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    Clinical Trial Results:
    Stem cells in Rapidly Evolving Active Multiple Sclerosis (STREAMS)

    Summary
    EudraCT number
    		 2012-002357-35
    Trial protocol
    		 GB  
    Global end of trial date
    31 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Dec 2019
    First version publication date
    29 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO1959
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01606215
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Clinicaltrials.gov: NCT01606215
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    160 Du Cane Road Burlington Danes Building Hammersmith Campus , London, United Kingdom, W12 0NN
    Public contact
    Dr Paolo Muraro, Imperial College London, +44 02075946670, p.muraro@imperial.ac.uk
    Scientific contact
    Dr Paolo Muraro, Imperial College London, +44 02075946670, p.muraro@imperial.ac.uk
    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
    Interim
    Date of interim/final analysis
    16 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    There are two co-primary objectives. The first is to assess the safety of intravenous therapy with autologous (derived from the individuals themselves) MSCs in MS patients. The safety of MSCs infusion will be evaluated including frequency, timing and severity of any adverse events in both MSCs and placebo treatment groups. The second is to evaluate the activity of autologous MSCs in MS patients, quantified by the reduction in the number of new contrast-enhancing lesions on MRI scans over 24 weeks, the latter suggesting new inflammation.
    Protection of trial subjects
    1. For procedures such as lumbar punctures, skin biopsy and the bone marrow harvest, local anaesthetic was used to minimise pain during the procedure 2. Patients could voluntarily withdraw at any time from the study and follow-up assessments. 3. Unblinding could be requested if the clinical situation warranted it on patient safety grounds 4. The patient’s participation in the study could also be discontinued at any time at the discretion of the investigator - justifiable reasons include dSuspected Unexpected Serious Adverse Reactions (SUSAR) or deterioration in the disease activity requiring immunomodulatory treatment
    Background therapy
    		 N/A - the patients were not on any other treatment during the trial.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Mar 2013
    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
    United Kingdom: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    21
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients from the UK were recruited at Imperial College Healthcare Trust between 23 March 2013 and 26 June 2015

    Pre-assignment
    Screening details
    		 A total of 21 patients with multiple sclerosis were screened and randomised but only 13 patients completed the trial. Details: 1 patient withdrew consent after screening, 1 patient's MRI did not meet criteria after review and 6 patients failed to meet the required MSC dose after expansion

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    All subjects were randomised after verifying that they are eligible. Randomisation was carried out within a web-based system, made available to authorised researchers, by the Clinical Research Organisation (CRO) in charge. The stem cell laboratory was made aware of the allocation (so that the order of the infusion) - both infusions were made to identical volumes and appearance - was known but the patients, investigators and data analysts were blinded to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Early MSC-treated
    Arm description
    		 Patients receiving 1-2 x106cells/kg MSCs in the first infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mesenchymal Stem cells
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1-2 x106 million MSC cells/kg suspended in 5% HAS/10% DMSO

    Arm title
    		 Placebo
    Arm description
    		 placebo Drug Product comprising 5% HAS/10% DMSO is prepared - only lacks the MSCs that are present in the active arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    equal volume of 5% HAS/10% DMSO

    Number of subjects in period 1
    		Early MSC-treated Placebo
    Started
    10
    11
    Completed
    6
    7
    Not completed
    4
    4
         Consent withdrawn by subject
    1
    -
         mscs did not expand
    3
    -
         mri on re-review did not meet criteria
    -
    1
         mscs failed to expand
    -
    3
    Period 2
    Period 2 title
    Crossover
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MSCs after placebo
    Arm description
    		 Patients receiving 1-2 x106cells/kg MSCs in the first infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mesenchymal Stem cells
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1-2 x106 million MSC cells/kg suspended in 5% HAS/10% DMSO

    Arm title
    		 Placebo after treatment
    Arm description
    		 placebo Drug Product comprising 5% HAS/10% DMSO is prepared - only lacks the MSCs that are present in the active arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    equal volume of 5% HAS/10% DMSO

    Number of subjects in period 2
    		MSCs after placebo Placebo after treatment
    Started
    7
    6
    Completed
    7
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomisation
    Reporting group description
    		 -

    Reporting group values
    		 Randomisation Total
    Number of subjects
    		 21 21
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 21 21
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 38 (25 to 50) -
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 6 6
    Ethnic group
    Units: Subjects
        Caucasian
    		 20 20
        Afro-Caribbean
    		 0 0
        Middle Eastern
    		 1 1
    Disease duration
    Units: years
        arithmetic mean (full range (min-max))
    		 5.49 (0.5 to 9.83) -
    baseline EDSS
    Units: units
        arithmetic mean (full range (min-max))
    		 3.85 (2.0 to 6.0) -
    relapses in 18 months pre-trial
    Units: n/a
        arithmetic mean (full range (min-max))
    		 2.23 (1 to 4) -
    no of gadolinium enhancing lesions on MRI at baseline
    Units: number
        arithmetic mean (full range (min-max))
    		 1.38 (1 to 3) -
    Subject analysis sets

    Subject analysis set title
    early msc treated completed
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    early msc treated period 1 pts who completed treatment

    Subject analysis set title
    delayed MSC group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    pts receiving MSCs at Week 24 having received placebo at Week 0

    Subject analysis sets values
    		 early msc treated completed delayed MSC group
    Number of subjects
    6
    7
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    6
    7
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    41.7 (30 to 50)
    32.1 (25 to 43)
    Gender categorical
    Units: Subjects
        Female
    4
    5
        Male
    2
    2
    Ethnic group
    Units: Subjects
        Caucasian
    6
    6
        Afro-Caribbean
        Middle Eastern
    1
    Disease duration
    Units: years
        arithmetic mean (full range (min-max))
    baseline EDSS
    Units: units
        arithmetic mean (full range (min-max))
    relapses in 18 months pre-trial
    Units: n/a
        arithmetic mean (full range (min-max))
    no of gadolinium enhancing lesions on MRI at baseline
    Units: number
        arithmetic mean (full range (min-max))

    End points

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    End points reporting groups
    Reporting group title
    Early MSC-treated
    Reporting group description
    		 Patients receiving 1-2 x106cells/kg MSCs in the first infusion

    Reporting group title
    Placebo
    Reporting group description
    		 placebo Drug Product comprising 5% HAS/10% DMSO is prepared - only lacks the MSCs that are present in the active arm
    Reporting group title
    MSCs after placebo
    Reporting group description
    		 Patients receiving 1-2 x106cells/kg MSCs in the first infusion

    Reporting group title
    Placebo after treatment
    Reporting group description
    		 placebo Drug Product comprising 5% HAS/10% DMSO is prepared - only lacks the MSCs that are present in the active arm

    Subject analysis set title
    early msc treated completed
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    early msc treated period 1 pts who completed treatment

    Subject analysis set title
    delayed MSC group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    pts receiving MSCs at Week 24 having received placebo at Week 0

    Primary: number of adverse events

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    End point title
    		 number of adverse events [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    24 week period in each half of the trial
    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: numbers too small
    [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: numbers too small
    End point values
    		 Placebo early msc treated completed
    Number of subjects analysed
    7
    6
    Units: number
        number (not applicable)
    4
    5
    No statistical analyses for this end point

    Secondary: number of relapses in first period

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    End point title
    		 number of relapses in first period
    End point description
    total number of relapses in MSC treated periods vs sham periods
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Early MSC-treated Placebo
    Number of subjects analysed
    6
    7
    Units: number
        number (not applicable)
    2
    10
    No statistical analyses for this end point

    Secondary: total number of relapses in second period

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    End point title
    		 total number of relapses in second period
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 MSCs after placebo Placebo after treatment
    Number of subjects analysed
    7
    6
    Units: number
        number (not applicable)
    4
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    msc treated
    Reporting group description
    		 13 patients receiving MSCs either at Week 0 or Week 24 11 total AEs in 7 pts

    Reporting group title
    placebo group
    Reporting group description
    		 13 patients given sham infusion either at week 0 or at week 24 4 adverse events in total in 3 patients

    Serious adverse events
    		 msc treated placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 msc treated placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 13 (53.85%)
    3 / 13 (23.08%)
    Vascular disorders
    DVT
    Additional description: unrelated to infusion - flight and family history
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    headache
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    back pain
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    4
    1
    upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    loss of appetite
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2013
    requesting additional blood samples and inserting an additional mantoux test
    03 Jan 2014
    1.The inclusion criterion “Disease duration 2-10 years from diagnosis” was changed to “Disease duration 0-10 years from diagnosis”. T 2. The inclusion criterion “EDSS 3.0 - 6.5 at screening evaluation” was changed to “EDSS 2.0 - 6.5 at screening evaluation” 3.inclusion criterion “≥1GEL on MRI within 3 months prior to harvesting” was changed to “≥1GEL on MRI within 6 months prior to harvesting”
    02 Apr 2014
    to allow a dose range of 1-2 x106 cells/kg rather than stipulate 2 x 106 cells/kg
    14 Jan 2015
    to allow second phase of recruitment into streams

    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.
    small study but double blind and randomised
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