - Normal to CS high
    1
    0
        Alanine transaminase - High to CS high
    1
    0
        Gamma-glutamyl transferase - Normal to CS high
    3
    0
        Lactate dehydrogenase - Low to CS high
    1
    0
        Alkaline phosphatase - Normal to CS high
    2
    1
        Creatinine - Normal to CS high
    1
    1
        Creatinine - Missing to CS high
    1
    0
        C-reactive protein - High to CS high
    2
    0
        LDL-cholesterol - Normal to CS high
    1
    0
        HDL-cholesterol - Normal to CS low
    2
    0
        Triglycerides - Normal to CS high
    0
    1
        Total bilirubin - Normal to CS high
    1
    0
        Bilirubin direct - Missing to CS high
    1
    0
        Glomerular filtration rate - Normal to CS low
    1
    0
        International normalised ratio - High to CS high
    1
    0
        Activated partial thromboplastin time - Normal to
    2
    0
    No statistical analyses for this end point

    Other pre-specified: Clinically Significant Urinalysis Abnormalities - Urinalysis

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    End point title
    		 Clinically Significant Urinalysis Abnormalities - Urinalysis
    End point description
    Safety endpoint: The urinalysis is based on pH, specific gravity, protein, blood, glucose, ketones, bilirubin, urobilinogen (local dipstick). Microscopy and other appropriate tests (as needed) will be performed if dipstick indicates any significant abnormality. All laboratory values will be classified as normal or abnormal according to the laboratories normal ranges and as clinically significant according to the assessment of the investigator. The number analyzed are patients with data available.
    End point type
    Other pre-specified
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61 [5]
    62 [6]
    Units: Participants
    number (not applicable)
        Clinically Significant abnormality - Baseline - No
    46
    42
        Clinically Significant abnormality - Baseline-Yes
    14
    14
        Clinically Significant abnormality - Endpoint - No
    36
    34
        Clinically Significant abnormality - Endpoint-Yes
    13
    9
    Notes
    [5] - 1ª Category: Group A - 60 participants 2ª Categ: A - 60 3ª Categ: A - 49 4ª Categ: A - 49
    [6] - 1ª Category: Group B - 56 participants 2ª Categ: A - 56 3ª Categ: A - 43 4ª Categ: A - 43
    No statistical analyses for this end point

    Other pre-specified: Clinically Significant Vital Sign Abnormalities: Blood Pressure

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    End point title
    		 Clinically Significant Vital Sign Abnormalities: Blood Pressure
    End point description
    Safety endpoint: The systolic and diastolic blood pressure (mmHg) were to be measured after the patient had rested for at least 5 minutes. Painful procedures, like drawing blood, had to be performed after vital signs measurements (not before). The analyses of variables for vital sign parameters will focus on the evaluation of the change from baseline to the scheduled time points after baseline. Descriptive statistics of the time course and of changes from baseline to each post-baseline time point will be presented by treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Systolic BP [mmHg] - Baseline - CS high
    1
    3
        Diastolic BP [mmHg] - Baseline - CS low
    0
    0
        Diastolic BP [mmHg] - Baseline - CS high
    0
    1
        Systolic BP [mmHg] - Endpoint - CS high
    1
    1
        Diastolic BP [mmHg] - Endpoint - CS low
    0
    1
        Diastolic BP [mmHg] - Endpoint - CS high
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Clinically Significant Vital Sign Abnormalities: Heart Rate

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    End point title
    		 Clinically Significant Vital Sign Abnormalities: Heart Rate
    End point description
    Safety endpoint: The Heart Rate (bpm) were to be measured after the patient had rested for at least 5 minutes. Painful procedures, like drawing blood, had to be performed after vital signs measurements (not before). The analyses of variables for vital sign parameters will focus on the evaluation of the change from baseline to the scheduled time points after baseline. Descriptive statistics of the time course and of changes from baseline to each post-baseline time point will be presented by treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Participants
    number (not applicable)
        Pulse rate [bpm] - Baseline - CS high
    0
    0
        Pulse rate [bpm] - Endpoint - CS high
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Suicidal Ideation and Behaviour, Assessed by PHQ-9 (Question 9)

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    End point title
    		 Suicidal Ideation and Behaviour, Assessed by PHQ-9 (Question 9)
    End point description
    Safety endpoint: Suicidal ideation and suicidal behaviour as assessed by the PHQ-9 question 9 will be presented for each time of assessment by the number and frequency of patients in each response category by treatment group. 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 will be evaluated exploratively using the Wilcoxon-Mann-Whitney Test and Hodge-Lehmann CIs. Cumulative incidence curves of USs vs. the PHQ-9 score will be displayed graphically by time of examination and treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Over 18 months follow-up period
    End point values
    		 Group A - ESL Group B - Placebo
    Number of subjects analysed
    61
    62
    Units: Points
    log mean (standard deviation)
        Baseline - Observed Value
    0 ( 0 )
    0.1 ( 0.45 )
        V3 - Observed Value
    0.1 ( 0.47 )
    0.1 ( 0.39 )
        V3 - Change from Baseline
    0 ( 0.20 )
    0 ( 0.66 )
        V5 - Observed Value
    0.1 ( 0.56 )
    0.1 ( 0.29 )
        V5 - Change from Baseline
    0.1 ( 0.47 )
    0 ( 0.60 )
        V7 - Observed Value
    0 ( 0 )
    0 ( 0 )
        V7 - Change from Baseline
    0 ( 0 )
    -0.1 ( 0.55 )
        Early discontinuation visit - Observed Value
    0 ( 0 )
    0 ( 0 )
        Early discontinuation visit - Change from Baseline
    0 ( 0 )
    0 ( 0 )
        End of trial visit - Observed Value
    0.1 ( 0.23 )
    0.1 ( 0.52 )
        End of trial visit - Change from Baseline
    0 ( 0.16 )
    0 ( 0.77 )
        Endpoint - Observed Value
    0.1 ( 0.45 )
    0.1 ( 0.45 )
        Endpoint - Change from Baseline
    0.1 ( 0.44 )
    0 ( 0.69 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events with the first onset or worsening after the first IMP intake until 14 days after the last IMP intake.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Group A - ESL
    Reporting group description
    		 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.

    Reporting group title
    Group B - Placebo
    Reporting group description
    		 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.

    Serious adverse events
    		 Group A - ESL Group B - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 61 (19.67%)
    13 / 62 (20.97%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of bladder
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney angiomyolipoma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac valve disease
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal arrhythmia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Basal ganglia infarction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral vasoconstriction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Endocarditis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group A - ESL Group B - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 61 (81.97%)
    48 / 62 (77.42%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of bladder
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Kidney angiomyolipoma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Vascular disorders
    Blood pressure inadequately controlled
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Circulatory collapse
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Haematoma
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    10 / 61 (16.39%)
    13 / 62 (20.97%)
         occurrences all number
    10
    13
    Hypotension
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Feeling of body temperature change
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Gait disturbance
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Inflammation
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 62 (3.23%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Aspiration
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Asthma-chronic obstructive pulmonary disease overlap syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Lung infiltration
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Productive cough
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 62 (3.23%)
         occurrences all number
    1
    3
    Anxiety
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    Anxiety disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Delirium
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Depressed mood
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 62 (6.45%)
         occurrences all number
    3
    4
    Insomnia
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 62 (8.06%)
         occurrences all number
    4
    5
    Major depression
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Mood swings
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Nightmare
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Post stroke depression
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Restlessness
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Sleep disorder
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Sleep disorder due to general medical condition, insomnia type
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Sopor
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 62 (1.61%)
         occurrences all number
    3
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Blood glucose increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Blood potassium increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Eosinophil count increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    3
    Haemoglobin urine present
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    High density lipoprotein decreased
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Lipase increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Muscle enzyme increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 62 (4.84%)
         occurrences all number
    4
    3
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Cardiac valve disease
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Intracardiac thrombus
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Nodal arrhythmia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Basal ganglia infarction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Brain oedema
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Cerebral vasoconstriction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Diabetic neuropathy
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Disturbance in attention
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Dizziness
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Dysarthria
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    4 / 61 (6.56%)
    8 / 62 (12.90%)
         occurrences all number
    4
    8
    Hemiparesis
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    3
    Loss of consciousness
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Memory impairment
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Muscle spasticity
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Neuralgia
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    3
    Paraesthesia
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Partial seizures
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Polyneuropathy
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Seizure
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 62 (3.23%)
         occurrences all number
    1
    2
    Sensory loss
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Status epilepticus
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Thalamic infarction
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Anaemia macrocytic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Eosinophilia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Lymphopenia
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Visual impairment
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Anal incontinence
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 62 (9.68%)
         occurrences all number
    3
    6
    Diarrhoea
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Dry mouth
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Duodenal ulcer
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Gastritis erosive
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 62 (4.84%)
         occurrences all number
    3
    3
    Pancreatitis chronic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Rectal polyp
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 62 (3.23%)
         occurrences all number
    2
    2
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 62 (3.23%)
         occurrences all number
    2
    2
    Rash erythematous
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Rash generalised
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Hypertonic bladder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Ketonuria
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Renal impairment
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Urinary incontinence
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Back pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Endocarditis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Pneumonia
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Prostatic abscess
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Pulmonary sepsis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 62 (8.06%)
         occurrences all number
    4
    5
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Urosepsis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Diabetes mellitus
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Dyslipidaemia
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Fluid overload
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Folate deficiency
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 62 (4.84%)
         occurrences all number
    5
    4
    Hyponatraemia
         subjects affected / exposed
    6 / 61 (9.84%)
    1 / 62 (1.61%)
         occurrences all number
    7
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Oct 2018
    Version 2.0: Updated study design; first version for submission to authorities.
    20 Jan 2020
    Version 3.0: Global Amendment #1, dated 20-JAN-2020: Adjustments of inclusion and exclusion criteria for specification of patient population in accordance with the discussions with the investigators that are participating in the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Recruitment was closed by the end of February 2022, due to the unforeseen COVID-19 pandemic circumstances, recruitment had not progressed as initially estimated. This decision was not based on safety concerns or circumstances related to the IMP.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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