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    Clinical Trial Results:
    Intrathecal administration (pattern 100/3) of expanded autologous adult bone marrow mesenchymal troncal cells in established chronic spinal cord injuries

    Summary
    EudraCT number
    		 2014-005613-24
    Trial protocol
    		 ES  
    Global end of trial date
    04 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jun 2022
    First version publication date
    11 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CME-LEM3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundación Investigación Biomédica Hospital Universitario Puerta de Hierro
    Sponsor organisation address
    C/ Joaquín Rodrigo, 2 Majadahonda, Madrid, Spain, 28222
    Public contact
    SIte contact point, Fundación Investigación Biomédica Hospital Universitario Puerta de Hierro, +34 911917760,
    Scientific contact
    SIte contact point, Fundación Investigación Biomédica Hospital Universitario Puerta de Hierro, +34 911917760,
    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
    04 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To analyze the potential clinical efficacy of intrathecal administration, in the subarachnoid space, of in vitro expanded autologous adult bone marrow mesenchymal troncal cells in the treatment of patients with established chronic spinal cord injury (LEM)
    Protection of trial subjects
    Previous to NC1 preparation, a sample of peripheral blood was retrieved from each patient for genomic studies in order to rule out chromosomal abnormalities that could discourage cell expansion.
    Background therapy
    		 From the start of treatment until the end of the trial (month 10 after the first MSC administration) patients performed physical therapy exercises.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    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)
    11
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The planned duration of the clinical trial was 24 months. The duration of the recruitment phase was 12 months, the duration of the treatment phase was 7 months, and the duration of the follow-up period after the first administration of MSC was 10 months.

    Pre-assignment
    Screening details
    		 After signing the Informed Consent Form, participants were tested to determine if they met all the inclusion criteria and none of the exclusion criteria.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable. All the participants received the same treatment.

    Arms
    Arm title
    		 Arm 1
    Arm description
    		 Treatment arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    NC1
    Investigational medicinal product code
    Other name
    PEI number 12–141 (by the Spanish Agency of Medicament and Health Products)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subarachnoid administration, by lumbar puncture, of 3 doses of 100 x 10^6 autologous mesenchymal stromal cells (MSCs) obtained from bone marrow, expanded and supported in autologous plasma, with intervals of 3 months between each administration (month 1, 4 and 7) reaching a total administration of 300 x 10^6 mesenchymal stromal cells for each patient.

    Number of subjects in period 1
    		Arm 1
    Started
    11
    Completed
    10
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 11 11
    Age categorical
    Age ranged between 28 and 62 years (mean ± standard deviation [SD], 44.91 ± 10.17 years)
    Units: Subjects
        Adults (18-64 years)
    		 11 11
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 7 7
    American Spinal Injury Association Impairment Scale (ASIA) grade
    Units: Subjects
        ASIA A
    		 3 3
        ASIA B
    		 4 4
        ASIA C
    		 3 3
        ASIA D
    		 1 1
    Spinal cord injury (SCI) vertebral level
    Units: Subjects
        Cervical level
    		 4 4
        Dorsal level
    		 4 4
        Dorsolumbar level
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 Treatment arm

    Subject analysis set title
    Before treatment
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Baseline characteristics of the subjects

    Subject analysis set title
    At 4 months follow-up
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Characteristics of the subjects at 4 months follow-up

    Subject analysis set title
    At 7 months follow-up
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Characteristics of the subjects at 7 months follow-up

    Subject analysis set title
    At 10 months follow-up
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Characteristics of the subjects at 10 months follow-up

    Primary: Change in the score in ASIA scale

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    End point title
    		 Change in the score in ASIA scale
    End point description
    ASIA scale was used for sensitivity and motor assessments. Efficacy was assessed by taking into account the variation in the scores in the different scales between the subject´s inclusion in the study and the scores obtained at the end of the follow-up period.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up (FU) period.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up At 10 months follow-up
    Number of subjects analysed
    9
    9
    9
    9
    Units: Score
    arithmetic mean (standard deviation)
        Total Score
    181.56 ( 66.44 )
    204.22 ( 57.40 )
    213.22 ( 59.22 )
    216.56 ( 61.63 )
        Pin Prick Score
    61.11 ( 30.56 )
    74.56 ( 26.82 )
    79.56 ( 27.85 )
    80.11 ( 28.41 )
        Light Touch Score
    67.44 ( 24.00 )
    75.11 ( 19.19 )
    78.33 ( 19.66 )
    80.44 ( 21.80 )
        Motor Score
    53.00 ( 17.90 )
    54.56 ( 18.20 )
    55.33 ( 17.75 )
    56.00 ( 18.41 )
    Statistical analysis title
    		 Total Score: before treatment vs at 4 months FU
    Comparison groups
    At 4 months follow-up v Before treatment
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.012
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Total Score: before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Total Score: before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.021
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 PinPrick Score: before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.012
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 PinPrick Score: before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 PinPrick Score: before treatment vs 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.018
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Light Touch Score: before treatment vs 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.018
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Light Touch Score: before treatment vs 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Light Touch Score: before treatment vs 10 month FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Motor Score: before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.048
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Motor Score: before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.028
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Motor Score: before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.028
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in the score in IANR-SCIFRS scale

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    End point title
    		 Change in the score in IANR-SCIFRS scale
    End point description
    IANR-SCIFRS scale: the SCI Functional Rating Scale of the International Association of Neurorestoratology scale. This scale evaluates the global spinal cord function through nine sections, with a final section that only applies to men and assesses sexual function. Efficacy was assessed by taking into account the variation in the scores on the different scales between the subject´s inclusion in the study and the scores obtained at the end of the follow-up period.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up At 10 months follow-up
    Number of subjects analysed
    9
    9
    9
    9
    Units: Score
    arithmetic mean (standard deviation)
        Global Score
    27.36 ( 9.38 )
    32.10 ( 7.23 )
    34.90 ( 5.59 )
    36.20 ( 5.71 )
        Sexual Score (only males)
    1.00 ( 0.82 )
    1.00 ( 0.82 )
    1.14 ( 0.69 )
    1.29 ( 0.76 )
        Sphincter Score
    2.00 ( 1.87 )
    2.56 ( 1.74 )
    3.22 ( 1.86 )
    3.33 ( 1.94 )
    Statistical analysis title
    		 Global Score: before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.012
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Global Score: before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Global Score: before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Sexual Score: before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - The p-value was non-computable
    Statistical analysis title
    		 Sexual Score: before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.317
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Sexual Score: before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.157
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Sphincter Score: before treatment vs 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.084
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Sphincter Score: before treatment vs 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.017
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Sphincter Score: before treatment vs 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.018
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in the score in VAS scale

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    End point title
    		 Change in the score in VAS scale
    End point description
    VAS: Visual Analog Scale. This scale evaluates neuropathic pain. Efficacy was assessed by taking into account the variation in the scores on the different scales between the subject´s inclusion in the study and the scores obtained at the end of the follow-up period.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up At 10 months follow-up
    Number of subjects analysed
    9
    9
    9
    9
    Units: Score
        arithmetic mean (standard deviation)
    4.89 ( 2.37 )
    3.67 ( 2.00 )
    2.22 ( 2.05 )
    1.33 ( 2.03 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.012
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.012
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in the score in PENN scale

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    End point title
    		 Change in the score in PENN scale
    End point description
    PENN scale measures the degree of spasms. Efficacy was assessed by taking into account the variation in the scores on the different scales between the subject´s inclusion in the study and the scores obtained at the end of the follow-up period.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up At 10 months follow-up
    Number of subjects analysed
    9
    9
    9
    9
    Units: Score
        arithmetic mean (standard deviation)
    1.33 ( 1.50 )
    1.22 ( 1.48 )
    1.11 ( 1.45 )
    1.11 ( 1.36 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.317
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.157
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.317
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in the score in Ashworth scale

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    End point title
    		 Change in the score in Ashworth scale
    End point description
    Ashworth scale measures the degree of spasticity. Efficacy was assessed by taking into account the variation in the scores on the different scales between the subject´s inclusion in the study and the scores obtained at the end of the follow-up period.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up At 10 months follow-up
    Number of subjects analysed
    9
    9
    9
    9
    Units: Score
        arithmetic mean (standard deviation)
    1.44 ( 1.74 )
    1.33 ( 1.58 )
    1.11 ( 1.27 )
    1.11 ( 1.27 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.317
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.158
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.158
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in the score in Geffner scale

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    End point title
    		 Change in the score in Geffner scale
    End point description
    Geffner scale was used for the study of bladder function. Efficacy was assessed by taking into account the variation in the scores on the different scales between the subject´s inclusion in the study and the scores obtained at the end of the follow-up period.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up At 10 months follow-up
    Number of subjects analysed
    9
    9
    9
    9
    Units: Score
        arithmetic mean (standard deviation)
    2.33 ( 1.66 )
    2.78 ( 1.48 )
    3.11 ( 1.83 )
    3.11 ( 1.83 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.084
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.028
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.028
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in the score in NBD scale

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    End point title
    		 Change in the score in NBD scale
    End point description
    NBD scale was used for the study of of neurogenic bowel dysfunction (NBD). Efficacy was assessed by taking into account the variation in the scores on the different scales between the subject´s inclusion in the study and the scores obtained at the end of the follow-up period.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up At 10 months follow-up
    Number of subjects analysed
    9
    9
    9
    9
    Units: Score
        arithmetic mean (standard deviation)
    13.89 ( 8.45 )
    8.33 ( 9.87 )
    7.11 ( 8.13 )
    5.78 ( 6.14 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.028
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.018
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.012
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in neurophysiological parameters: improvement in Somatosensory Evoked Potentials (SSEP)

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    End point title
    		 Change in neurophysiological parameters: improvement in Somatosensory Evoked Potentials (SSEP) [2]
    End point description
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    Notes
    [2] - 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: A qualitative evaluation was performed, comparing the results with the baseline values.
    End point values
    		 Arm 1
    Number of subjects analysed
    9
    Units: Subjects
        Improvement in SSEP
    6
        No improvement in SSEP
    3
    No statistical analyses for this end point

    Primary: Change in neurophysiological parameters: improvement in Motor Evoked Potentials (MEP)

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    End point title
    		 Change in neurophysiological parameters: improvement in Motor Evoked Potentials (MEP) [3]
    End point description
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    Notes
    [3] - 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: A qualitative evaluation was performed, comparing the results with the baseline values.
    End point values
    		 Arm 1
    Number of subjects analysed
    9
    Units: Subjects
        Improvement in MEP
    5
        No improvement in MEP
    4
    No statistical analyses for this end point

    Primary: Change in neurophysiological parameters: improvement in sensitivity conduction

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    End point title
    		 Change in neurophysiological parameters: improvement in sensitivity conduction [4]
    End point description
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    Notes
    [4] - 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: A qualitative evaluation was performed, comparing the results with the baseline values.
    End point values
    		 Arm 1
    Number of subjects analysed
    9
    Units: Subjects
        Improvement
    3
        No improvement
    6
    No statistical analyses for this end point

    Primary: Change in neurophysiological parameters: improvement in motor conduction

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    End point title
    		 Change in neurophysiological parameters: improvement in motor conduction [5]
    End point description
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    Notes
    [5] - 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: A qualitative evaluation was performed, comparing the results with the baseline values.
    End point values
    		 Arm 1
    Number of subjects analysed
    9
    Units: Subjects
        Improvement
    2
        No improvement
    7
    No statistical analyses for this end point

    Primary: Change in neurophysiological parameters: improvement in voluntary muscle contraction

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    End point title
    		 Change in neurophysiological parameters: improvement in voluntary muscle contraction [6]
    End point description
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    Notes
    [6] - 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: A qualitative evaluation was performed, comparing the results with the baseline values.
    End point values
    		 Arm 1
    Number of subjects analysed
    9
    Units: Subjects
        Improvement
    4
        No improvement
    5
    No statistical analyses for this end point

    Primary: Change in neurophysiological parameters: presence of infralesional activity muscle reinnervation

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    End point title
    		 Change in neurophysiological parameters: presence of infralesional activity muscle reinnervation [7]
    End point description
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    Notes
    [7] - 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: A qualitative evaluation was performed, comparing the results with the baseline values.
    End point values
    		 Arm 1
    Number of subjects analysed
    9
    Units: Subjects
        Improvement
    4
        No improvement
    5
    No statistical analyses for this end point

    Primary: Change in urodynamic studies: first sensation at filling

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    End point title
    		 Change in urodynamic studies: first sensation at filling
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: cc
        arithmetic mean (standard deviation)
    275.33 ( 189.21 )
    244.56 ( 98.13 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.952
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in urodynamic studies: maximum bladder capacity at filling

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    End point title
    		 Change in urodynamic studies: maximum bladder capacity at filling
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: cc
        arithmetic mean (standard deviation)
    421.56 ( 175.73 )
    435.67 ( 138.20 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.953
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in urodynamic studies: bladder compliance at filling

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    End point title
    		 Change in urodynamic studies: bladder compliance at filling
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: cc
        arithmetic mean (standard deviation)
    31.61 ( 50.00 )
    24.26 ( 15.35 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.515
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in urodynamic studies: volume

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    End point title
    		 Change in urodynamic studies: volume
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: cc
        arithmetic mean (standard deviation)
    41.67 ( 97.54 )
    75.56 ( 100.93 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.018
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in urodynamic studies: time

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    End point title
    		 Change in urodynamic studies: time
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: seconds
        arithmetic mean (standard deviation)
    17.50 ( 42.00 )
    105.00 ( 104.47 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.014
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in urodynamic studies: Q max

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    End point title
    		 Change in urodynamic studies: Q max
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: ml/seg
        arithmetic mean (standard deviation)
    2.88 ( 6.08 )
    5.00 ( 4.50 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    At 10 months follow-up v Before treatment
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.178
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in urodynamic studies: detrusor pressure at filling

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    End point title
    		 Change in urodynamic studies: detrusor pressure at filling
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: cm H2O
        arithmetic mean (standard deviation)
    11.00 ( 19.83 )
    35.11 ( 31.67 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.097
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in urodynamic studies: postmictional residue

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    End point title
    		 Change in urodynamic studies: postmictional residue
    End point description
    Urodynamic studies were performed using a Solar Luna equipment (Medical Measurement Systems Inc.).
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    End point values
    		 Before treatment At 10 months follow-up
    Number of subjects analysed
    9
    9
    Units: cc
        arithmetic mean (standard deviation)
    339.33 ( 248.91 )
    334.22 ( 182.01 )
    Statistical analysis title
    		 Before treatment vs at 10 months FU
    Comparison groups
    Before treatment v At 10 months follow-up
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.722
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in spinal cord morphology

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    End point title
    		 Change in spinal cord morphology [8]
    End point description
    The measurements were taken by a 3T imager (XR InteraAchieva 3T, Philips Healthcare). Lesions were studied on T1-and T2-weighted images and on MR-myelography images, using turbo-spin-echo sequences. Qualitatively, it was observed that the patients did not present changes in spinal cord morphology.
    End point type
    Primary
    End point timeframe
    Between the subject´s inclusion in the study and the end of the follow-up period.
    Notes
    [8] - 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: A qualitative evaluation was performed, comparing the results with the baseline values.
    End point values
    		 Arm 1
    Number of subjects analysed
    11
    Units: mm
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Change in the levels of neurotrophins in cerebrospinal fluid: BDNF (brain-derived neurotrophic factor)

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    End point title
    		 Change in the levels of neurotrophins in cerebrospinal fluid: BDNF (brain-derived neurotrophic factor)
    End point description
    End point type
    Secondary
    End point timeframe
    Between the subject´s inclusion in the study and 7 month of follow-up.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up
    Number of subjects analysed
    7
    9
    8
    Units: pg/ml
        arithmetic mean (standard deviation)
    2.67 ( 5.73 )
    30.26 ( 90.78 )
    54.70 ( 110.47 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.662
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.118
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in the levels of neurotrophins in cerebrospinal fluid: GDNF (glial cell line-derived neurotrophic factor)

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    End point title
    		 Change in the levels of neurotrophins in cerebrospinal fluid: GDNF (glial cell line-derived neurotrophic factor)
    End point description
    End point type
    Secondary
    End point timeframe
    Between the subject´s inclusion in the study and 7 month of follow-up.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up
    Number of subjects analysed
    7
    9
    7
    Units: pg/ml
        arithmetic mean (standard deviation)
    0.70 ( 0.64 )
    1.15 ( 1.15 )
    1.19 ( 1.00 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.678
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.097
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in the levels of neurotrophins in cerebrospinal fluid: NGF (nerve growth factor)

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    End point title
    		 Change in the levels of neurotrophins in cerebrospinal fluid: NGF (nerve growth factor)
    End point description
    End point type
    Secondary
    End point timeframe
    Between the subject´s inclusion in the study and 7 month of follow-up.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up
    Number of subjects analysed
    7
    9
    7
    Units: pg/ml
        arithmetic mean (standard deviation)
    2.42 ( 3.20 )
    7.83 ( 18.09 )
    12.39 ( 23.46 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.504
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.585
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in the levels of neurotrophins in cerebrospinal fluid: NT3

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    End point title
    		 Change in the levels of neurotrophins in cerebrospinal fluid: NT3
    End point description
    End point type
    Secondary
    End point timeframe
    Between the subject´s inclusion in the study and 7 month of follow-up.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up
    Number of subjects analysed
    7
    9
    8
    Units: pg/ml
        arithmetic mean (standard deviation)
    37.01 ( 4.70 )
    47.40 ( 33.30 )
    67.02 ( 58.74 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.441
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    Before treatment v At 7 months follow-up
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.066
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in the levels of neurotrophins in cerebrospinal fluid: NT4

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    End point title
    		 Change in the levels of neurotrophins in cerebrospinal fluid: NT4
    End point description
    End point type
    Secondary
    End point timeframe
    Between the subject´s inclusion in the study and 7 month of follow-up.
    End point values
    		 Before treatment At 4 months follow-up At 7 months follow-up
    Number of subjects analysed
    7
    9
    8
    Units: pg/ml
        arithmetic mean (standard deviation)
    9.39 ( 14.97 )
    11.33 ( 12.72 )
    10.30 ( 8.63 )
    Statistical analysis title
    		 Before treatment vs at 4 months FU
    Comparison groups
    Before treatment v At 4 months follow-up
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.097
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Before treatment vs at 7 months FU
    Comparison groups
    At 7 months follow-up v Before treatment
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.441
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the entire clinical trial
    Adverse event reporting additional description
    Adverse events were collected asking questions to the participants and performing general clinical examinations and neurological examinations.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 Treatment arm

    Serious adverse events
    		 Arm 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Follicle centre lymphoma, follicular grade I, II, III
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Arm 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 11 (36.36%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant ascites
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    2
    Nervous system disorders
    Sciatica
    Additional description: Transitory sciatic pain
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
    Additional description: Pleural and peritoneal effusion
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Infections and infestations
    Urinary tract infection
    Additional description: Urine infection
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Number of patients studied and the variability of lesions.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29853256
    For support, Contact us.
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