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    Clinical Trial Results:
    Double-Blind, Randomized, Placebo-Controlled, Phase 2 Safety and Efficacy Trial of MultiStem® in Adults With Ischemic Stroke

    Summary
    EudraCT number
    		 2012-005749-18
    Trial protocol
    		 GB  
    Global end of trial date
    07 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2021
    First version publication date
    14 May 2021
    Other versions
    Summary report(s)
    		 Hess 2017
    Hess 2017 - Supplement

    Trial information

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    Trial identification
    Sponsor protocol code
    B01-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01436487
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ReGenesys, BVBA
    Sponsor organisation address
    Gaston Geenslaan 1, Heverlee, Belgium, 3001
    Public contact
    Manal Morsy, ReGenesys, BVBA, 1 2162153071, mmorsy@regenesys.eu
    Scientific contact
    Manal Morsy, ReGenesys, BVBA, 1 2162153071, mmorsy@regenesys.eu
    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
    07 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to: -To determine the highest well tolerated and safest single dose of MultiStem up to a maximum of 1200 million (1.2 billion) total cells in subjects with ischemic stroke -To determine the efficacy of MultiStem on stroke recovery in subjects with ischemic stroke.
    Protection of trial subjects
    An Independent Safety Committee with multidisciplinary representation evaluated accumulating trial data and assessed the ongoing safety of the trial for the subjects enrolled. Following each data review, the Independent Safety Committee made a recommendation to the sponsor regarding continuation, revision of dosage, or termination of the trial. The study was conducted in compliance with Good Clinical Practice, an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects. Compliance with this standard provides public assurance that the rights, safety, and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 131
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    137
    EEA total number of subjects
    0
    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)
    80
    From 65 to 84 years
    57
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients 18–79 years with a moderately severe ischaemic stroke with motor or speech deficit defined by a National Institutes of Health Stroke Scale (NIHSS) score of 8–20 at baseline just before administration (≥24 h).

    Pre-assignment period milestones
    Number of subjects started
    		 137
    Number of subjects completed
    		 134

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single intravenous placebo infusion

    Arm title
    		 Cohort 1 400 million cells
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 million cells

    Arm title
    		 Cohort 2/3 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single intravenous placebo infusion

    Arm title
    		 Cohort 2/3 1.2 billion cells
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiStem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.2 billion cells single intravenous infusion

    Number of subjects in period 1 [1]
    		Cohort 1 Placebo Cohort 1 400 million cells Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells
    Started
    2
    6
    61
    65
    Completed
    2
    6
    48
    58
    Not completed
    0
    0
    13
    7
         Adverse event, serious fatal
    -
    -
    9
    5
         Consent withdrawn by subject
    -
    -
    -
    1
         Lost to follow-up
    -
    -
    4
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three subjects withdrew consent before receiving allocated intervention.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 400 million cells
    Reporting group description
    		 -

    Reporting group title
    Cohort 2/3 Placebo
    Reporting group description
    		 -

    Reporting group title
    Cohort 2/3 1.2 billion cells
    Reporting group description
    		 -

    Reporting group values
    		 Cohort 1 Placebo Cohort 1 400 million cells Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Total
    Number of subjects
    		 2 6 61 65 134
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 6 33 37 77
        From 65-84 years
    		 1 0 28 28 57
    Gender categorical
    Units: Subjects
        Female
    		 1 1 28 30 60
        Male
    		 1 5 33 35 74
    Patients with left hemisphere event
    Units: Subjects
        Yes
    		 2 5 36 37 80
        No
    		 0 1 25 28 54
    Patients treated with tPA
    Units: Subjects
        Yes
    		 1 0 29 29 59
        No
    		 1 6 32 36 75
    Patients treated with endovascular thrombectomy
    Units: Subjects
        Yes
    		 0 0 12 17 29
        No
    		 2 6 49 48 105
    Both tPA and endovascular thrombectomy
    Units: Subjects
        Yes
    		 0 0 9 8 17
        No
    		 2 6 52 57 117
    Any reperfusion therapy (tPA, thrombectomy, both)
    Units: Subjects
        Yes
    		 1 0 32 38 71
        No
    		 1 6 29 27 63
    NIHSS 8-12 at baseline
    Units: Subjects
        Yes
    		 1 3 27 29 60
        No
    		 1 3 34 36 74
    Infarct size
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    		 9.3 ± 1.1 55.8 ± 27.1 50.9 ± 41.3 43.7 ± 26.9 -
    Mean NIHSS at baseline
    National Institutes of Health Stroke Scale Score
    Units: none
        arithmetic mean (standard deviation)
    		 15.5 ± 5.0 12.2 ± 2.9 13.3 ± 3.7 13.4 ± 3.6 -
    Median NIHSS at baseline
    National Institutes of Health Stroke Scale Score
    Units: none
        median (full range (min-max))
    		 13 (9 to 19) 12 (9 to 17) 13 (8 to 20) 13 (8 to 20) -
    Symptom onset to drug infusion
    Units: hour
        arithmetic mean (standard deviation)
    		 32.8 ± 3.4 31.7 ± 2.8 39.3 ± 6.7 37.2 ± 6.9 -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 400 million cells
    Reporting group description
    		 -

    Reporting group title
    Cohort 2/3 Placebo
    Reporting group description
    		 -

    Reporting group title
    Cohort 2/3 1.2 billion cells
    Reporting group description
    		 -

    Subject analysis set title
    Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cohort 2/3 Placebo excluding subjects who received both tPA and mechanical reperfusion therapy.

    Subject analysis set title
    Cohort 2/3 Original Trial Protocol - MultiStem
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects receiving MultiStem within 36 hours of symptom onset excluding subjects treated with both tPA and mechanical reperfusion.

    Subject analysis set title
    Cohort 2/3 Early Treatment - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects treated with placebo < 36 hours after symptom onset.

    Subject analysis set title
    Cohort 2/3 Early Treatment - MultiStem
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects treated with MultiStem < 36 hours after symptom onset.

    Primary: Global Stroke Recovery

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    End point title
    		 Global Stroke Recovery [1] [2]
    End point description
    The primary efficacy outcome was the multivariate global stroke recovery at day 90, which assesses global disability, neurological deficit, and activities of daily living and consists of mRS 2 or less; NIHSS total score improvement of 75% or more from baseline; and Barthel index of 95 or more in the multipotent adult progenitor cells treatment group, compared with the placebo treatment. The data from these three binary variables from each patient were analysed with an additive logistic regression model with the treatment group and baseline NIHSS score (≤12 or ≥13) as dependent variables.
    End point type
    Primary
    End point timeframe
    Day 90
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Odds ratio
        number (confidence interval 95%)
    1.08 (0.55 to 2.09)
    1.08 (0.55 to 2.09)
    2.28 (0.98 to 5.30)
    2.28 (0.98 to 5.30)
    2.07 (0.70 to 6.10)
    2.07 (0.70 to 6.10)
    No statistical analyses for this end point

    Secondary: Modified Rankin Scale ≤ 2

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    End point title
    		 Modified Rankin Scale ≤ 2 [3]
    End point description
    Number of subjects obtaining mRS outcome of two or better at Day 90 assessment.
    End point type
    Secondary
    End point timeframe
    90 Days
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        mRS ≤ 2
    22
    24
    16
    13
    5
    14
    No statistical analyses for this end point

    Secondary: NIHSS Improvement ≥ 75%

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    End point title
    		 NIHSS Improvement ≥ 75% [4]
    End point description
    Number of subjects exhibiting 75% or greater improvement in NIHSS from baseline to Day 90 assessment.
    End point type
    Secondary
    End point timeframe
    90 days
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        NIHSS Improvement ≥ 75%
    23
    26
    16
    14
    6
    15
    No statistical analyses for this end point

    Secondary: Barthel Index ≥ 95

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    End point title
    		 Barthel Index ≥ 95 [5]
    End point description
    Number of subjects achieving Barthel Index ≥ 95 at day 90.
    End point type
    Secondary
    End point timeframe
    90 days
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        Barthel Index ≥ 95
    27
    30
    20
    15
    8
    18
    No statistical analyses for this end point

    Secondary: NIHSS ≤ 1 or ≥ 11 point improvement

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    End point title
    		 NIHSS ≤ 1 or ≥ 11 point improvement [6]
    End point description
    Number of subjects achieving NIHSS ≤ 1 at day 90 or exhibiting ≥ 11 point improvement in NIHSS from baseline to day 90.
    End point type
    Secondary
    End point timeframe
    90 days
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    Units: Subjects
        NIHSS ≤ 1 or ≥ 11 point improvement
    18
    25
    15
    12
    No statistical analyses for this end point

    Secondary: mRS ≤ 1

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    End point title
    		 mRS ≤ 1 [7]
    End point description
    Number of subjects achieving mRS ≤ 1 at day 90.
    End point type
    Secondary
    End point timeframe
    90 days
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        mRS ≤ 1
    7
    10
    3
    5
    1
    5
    No statistical analyses for this end point

    Secondary: NIHSS ≤ 1

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    End point title
    		 NIHSS ≤ 1 [8]
    End point description
    Number of subjects achieving NIHSS ≤ 1 at day 90.
    End point type
    Secondary
    End point timeframe
    90 days
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        NIHSS ≤ 1
    10
    17
    8
    9
    5
    10
    No statistical analyses for this end point

    Secondary: Excellent outcome

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    End point title
    		 Excellent outcome [9]
    End point description
    Number of subjects achieving Excellent Outcome. Defined as a composite of mRS ≤ 1, NIHSS ≤ 1, and Barthel Index ≥ 95.
    End point type
    Secondary
    End point timeframe
    90 days
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        Excellent Outcome
    4
    10
    2
    5
    0
    5
    No statistical analyses for this end point

    Secondary: Global Stroke Recovery

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    End point title
    		 Global Stroke Recovery [10]
    End point description
    Multivariate global stroke recovery at 1 year, which assesses global disability, neurological deficit, and activities of daily living and consists of mRS 2 or less; NIHSS total score improvement of 75% or more from baseline; and Barthel index of 95 or more in the multipotent adult progenitor cells treatment group, compared with the placebo treatment. The data from these three binary variables from each patient were analysed with an additive logistic regression model with the treatment group and baseline NIHSS score (≤12 or ≥13) as dependent variables.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Odds ratio
        number (confidence interval 95%)
    1.48 (0.77 to 2.84)
    1.48 (0.77 to 2.84)
    1.84 (0.81 to 4.20)
    1.84 (0.81 to 4.20)
    1.14 (0.38 to 3.43)
    1.14 (0.38 to 3.43)
    No statistical analyses for this end point

    Secondary: Modified Rankin Scale ≤ 2

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    End point title
    		 Modified Rankin Scale ≤ 2 [11]
    End point description
    Number of subjects obtaining mRS outcome of two or better at 1 year assessment.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        Modified Rankin Scale ≤ 2
    27
    33
    20
    13
    10
    15
    No statistical analyses for this end point

    Secondary: NIHSS Improvement ≥ 75%

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    End point title
    		 NIHSS Improvement ≥ 75% [12]
    End point description
    Number of subjects achieving NIHSS Improvement ≥ 75% from baseline to 1 year.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        NIHSS Improvement ≥ 75%
    28
    32
    23
    15
    10
    16
    No statistical analyses for this end point

    Secondary: Barthel Index ≥ 95

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    End point title
    		 Barthel Index ≥ 95 [13]
    End point description
    Number of subjects achieving Barthel Index ≥ 95 at 1 year.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        Barthel Index ≥ 95
    27
    40
    22
    19
    10
    21
    No statistical analyses for this end point

    Secondary: mRS ≤ 1

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    End point title
    		 mRS ≤ 1 [14]
    End point description
    Number of subjects obtaining mRS outcome of ≤ 1 at 1 year assessment.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        mRS ≤ 1
    8
    18
    5
    9
    2
    10
    No statistical analyses for this end point

    Secondary: NIHSS ≤ 1

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    End point title
    		 NIHSS ≤ 1 [15]
    End point description
    Number of subjects achieving NIHSS ≤ 1 at 1 year.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        NIHSS ≤ 1
    12
    19
    8
    10
    4
    11
    No statistical analyses for this end point

    Secondary: Excellent outcome

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    End point title
    		 Excellent outcome [16]
    End point description
    Number of subjects achieving Excellent Outcome at 1 year. Defined as a composite of mRS ≤ 1, NIHSS ≤ 1, and Barthel Index ≥ 95.
    End point type
    Secondary
    End point timeframe
    1 year
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary and secondary efficacy endpoints are reported for all subjects receiving investigational product at the target dose of 1.2 billion cells (or match placebo) - Cohorts 2 and 3 combined.
    End point values
    		 Cohort 2/3 Placebo Cohort 2/3 1.2 billion cells Cohort 2/3 Placebo Excluding Dual Reperfusion Therapy Cohort 2/3 Original Trial Protocol - MultiStem Cohort 2/3 Early Treatment - Placebo Cohort 2/3 Early Treatment - MultiStem
    Number of subjects analysed
    61
    65
    52
    27
    19
    31
    Units: Subjects
        Excellent outcome
    5
    15
    3
    8
    0
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Through Day 365
    Adverse event reporting additional description
    There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Treatment-emergent adverse events (serious and non-serious) were not different between the multipotent adult progenitor cells and placebo arms. There was also no difference in the incidence of serious adverse events between the arms. Mortality was not different between the arms (5 [8%] patients died in the multipotent adult progenitor cell group vs 9 [15%] patients died in the placebo group; p=0·21). See attached Lancet Neurology publication from 2017 for more details describing safety endpoints

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jul 2013
    In response to lower-than-expected enrolment rates in the early stages of the study, the protocol’s inclusion and exclusion criteria were amended to broaden the eligible patient population: • The upper age limit was increased from 79 years to 83 years. • The treatment window was expanded from 24–36 h to 24–48 h after stroke onset to better accommodate limited hours of operations of cell processing laboratories needed to prepare the investigational, first-generation MultiStem product configuration used in this study • Allowed inclusion of patients receiving both tPA treatment and endovascular thrombectomy to accommodate evolving standards of care that included increasing use of endovascular thrombectomy following thrombolysis.

    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/28320635
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