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    Clinical Trial Results:
    Cerebrolysin and Recovery after Stroke (CARS) - A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase II Clinical Study.

    Summary
    EudraCT number
    		 2007-000870-21
    Trial protocol
    		 PL  
    Global end of trial date
    29 Dec 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EBE-RO-061215
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    EVER Neuro Pharma GmbH
    Sponsor organisation address
    Oberburgau 3, Unterach, Austria, 4866
    Public contact
    Clinical Research & Development, EVER Neuro Pharma GmbH , +43 7665 20555 0, studies@everpharma.com
    Scientific contact
    Clinical Research & Development, EVER Neuro Pharma GmbH , +43 7665 20555 0, studies@everpharma.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
    12 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Dec 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of this trial was to investigate whether patients randomized to Cerebrolysin showed improved ARAT scores over the 90-day study observation period in comparison with patients randomized to placebo.
    Protection of trial subjects
    Informed consent was obtained from all trial subjects. Safety assessments included physical examination, lab tests (haematology, chemistry panel and urinalysis), vital signs (incl. blood pressure in supine position, heart rate, and respiration rate), and adverse events. A negative urine pregnancy test was required for female patients in reproductive years. Concomitant illnesses and medication were documented.
    Background therapy
    		 At the investigator’s discretion: Basic stroke treatment for general management including thrombolysis on an as-needed basis without restriction, a compensation of fluid and electrolyte balance and acid-base balance, and substances needed for adequate management of secondary symptoms including but not limited to antihypertensive agents, cardiovascular treatment, anti-diabetic agents, antibiotics, and treatment for sleep disturbances and body temperature lowering.
    Evidence for comparator
    		 The comparator is a placebo (sodium chloride solution 0.9%).
    Actual start date of recruitment
    17 Apr 2008
    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
    Romania: 182
    Country: Number of subjects enrolled
    Ukraine: 26
    Worldwide total number of subjects
    208
    EEA total number of subjects
    182
    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)
    97
    From 65 to 84 years
    111
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: 17 April 2008 - 01 October 2010 Recruitment territories: Romania (N=182; 8 sites), Ukraine (N=26; 3 sites), Poland (N=0)

    Pre-assignment
    Screening details
    		 In-patients were screened for in-/exclusion criteria. Screening failures and reasons were not documented as agreed pre-study.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Carer, Assessor
    Blinding implementation details
    The packaging material for the infusion solution was designed to ensure the study medication of both treatment groups to be indistinguishable in appearance: - the volume of the infusion solution was identical in both treatment groups - a colored sleeve was put over the infusion bag to mask potential slight colour differences between the active treatment and placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cerebrolysin
    Arm description
    		 Cerebrolysin was administered once daily as an intravenous infusion. Each infusion consisted of 30 ml Cerebrolysin + 70 ml sodium choloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cerebrolysin
    Investigational medicinal product code
    EV Substance code: SUB74627; CAS number:12656-61-0
    Other name
    Renacenz, Cognicer
    Pharmaceutical forms
    Solution for injection, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 30 ml/day (3x10 ml ampoules) Administration: intravenous infusion of 30 ml Cerebrolysin + 70 ml sodium chloride solution 0.9%, once daily for 21 consecutive days

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administered once daily as an intravenous infusion. Each infusion consisted of 100 ml sodium chloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride solution 0.9%
    Investigational medicinal product code
    EV Substance code: SUB20079
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 100 ml/day Administration: intravenous infusion, once daily for 21 consecutive days

    Number of subjects in period 1
    		Cerebrolysin Placebo
    Started
    104
    104
    Completed
    104
    104
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The packaging material for the infusion solution was designed to ensure the study medication of both treatment groups to be indistinguishable in appearance: - the volume of the infusion solution was identical in both treatment groups - a colored sleeve was put over the infusion bag to mask potential slight colour differences between the active treatment and placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cerebrolysin
    Arm description
    		 Cerebrolysin was administered once daily as an intravenous infusion. Each infusion consisted of 30 ml Cerebrolysin + 70 ml sodium choloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cerebrolysin
    Investigational medicinal product code
    EV Substance code: SUB74627; CAS number:12656-61-0
    Other name
    Renacenz, Cognicer
    Pharmaceutical forms
    Solution for injection, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 30 ml/day (3x10 ml ampoules) Administration: intravenous infusion of 30 ml Cerebrolysin + 70 ml sodium chloride solution 0.9%, once daily for 21 consecutive days

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administered once daily as an intravenous infusion. Each infusion consisted of 100 ml sodium chloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride solution 0.9%
    Investigational medicinal product code
    EV Substance code: SUB20079
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 100 ml/day Administration: intravenous infusion, once daily for 21 consecutive days

    Number of subjects in period 2
    		Cerebrolysin Placebo
    Started
    104
    104
    Completed
    100
    96
    Not completed
    4
    8
         Adverse event, serious fatal
    -
    3
         Administrative cause
    -
    1
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cerebrolysin
    Reporting group description
    		 Cerebrolysin was administered once daily as an intravenous infusion. Each infusion consisted of 30 ml Cerebrolysin + 70 ml sodium choloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered once daily as an intravenous infusion. Each infusion consisted of 100 ml sodium chloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.

    Reporting group values
    		 Cerebrolysin Placebo Total
    Number of subjects
    		 104 104 208
    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)
    		 46 51 97
        From 65-84 years
    		 58 53 111
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.9 ( 9.8 ) 63.0 ( 10.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 34 41 75
        Male
    		 70 63 133

    End points

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    End points reporting groups
    Reporting group title
    Cerebrolysin
    Reporting group description
    		 Cerebrolysin was administered once daily as an intravenous infusion. Each infusion consisted of 30 ml Cerebrolysin + 70 ml sodium choloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered once daily as an intravenous infusion. Each infusion consisted of 100 ml sodium chloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.
    Reporting group title
    Cerebrolysin
    Reporting group description
    		 Cerebrolysin was administered once daily as an intravenous infusion. Each infusion consisted of 30 ml Cerebrolysin + 70 ml sodium choloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered once daily as an intravenous infusion. Each infusion consisted of 100 ml sodium chloride solution 0.9%. The infusion was administered over 20 minutes, once daily over 21 consecutive days. The first infusion was administered after baseline assessment and within 24-72 h after onset of stroke.

    Subject analysis set title
    mITT-LOCF (nonparametric re-analysis)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT analysis set was defined as all randomized patients who have had at least 1 dose of study medication and have assessments for the primary end point (ARAT) at baseline and at least 1 time point after the first dose of study medication.

    Subject analysis set title
    Full analysis LOCF (parametric analysis)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients who have had at least one dose of study medication and have assessments for the primary endpoint (ARAT score) at baseline and at least one time point after first dose of study medication.

    Primary: ARAT score change from baseline to day 90 in the paretic arm

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    End point title
    		 ARAT score change from baseline to day 90 in the paretic arm
    End point description
    The Action Reasearch arm test (ARAT) assesses upper limb functioning and is a 19 item measure divided into 4 sub-tests (grasp, grip, pinch, and gross arm movement). Performance on each item is rated on a 4-point ordinal scale (performs test normally: 3, completes test but takes abnormally long or has great difficulty: 2, performs test partially: 1, can perform no part of test: 0). The first item of each sub-test represents the most difficult item, thus, if a patient scores 3 points on the first item, he will be automatically credited with 3 points on the following items of that sub-test. Similarly, the second item of each sub-test represents the easiest item, thus, if a patient scores 0 points in the second item, he will be automatically credited with 0 points on the following items of that sub-test. The score ranges from 0 – 57.
    End point type
    Primary
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo Full analysis LOCF (parametric analysis)
    Number of subjects analysed
    104
    103
    207
    Units: Score
        least squares mean (confidence interval 95%)
    30.5 (27.0 to 34.0)
    15.3 (11.8 to 18.8)
    30.5 (27.0 to 34.0)
    Attachments
    		 ARAT score change from baseline
    Statistical analysis title
    		 ARAT change from baseline - parametric analysis
    Statistical analysis description
    The primary evaluation on ARAT was an analysis of covariance (ANCOVA) on the change scores from baseline to day 90 comparing the differences among study groups. The ANCOVA model included the day 90 change score as dependent variable and the baseline score as a covariate. Estimates of least square means and associated 95% confidence intervals were provided. The LOCF approach was used for missing data, baseline data were not carried forward.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Least square means
    Point estimate
    15.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.3
         upper limit
    		 20.1

    Post-hoc: ARAT score change from baseline to day 90 in the paretic arm - nonparametric re-analysis

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    End point title
    		 ARAT score change from baseline to day 90 in the paretic arm - nonparametric re-analysis
    End point description
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    104
    101
    205
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.7118 (0.6307 to 0.7928)
    0.7118 (0.6307 to 0.7928)
    0.7118 (0.6307 to 0.7928)
    Attachments
    		 ARAT score change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of ARAT
    Statistical analysis description
    Nonparametric analyses were performed using the Wilcoxon–Mann–Whitney test because of the skewness and non-normality of the distributions (Shapiro–Wilk; P=0.0137) and the presence of outliers. The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon–Mann–Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    205
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [1]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.7118
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6307
         upper limit
    		 0.7928
    Notes
    [1] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50 The traditional benchmark values for the MW are 0.29 (large inferiority), 0.36 (medium inferiority), 0.44 (small inferiority), 0.50 (equality), 0.56 (small superiority), 0.64 (medium superiority), and 0.71 (large superiority).

    Post-hoc: Gait velocity change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 Gait velocity change from baseline to day 90 - nonparametric re-analysis
    End point description
    Gait velocity is measured as the time taken to walk the middle 8 meters of 10 meters and is timed by a chronometer. The first and last meters, considered respectively warm-up and the deceleration phases, are not included in the calculation. Participants begin the GV test on the word "go" and are instructed to "walk at a comfortable and secure pace." Each participant performs the task twice, with the final score being the time in seconds of the quicker of the two timed trials.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    34
    35
    69
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.5937 (0.4585 to 0.7289)
    0.5937 (0.4585 to 0.7289)
    0.5937 (0.4585 to 0.7289)
    Attachments
    		 Gait velocity change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of gait velocity
    Statistical analysis description
    The Mann-Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon-Mann-Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    69
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [2]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.5937
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4585
         upper limit
    		 0.7289
    Notes
    [2] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: 9-Hole Peg Test change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 9-Hole Peg Test change from baseline to day 90 - nonparametric re-analysis
    End point description
    The 9-HPT is a brief, standardized, quantitative test of upper extremity function. Both the dominant and non-dominant hands are tested twice. The patient is seated at a table with a small, shallow container holding nine pegs and a wood or plastic block containing nine empty holes. On a start command when a stopwatch is started, the patient picks up the nine pegs one at a time as quickly as possible, puts them in the nine holes, and, once they are in the holes, removes them again as quickly as possible one at a time, replacing them into the shallow container. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    90
    93
    183
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.5612 (0.4777 to 0.6448)
    0.5612 (0.4777 to 0.6448)
    0.5612 (0.4777 to 0.6448)
    Attachments
    		 9 Hole Peg Test change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of 9 Hole Peg Test
    Statistical analysis description
    The Mann-Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon-Mann-Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    183
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [3]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.5612
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4777
         upper limit
    		 0.6448
    Notes
    [3] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: NIHSS change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 NIHSS change from baseline to day 90 - nonparametric re-analysis
    End point description
    The NIHSS assesses neurologic deficit and is a 15 item scale that covers the level of consciousness, gaze, visual fields, facial palsy, motor functions, limb ataxia, aphasia, dysarthria and extinction and inattention. Items have 3- to 5-point response scales, scored from 0 to 4 with higher score indicative of more severe disability. In case of patient death, the worst score possible is assigned.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    104
    101
    205
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.6754 (0.5977 to 0.7530)
    0.6754 (0.5977 to 0.7530)
    0.6754 (0.5977 to 0.7530)
    Attachments
    		 NIHSS change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of NIHSS
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon–Mann–Whitney test.
    Comparison groups
    Cerebrolysin v Placebo
    Number of subjects included in analysis
    205
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [4]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.6754
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5977
         upper limit
    		 0.753
    Notes
    [4] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: Barthel Index change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 Barthel Index change from baseline to day 90 - nonparametric re-analysis
    End point description
    The Barthel Index is a functional outcome scale measuring activities of daily living and is based on observed functions. The scale covers feeding, mobility from bed to chair, personal toilet (washing etc.), getting on/off the toilet, bathing, walking on level surface, going up/down stairs, dressing and incontinence (bladder and bowel). Items have 2- to 3-point response scales, scored 0, 5 or 0, 5, and 10 with higher scores indicative of better function. Individuals are scored on ten activities which give a total score of 0 (totally dependent) to 100 (fully independent) with 5-point increments. In case of patient death, the worst score possible is assigned.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    104
    101
    205
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.6720 (0.5922 to 0.7518)
    0.6720 (0.5922 to 0.7518)
    0.6720 (0.5922 to 0.7518)
    Attachments
    		 Barthel Index change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of Barthel Index
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon–Mann–Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    205
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [5]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.672
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5922
         upper limit
    		 0.7518
    Notes
    [5] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: mRS change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 mRS change from baseline to day 90 - nonparametric re-analysis
    End point description
    The modified Rankin Scale (mRS) is a functional outcome scale measuring global outcome. It is used for grading the outcome and the level of disability after a stroke. The mRS is a 7-point ordinal scale with a score of 0 indicative of no residual symptoms at all and the worst possible score of 6 which is assigned in case of death.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    104
    101
    205
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.7339 (0.6612 to 0.8065)
    0.7339 (0.6612 to 0.8065)
    0.7339 (0.6612 to 0.8065)
    Attachments
    		 mRS change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of mRS
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon–Mann–Whitney test.
    Comparison groups
    Cerebrolysin v Placebo
    Number of subjects included in analysis
    205
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [6]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.7339
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6612
         upper limit
    		 0.8065
    Notes
    [6] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: Goodglass and Kaplan Communication Scale change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 Goodglass and Kaplan Communication Scale change from baseline to day 90 - nonparametric re-analysis
    End point description
    This 6-point ordinal scale requires simple categorical assignment to determine the severity of an aphasia, which is based entirely on communicative ability.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    104
    101
    205
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.5614 (0.4938 to 0.6290)
    0.5614 (0.4938 to 0.6290)
    0.5614 (0.4938 to 0.6290)
    Attachments
    		 G&K Comm Scale change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of Goodglass and Kaplan
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon–Mann–Whitney test.
    Comparison groups
    Cerebrolysin v Placebo
    Number of subjects included in analysis
    205
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [7]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.5614
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4938
         upper limit
    		 0.629
    Notes
    [7] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: SF-36 physical component summary change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 SF-36 physical component summary change from baseline to day 90 - nonparametric re-analysis
    End point description
    The SF-36 Health Survey is a 36-item short-form (SF-36) and consists of eight scales yielding two summary measures: physical and mental health. The physical health measure includes four scales of physical functioning (10 items), role-physical (4 items), bodily pain (2 items), and general health (5 items). The mental health measure is composed of vitality (4 items), social functioning (2 items), role-emotional (3 items), and mental health (5 items).
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    102
    95
    197
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.6727 (0.5900 to 0.7553)
    0.6727 (0.5900 to 0.7553)
    0.6727 (0.5900 to 0.7553)
    Attachments
    		 SF-36 PCS change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of SF-36 PCS
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon–Mann–Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    197
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [8]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.6727
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.7553
    Notes
    [8] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: Line cancellation test change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 Line cancellation test change from baseline to day 90 - nonparametric re-analysis
    End point description
    At the line cancellation test (score range from 0 to 36 points), subjects are presented with a single sheet of paper on which 6 lines in varying orientations are drawn, 18 on each side. They are instructed to make a mark through all of the lines. Left- sided neglect was indicated by a failure to mark more lines on the left side than on the right. Degree of neglect is assessed by the proportion of lines omitted relative to the total number of lines. The line cancellation test sheet is divided into right and left portions and a right and then a left correct answer rates are analyzed.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    98
    100
    198
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.4696 (0.4041 to 0.5351)
    0.4696 (0.4041 to 0.5351)
    0.4696 (0.4041 to 0.5351)
    Attachments
    		 Line Canc Test change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of Line Canc Test
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the Wilcoxon–Mann–Whitney test.
    Comparison groups
    Cerebrolysin v Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [9]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.4696
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4041
         upper limit
    		 0.5351
    Notes
    [9] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: Gap detection test change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 Gap detection test change from baseline to day 90 - nonparametric re-analysis
    End point description
    In the gap-detection test, twenty circles and forty pseudo-circles, each with a diameter of 15 mm, are drawn in a random manner on a sheet of white paper (29.7 x 42 cm) and are arranged evenly on either side of the vertical midline of the paper. Half of the pseudo-circles have a missing portion on the right side, and the rest have a missing portion on the left side. The patient is instructed to circle every complete circle and to cross out every incomplete circle with a pen held in the hand. To investigate neglect, the total number of figures correctly circled or crossed out is calculated for the left and right side of the stimulus sheet (body-centered neglect) and with respect to the three types of circles (stimulus-centered neglect).
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    97
    100
    197
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.4981 (0.4281 to 0.5681)
    0.4981 (0.4281 to 0.5681)
    0.4981 (0.4281 to 0.5681)
    Attachments
    		 Gap Detect Test change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of Gap Detection Test
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the well-known Wilcoxon–Mann–Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    197
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [10]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.4981
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4281
         upper limit
    		 0.5681
    Notes
    [10] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: SF-36 mental component summary change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 SF-36 mental component summary change from baseline to day 90 - nonparametric re-analysis
    End point description
    The SF-36 Health Survey is a 36-item short-form (SF-36) and consists of eight scales yielding two summary measures: physical and mental health. The physical health measure includes four scales of physical functioning (10 items), role-physical (4 items), bodily pain (2 items), and general health (5 items). The mental health measure is composed of vitality (4 items), social functioning (2 items), role-emotional (3 items), and mental health (5 items).
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    102
    95
    197
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.5602 (0.4795 to 0.6409)
    0.5602 (0.4795 to 0.6409)
    0.5602 (0.4795 to 0.6409)
    Attachments
    		 SF-36 MCS change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of SF-36 MCS
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the well-known Wilcoxon–Mann–Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    197
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [11]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.5602
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4795
         upper limit
    		 0.6409
    Notes
    [11] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: Geriatric Depression Scale change from baseline to day 90 - nonparametric re-analysis

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    End point title
    		 Geriatric Depression Scale change from baseline to day 90 - nonparametric re-analysis
    End point description
    The Geriatric Depression Scale (GDS) is a 30-item self-report assessment designed specifically to identify depression in the elderly. The items may be answered yes or no, which is thought to be simpler than scales that use a five-category response set. It is generally recommended as a routine part of a comprehensive geriatric assessment. One point is assigned to each answer and corresponds to a scoring grid. A score of 10 or 11 or lower is the usual threshold to separate depressed from nondepressed patients.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    102
    96
    198
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.6805 (0.6007 to 0.7603)
    0.6805 (0.6007 to 0.7603)
    0.6805 (0.6007 to 0.7603)
    Attachments
    		 GDS change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of GDS
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the well-known Wilcoxon–Mann–Whitney test.
    Comparison groups
    Cerebrolysin v Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [12]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.6805
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6007
         upper limit
    		 0.7603
    Notes
    [12] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Post-hoc: Global status change from basline to day 90 - nonparametric re-analysis

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    End point title
    		 Global status change from basline to day 90 - nonparametric re-analysis
    End point description
    The global outcome is the summary of all 12 efficacy parameter.
    End point type
    Post-hoc
    End point timeframe
    Baseline to day 90
    End point values
    		 Cerebrolysin Placebo mITT-LOCF (nonparametric re-analysis)
    Number of subjects analysed
    104
    101
    205
    Units: Mann-Whitney (MW)
        number (confidence interval 95%)
    0.6159 (0.5799 to 0.6518)
    0.6159 (0.5799 to 0.6518)
    0.6159 (0.5799 to 0.6518)
    Attachments
    		 Global status change from baseline (MW estimate)
    Statistical analysis title
    		 Nonparametric re-analysis of global status
    Statistical analysis description
    The Mann–Whitney estimator (MW) was calculated as the effect size measure associated with the well-known Wilcoxon–Mann–Whitney test.
    Comparison groups
    Placebo v Cerebrolysin
    Number of subjects included in analysis
    205
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [13]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mann-Whitney
    Point estimate
    0.6159
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5799
         upper limit
    		 0.6518
    Notes
    [13] - The null and alternative hypotheses for the comparison of the effects of Cerebrolysin versus placebo can be formulated as follows (superiority test; T: test treatment; C: control treatment): Null hypothesis H0: MWTC≤0.50 Alternative hypothesis HA: MWTC>0.50

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to day 90.
    Adverse event reporting additional description
    At each visit, AEs were documented and evaluated in terms of nature, date and time of onset, duration, severity, causality, action taken, outcome, and seriousness. Patients with AEs were followed up until the event has subsided, the condition was considered medically stable, or the patient was no longer available to follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Cerebrolysin
    Reporting group description
    		 Subjects entering the treatment phase (randomization V2) and randomized to active treatment group, received intravenous infusion of 100 ml solution (3 x 10 ml ampoules of Cerebrolysin in 70 ml NaCl 0.9 %) once daily for 21 successive days at the same time every day.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects entering the treatment phase (randomization V2) and randomized to placebo group, received intravenous infusion of 100 ml 0.9 % NaCl once daily for 21 successive days at the same time every day.

    Serious adverse events
    		 Cerebrolysin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 104 (2.88%)
    7 / 104 (6.73%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    0
    4
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Peripheral ischemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 104 (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
    Coma
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Carotid artery occlusion
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Multi-organ disorder
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cerebrolysin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 104 (64.42%)
    60 / 104 (57.69%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 104 (8.65%)
    12 / 104 (11.54%)
         occurrences all number
    15
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 104 (5.77%)
    3 / 104 (2.88%)
         occurrences all number
    8
    3
    Carotid artery stenosis
         subjects affected / exposed
    6 / 104 (5.77%)
    2 / 104 (1.92%)
         occurrences all number
    6
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    6 / 104 (5.77%)
    4 / 104 (3.85%)
         occurrences all number
    6
    5
    Hepatobiliary disorders
    Cytolytic hepatitis
         subjects affected / exposed
    10 / 104 (9.62%)
    8 / 104 (7.69%)
         occurrences all number
    10
    8
    Psychiatric disorders
    Depression
         subjects affected / exposed
    11 / 104 (10.58%)
    10 / 104 (9.62%)
         occurrences all number
    11
    10
    Insomnia
         subjects affected / exposed
    6 / 104 (5.77%)
    4 / 104 (3.85%)
         occurrences all number
    6
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    13 / 104 (12.50%)
    17 / 104 (16.35%)
         occurrences all number
    15
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2008
    Amendment 1 / Study protocol V2.0: - inclusion of further study sites - increase of sample size
    02 Sep 2008
    Amendment 2 / Study protocol V2.1: - change of study biometrician - revision of the statistics section - change of inclusion criterion 2
    21 Nov 2008
    Amendment 3 / Study protocol V2.2: - re-change of inclusion criterion 2 - correction of time windows for visits 3, 4, 5; - adjustment of discontinuation criteria and action taken/outcome - inclusion of further study sites - change of sponsor's company name
    15 Apr 2009
    Amendment 4 / Study Protocol V2.3: - inclusion of further study sites - update of sample size calculation - increase of sample size - update of study timelines - changes in packaging and preparation of study drug
    12 Nov 2009
    Amendment 5 / Study protocol V2.4 - change of sponsor’s company name - update of study timelines - amended information on the Gap Detection Test
    10 Jun 2010
    Amendment 6 / Study protocol V2.5 - change of sponsor's company address and phone number - change of study safety officer - update of study medication label - correction of information on NIHSS

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26564102
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