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    Clinical Trial Results:
    Clarifying the mechanism of action of cladribine in relapsing multiple sclerosis

    Summary
    EudraCT number
    		 2018-004557-24
    Trial protocol
    		 DE  
    Global end of trial date
    23 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UKM17_0056
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universität Münster
    Sponsor organisation address
    Schlossplatz 2, Münster, Germany, 48149
    Public contact
    Coordinating investigator, Universitätsklinikum Münster, Klinik für Neurologie, luisa.klotz@ukmuenster.de
    Scientific contact
    Coordinating investigator, Universitätsklinikum Münster, Klinik für Neurologie, luisa.klotz@ukmuenster.de
    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
    15 Aug 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Analysis of the T cell receptor repertoire of CD4 and CD8 T cells, and the B cell receptor repertoire of CD19 B cells before and during the first year after onset of cladribine treatment in patients with relapsing-remitting multiple sclerosis (RRMS).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and the ICH Guidelines in Good Clinical Practice. The study was not started before the competent ethics committee had given a favorable opinion. Written informed consent was obtained from all patients and the study was only conducted as approved by the Ethics committee and the competent authority. Amendments were only implemented after approval.
    Background therapy
    		 If the lymphocyte count dropped below 200 cells/mm³, anti-herpes prophylaxis was considered in accordance with local standard practice for the duration of grade 4 lymphopenia. In the event of infections (e.g. herpes zoster), anti-infective treatment was initiated as clinically indicated.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    28 Oct 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 24 patients with RRMS were recruited for this study from October 2019 until January 2022.

    Pre-assignment
    Screening details
    		 Each patient's eligibility was verified during a screening visit. Informed consent was obtained prior to any clinical procedures performed solely for study-related purposes.

    Period 1
    Period 1 title
    Month 0
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Month 0
    Arm description
    		 Cladribine-treated patients at month 0.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MAVENCLAD
    Investigational medicinal product code
    Other name
    Cladribine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The recommended cumulative dose of MAVENCLAD was 3.5 mg/kg body weight over 2 years, administered as one treatment course of 1.75 mg/kg per year. Each treatment course consisted of two treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consisted of 4 or 5 days on which a patient received 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.

    Number of subjects in period 1
    		Month 0
    Started
    24
    Completed
    24
    Period 2
    Period 2 title
    Month 3
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Month 3
    Arm description
    		 Cladribine-treated patients at month 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MAVENCLAD
    Investigational medicinal product code
    Other name
    Cladribine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The recommended cumulative dose of MAVENCLAD was 3.5 mg/kg body weight over 2 years, administered as one treatment course of 1.75 mg/kg per year. Each treatment course consisted of two treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consisted of 4 or 5 days on which a patient received 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.

    Number of subjects in period 2
    		Month 3
    Started
    24
    Completed
    23
    Not completed
    1
         Consent withdrawn by subject
    1
    Period 3
    Period 3 title
    Month 12
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Month 12
    Arm description
    		 Cladribine-treated patients at month 12.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MAVENCLAD
    Investigational medicinal product code
    Other name
    Cladribine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The recommended cumulative dose of MAVENCLAD was 3.5 mg/kg body weight over 2 years, administered as one treatment course of 1.75 mg/kg per year. Each treatment course consisted of two treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consisted of 4 or 5 days on which a patient received 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.

    Number of subjects in period 3
    		Month 12
    Started
    23
    Completed
    23
    Period 4
    Period 4 title
    Month 24
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Month 24
    Arm description
    		 Cladribine-treated patients at month 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MAVENCLAD
    Investigational medicinal product code
    Other name
    Cladribine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The recommended cumulative dose of MAVENCLAD was 3.5 mg/kg body weight over 2 years, administered as one treatment course of 1.75 mg/kg per year. Each treatment course consisted of two treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consisted of 4 or 5 days on which a patient received 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.

    Number of subjects in period 4
    		Month 24
    Started
    23
    Completed
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Month 0
    Reporting group description
    		 Demographics and disease characteristics for cladribine-treated patients with RRMS at month 0.

    Reporting group values
    		 Month 0 Total
    Number of subjects
    		 24 24
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 24 24
    Age continuous
    Units: years
        median (full range (min-max))
    		 36.5 (21 to 56) -
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 9 9
    John Cunningham (JC) virus screening
    Units: Subjects
        Negative
    		 7 7
        Positive
    		 17 17
    Number of patients who already received a MS therapy
    Units: Subjects
        Patient received a MS therapy
    		 18 18
        Unknown
    		 6 6
    Last MS therapy received
    Units: Subjects
        Interferon Beta
    		 1 1
        Dimethyl Fumarate
    		 4 4
        Glatirameracetat
    		 1 1
        Fingolimod
    		 3 3
        Natalizumab
    		 6 6
        Ocrelizumab
    		 2 2
        Other
    		 1 1
        Unknown
    		 6 6
    Time from MS diagnosis to baseline visit
    Units: Years
        arithmetic mean (full range (min-max))
    		 5.19 (0.05 to 26.17) -
    Time from first MS symptoms to baseline visit
    Units: Years
        arithmetic mean (full range (min-max))
    		 5.36 (0.05 to 26.17) -
    Number of relapses since MS diagnosis
    Units: Number of relapses
        median (full range (min-max))
    		 2 (1 to 10) -
    Time from most recent relapse to baseline visit
    Units: Months
        median (full range (min-max))
    		 4.12 (0.59 to 112.56) -

    End points

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    End points reporting groups
    Reporting group title
    Month 0
    Reporting group description
    		 Cladribine-treated patients at month 0.
    Reporting group title
    Month 3
    Reporting group description
    		 Cladribine-treated patients at month 3.
    Reporting group title
    Month 12
    Reporting group description
    		 Cladribine-treated patients at month 12.
    Reporting group title
    Month 24
    Reporting group description
    		 Cladribine-treated patients at month 24.

    Subject analysis set title
    Month 0 - unstable disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cladribine-treated patients with unstable disease at month 0.

    Subject analysis set title
    Month 0 - stable disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cladribine-treated patients with stable disease at month 0.

    Subject analysis set title
    Month 12 - unstable disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cladribine-treated patients with unstable disease at month 12.

    Subject analysis set title
    Month 12 - stable disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cladribine-treated patients with stable disease at month 12.

    Subject analysis set title
    Month 24 - unstable disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cladribine-treated patients with unstable disease at month 24.

    Subject analysis set title
    Month 24 - stable disease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cladribine-treated patients with stable disease at month 24.

    Subject analysis set title
    Month 3 - Kaplan-Meier method
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Month 3 - Kaplan-Meier method

    Subject analysis set title
    Month 6 - Kaplan-Meier method
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Month 6 - Kaplan-Meier method

    Subject analysis set title
    Month 12 - Kaplan-Meier method
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Month 12 - Kaplan-Meier method

    Subject analysis set title
    Month 18 - Kaplan-Meier method
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Month 18 - Kaplan-Meier method

    Subject analysis set title
    Month 24 - Kaplan-Meier method
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Month 24 - Kaplan-Meier method

    Subject analysis set title
    Overall study
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients in the study

    Primary: T cell receptor repertoire – Number of clones

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    End point title
    		 T cell receptor repertoire – Number of clones
    End point description
    Due to insufficient availability of blood sample material, only 20 patients were analysed.
    End point type
    Primary
    End point timeframe
    Month 0, 12 and 24
    End point values
    		 Month 0 Month 12 Month 24
    Number of subjects analysed
    20
    18
    19
    Units: Number of clones
        arithmetic mean (standard deviation)
    1479299.45 ( 514265.58 )
    1287672.72 ( 516730.09 )
    1117550.79 ( 548980.80 )
    Statistical analysis title
    		 Absolute change from month 0 to month 12
    Statistical analysis description
    This study was intended as an explorative study, i.e. all results were interpreted as hypotheses-generating. The absolute change from month 0 to month 12 and from month 0 to month 24 were analyzed descriptively. Additionally, exploratory inferential analyses were performed. To assess the difference between two different time points, Student’s t-test for paired samples and Wilcoxon signed-rank test were used.
    Comparison groups
    Month 12 v Month 0
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1335
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 12
    Comparison groups
    Month 12 v Month 0
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1297
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 24 v Month 0
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 24 v Month 0
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Wilcoxon signed-rank test
    Confidence interval

    Secondary: T cell receptor repertoire – Number of unique clones

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    End point title
    		 T cell receptor repertoire – Number of unique clones
    End point description
    Due to insufficient availability of blood sample material, only 20 patients were analysed.
    End point type
    Secondary
    End point timeframe
    Month 0, 12 and 24
    End point values
    		 Month 0 Month 12 Month 24
    Number of subjects analysed
    20
    18
    19
    Units: Number of unique clones
        arithmetic mean (standard deviation)
    862025.60 ( 409681.87 )
    693093.61 ( 362987.09 )
    633434.42 ( 407096.02 )
    Statistical analysis title
    		 Absolute change from month 0 to month 12
    Comparison groups
    Month 0 v Month 12
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0063
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 12
    Comparison groups
    Month 0 v Month 12
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0056
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0024
    Method
    		 Wilcoxon signed-rank test
    Confidence interval

    Secondary: T cell receptor repertoire – Clonality

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    End point title
    		 T cell receptor repertoire – Clonality
    End point description
    Due to insufficient availability of blood sample material, only 20 patients were analysed.
    End point type
    Secondary
    End point timeframe
    Month 0, 12 and 24
    End point values
    		 Month 0 Month 12 Month 24
    Number of subjects analysed
    20
    18
    19
    Units: Clonality
        arithmetic mean (standard deviation)
    0.096 ( 0.052 )
    0.105 ( 0.061 )
    0.119 ( 0.084 )
    Statistical analysis title
    		 Absolute change from month 0 to month 12
    Comparison groups
    Month 0 v Month 12
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3262
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 12
    Comparison groups
    Month 0 v Month 12
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0385
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0961
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0401
    Method
    		 Wilcoxon signed-rank test
    Confidence interval

    Secondary: B cell receptor repertoire – Number of clones

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    End point title
    		 B cell receptor repertoire – Number of clones
    End point description
    Due to insufficient availability of blood sample material, only 22 patients were analysed.
    End point type
    Secondary
    End point timeframe
    Month 0 and 24
    End point values
    		 Month 0 Month 24
    Number of subjects analysed
    22
    22
    Units: Number of clones
        arithmetic mean (standard deviation)
    44494.91 ( 20894.87 )
    56806.27 ( 19366.05 )
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0402
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0271
    Method
    		 Wilcoxon signed-rank test
    Confidence interval

    Secondary: B cell receptor repertoire – Number of unique clones

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    End point title
    		 B cell receptor repertoire – Number of unique clones
    End point description
    Due to insufficient availability of blood sample material, only 22 patients were analysed.
    End point type
    Secondary
    End point timeframe
    Month 0 and 24
    End point values
    		 Month 0 Month 24
    Number of subjects analysed
    22
    22
    Units: Number of unique clones
        arithmetic mean (standard deviation)
    42846.41 ( 20321.30 )
    55449.27 ( 18954.07 )
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0316
    Method
    		 Student’s t-test for paired samples
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0246
    Method
    		 Wilcoxon signed-rank test
    Confidence interval

    Secondary: B cell receptor repertoire – Clonality

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    End point title
    		 B cell receptor repertoire – Clonality
    End point description
    Due to insufficient availability of blood sample material, only 22 patients were analysed.
    End point type
    Secondary
    End point timeframe
    Month 0 and 24
    End point values
    		 Month 0 Month 24
    Number of subjects analysed
    22
    22
    Units: Clonality
        arithmetic mean (standard deviation)
    0.022 ( 0.005 )
    0.018 ( 0.002 )
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Student’s t-test for paired samples Stat
    Confidence interval
    Statistical analysis title
    		 Absolute change from month 0 to month 24
    Comparison groups
    Month 0 v Month 24
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval

    Post-hoc: T cell receptor repertoire – Number of clones (disease status)

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    End point title
    		 T cell receptor repertoire – Number of clones (disease status)
    End point description
    Patients were grouped according to their disease status (“unstable disease” (n = 12) vs “stable disease” (n = 8)) and compared with each other. Due to insufficient availability of blood sample material, only 20 patients were analysed.
    End point type
    Post-hoc
    End point timeframe
    Month 0, 12 and 24
    End point values
    		 Month 0 - unstable disease Month 0 - stable disease Month 12 - unstable disease Month 12 - stable disease Month 24 - unstable disease Month 24 - stable disease
    Number of subjects analysed
    12
    8
    11
    7
    12
    7
    Units: Number of clones
        arithmetic mean (standard deviation)
    1456939.92 ( 603571.35 )
    1512838.75 ( 378461.58 )
    1183882.18 ( 582672.29 )
    1450772.14 ( 374030.43 )
    1043145.08 ( 609179.72 )
    1245103.43 ( 440154.70 )
    Statistical analysis title
    		 Comparison of disease status at month 0
    Statistical analysis description
    Comparison of disease status (“no unstable disease” vs “stable disease”) at month 0, month 12 and month 24 using Student’s t-test for unpaired sample or the Mann Whitney U test.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.9101
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.802
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 12
    Comparison groups
    Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3749
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 12
    Comparison groups
    Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2539
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.1003
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.4164
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 12
    Statistical analysis description
    The mean (±SD) number of clones changed from baseline to month 12 by -239449.55 ± 444762.39 for patients without stable disease and by -26870.43 ± 378013.67 for patients with stable disease.
    Comparison groups
    Month 12 - stable disease v Month 12 - unstable disease v Month 0 - stable disease v Month 0 - unstable disease
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3283
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 12
    Statistical analysis description
    The mean (±SD) number of clones changed from baseline to month 12 by -239449.55 ± 444762.39 for patients without stable disease and by -26870.43 ± 378013.67 for patients with stable disease.
    Comparison groups
    Month 12 - stable disease v Month 12 - unstable disease v Month 0 - stable disease v Month 0 - unstable disease
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2957
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of clones changed from baseline to month 24 by -413794.83 ± 413915.08 for patients without stable disease and by -313157.43 ± 419823.15 for patients with stable disease.
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease v Month 0 - stable disease v Month 0 - unstable disease
    Number of subjects included in analysis
    39
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5918
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of clones changed from baseline to month 24 by -413794.83 ± 413915.08 for patients without stable disease and by -313157.43 ± 419823.15 for patients with stable disease.
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease v Month 0 - stable disease v Month 0 - unstable disease
    Number of subjects included in analysis
    39
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6212
    Method
    		 t-test (Satterthwaite)
    Confidence interval

    Post-hoc: T cell receptor repertoire – Number of unique clones (disease status)

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    End point title
    		 T cell receptor repertoire – Number of unique clones (disease status)
    End point description
    Patients were grouped according to their disease status (“unstable disease” (n = 12) vs “stable disease” (n = 8)) and compared with each other. Due to insufficient availability of blood sample material, only 20 patients were analysed.
    End point type
    Post-hoc
    End point timeframe
    Month 0, 12 and 24
    End point values
    		 Month 0 - unstable disease Month 0 - stable disease Month 12 - unstable disease Month 12 - stable disease Month 24 - unstable disease Month 24 - stable disease
    Number of subjects analysed
    12
    8
    11
    7
    12
    7
    Units: Number of unique clones
        arithmetic mean (standard deviation)
    824845.92 ( 475027.78 )
    917795.13 ( 308292.59 )
    607361.09 ( 383500.92 )
    827816.14 ( 305854.61 )
    568364.50 ( 450424.63 )
    744982.86 ( 319758.46 )
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - stable disease v Month 0 - unstable disease
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.7345
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6022
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 12
    Comparison groups
    Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2854
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 12
    Comparison groups
    Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.1976
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.1198
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3345
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 12
    Statistical analysis description
    The mean (±SD) number of unique clones changed from baseline to month 12 by -183363.36 ± 237060.54 for patients without stable disease and by -103843.57 ± 154785.88 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.7914
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 12
    Statistical analysis description
    The mean (±SD) number of unique clones changed from baseline to month 12 by -183363.36 ± 237060.54 for patients without stable disease and by -103843.57 ± 154785.88 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.402
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of unique clones changed from baseline to month 24 by -256481.42 ± 271551.50 for patients without stable disease and by -200192.43 ± 277061.57 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    39
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.8369
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of unique clones changed from baseline to month 24 by -256481.42 ± 271551.50 for patients without stable disease and by -200192.43 ± 277061.57 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    39
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6743
    Method
    		 t-test (Satterthwaite)
    Confidence interval

    Post-hoc: T cell receptor repertoire – Clonality (disease status)

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    End point title
    		 T cell receptor repertoire – Clonality (disease status)
    End point description
    Patients were grouped according to their disease status (“unstable disease” (n = 12) vs “stable disease” (n = 8)) and compared with each other. Due to insufficient availability of blood sample material, only 20 patients were analysed.
    End point type
    Post-hoc
    End point timeframe
    Month 0, 12 and 24
    End point values
    		 Month 0 - unstable disease Month 0 - stable disease Month 12 - unstable disease Month 12 - stable disease Month 24 - unstable disease Month 24 - stable disease
    Number of subjects analysed
    12
    8
    11
    7
    12
    7
    Units: Clonality
        arithmetic mean (standard deviation)
    0.101 ( 0.060 )
    0.089 ( 0.042 )
    0.100 ( 0.068 )
    0.112 ( 0.052 )
    0.113 ( 0.090 )
    0.130 ( 0.076 )
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.9101
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6045
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 12
    Comparison groups
    Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5962
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 12
    Comparison groups
    Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6839
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3845
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    19
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6684
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 12
    Comparison groups
    Month 0 - stable disease v Month 0 - unstable disease v Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0154
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 12
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 12 - unstable disease v Month 12 - stable disease
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0346
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    39
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2614
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    39
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3195
    Method
    		 t-test (Satterthwaite)
    Confidence interval

    Post-hoc: B cell receptor repertoire – Number of clones (disease status)

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    End point title
    		 B cell receptor repertoire – Number of clones (disease status)
    End point description
    Patients were grouped according to their disease status (“unstable disease” (n = 14) vs “stable disease” (n = 8)) and compared with each other. Due to insufficient availability of blood sample material, only 22 patients were analysed.
    End point type
    Post-hoc
    End point timeframe
    Month 0 and 24
    End point values
    		 Month 0 - unstable disease Month 0 - stable disease Month 24 - unstable disease Month 24 - stable disease
    Number of subjects analysed
    14
    8
    14
    8
    Units: Number of clones
        arithmetic mean (standard deviation)
    43029.36 ( 23966.08 )
    47059.63 ( 15207.93 )
    57424.57 ( 20380.44 )
    55724.25 ( 18752.12 )
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5699
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6352
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.8676
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.8454
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5252
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6017
    Method
    		 t-test (Satterthwaite)
    Confidence interval

    Post-hoc: B cell receptor repertoire – Number of unique clones (disease status)

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    End point title
    		 B cell receptor repertoire – Number of unique clones (disease status)
    End point description
    Patients were grouped according to their disease status (“unstable disease” (n = 14) vs “stable disease” (n = 8)) and compared with each other. Due to insufficient availability of blood sample material, only 22 patients were analysed.
    End point type
    Post-hoc
    End point timeframe
    Month 0 and 24
    End point values
    		 Month 0 - unstable disease Month 0 - stable disease Month 24 - unstable disease Month 24 - stable disease
    Number of subjects analysed
    14
    8
    14
    8
    Units: Number of unique clones
        arithmetic mean (standard deviation)
    41430.00 ( 23450.22 )
    45325.13 ( 14372.34 )
    56134.71 ( 19948.17 )
    54249.75 ( 18335.04 )
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5699
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.6346
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.8676
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.8252
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of unique clones changed from baseline to month 24 by 14704.71 ± 29107.94 for patients without stable disease and by 8924.63 ± 19485.86 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5252
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of unique clones changed from baseline to month 24 by 14704.71 ± 29107.94 for patients without stable disease and by 8924.63 ± 19485.86 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5844
    Method
    		 t-test (Satterthwaite)
    Confidence interval

    Post-hoc: B cell receptor repertoire – Clonality (disease status)

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    End point title
    		 B cell receptor repertoire – Clonality (disease status)
    End point description
    Patients were grouped according to their disease status (“unstable disease” (n = 14) vs “stable disease” (n = 8)) and compared with each other. Due to insufficient availability of blood sample material, only 22 patients were analysed.
    End point type
    Post-hoc
    End point timeframe
    Month 0 and 24
    End point values
    		 Month 0 - unstable disease Month 0 - stable disease Month 24 - unstable disease Month 24 - stable disease
    Number of subjects analysed
    14
    8
    14
    8
    Units: Clonality
        arithmetic mean (standard deviation)
    0.023 ( 0.006 )
    0.020 ( 0.002 )
    0.018 ( 0.002 )
    0.018 ( 0.002 )
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.289
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 0
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.1233
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2731
    Method
    		 Mann-Whitney-U test
    Confidence interval
    Statistical analysis title
    		 Comparison of disease status at month 24
    Comparison groups
    Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.3185
    Method
    		 t-test (Satterthwaite)
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of clonality changed from baseline to month 24 by -0.006 ± 0.005 for patients without stable disease and by -0.002 ± 0.002 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0668
    Method
    		 Mann-Whitney U-test
    Confidence interval
    Statistical analysis title
    		 Change from month 0 to month 24
    Statistical analysis description
    The mean (±SD) number of clonality changed from baseline to month 24 by -0.006 ± 0.005 for patients without stable disease and by -0.002 ± 0.002 for patients with stable disease.
    Comparison groups
    Month 0 - unstable disease v Month 0 - stable disease v Month 24 - unstable disease v Month 24 - stable disease
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0301
    Method
    		 t-test (Satterthwaite)
    Confidence interval

    Post-hoc: Relapse evaluation

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    End point title
    		 Relapse evaluation
    End point description
    The percentage of patients without a relapse was analyzed with the Kaplan-Meier method.
    End point type
    Post-hoc
    End point timeframe
    Month 3, 6, 12, 18 and 24.
    End point values
    		 Month 3 - Kaplan-Meier method Month 6 - Kaplan-Meier method Month 12 - Kaplan-Meier method Month 18 - Kaplan-Meier method Month 24 - Kaplan-Meier method
    Number of subjects analysed
    24
    24
    24
    24
    24
    Units: Percentage without relapse
        number (confidence interval 95%)
    83.3 (61.5 to 93.4)
    74.6 (51.9 to 87.7)
    61.4 (38.9 to 77.8)
    57.0 (34.8 to 74.1)
    57.0 (34.8 to 74.1)
    No statistical analyses for this end point

    Post-hoc: Annualized relapse rate

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    End point title
    		 Annualized relapse rate
    End point description
    Annualized relapse rate calculated with Poisson regression.
    End point type
    Post-hoc
    End point timeframe
    In the course of the study.
    End point values
    		 Overall study
    Number of subjects analysed
    24
    Units: Annualized relapse rate
        number (confidence interval 95%)
    0.34 (0.21 to 0.56)
    No statistical analyses for this end point

    Post-hoc: EDSS (expanded disability status scale) score

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    End point title
    		 EDSS (expanded disability status scale) score
    End point description
    End point type
    Post-hoc
    End point timeframe
    Month 0, 3, 12 and 24.
    End point values
    		 Month 0 Month 3 Month 12 Month 24
    Number of subjects analysed
    24
    24
    23
    23
    Units: EDSS score
        median (full range (min-max))
    1.5 (0 to 4.5)
    1.25 (0 to 5.5)
    1 (0 to 5.5)
    1 (0 to 4)
    No statistical analyses for this end point

    Post-hoc: MSFC (multiple sclerosis functional composite) score

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    End point title
    		 MSFC (multiple sclerosis functional composite) score
    End point description
    End point type
    Post-hoc
    End point timeframe
    Month 0, 3, 12 and 24.
    End point values
    		 Month 0 Month 3 Month 12 Month 24
    Number of subjects analysed
    24
    21
    22
    18
    Units: MSFC score
        median (full range (min-max))
    0.35 (-0.51 to 1.25)
    0.74 (-0.10 to 1.30)
    0.77 (-0.06 to 1.29)
    0.55 (0.10 to 1.13)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time the informed consent was signed up to the study termination visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 -

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 24 (37.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 24 (100.00%)
    Vascular disorders
    Peripheral coldness
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Surgical and medical procedures
    Skin neoplasm excision
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    6
    Illness
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Immune system disorders
    Mycotic allergy
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Seasonal allergy
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Paranasal cyst
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Listless
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Panic attack
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    6
    Somatic symptom disorder
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Epicondylitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Dysarthria
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    10
    Hypoaesthesia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Multiple sclerosis relapse
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    6
    Paraesthesia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Post-traumatic neuralgia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Sensory disturbance
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Paraesthesia ear
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Tinnitus
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Eye disorders
    Cyclitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Dysphagia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Enteritis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Gastric disorder
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Nail bed inflammation
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Sensitive skin
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Renal and urinary disorders
    Albuminuria
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Bladder dysfunction
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Renal pain
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Urinary retention
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Back pain
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Muscle spasms
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    5
    Tenosynovitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Bronchitis bacterial
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    COVID-19
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    11
    Coronavirus infection
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Cystitis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Fungal infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Herpes simplex
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Hordeolum
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    12 / 24 (50.00%)
         occurrences all number
    17
    Oral herpes
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Tonsillitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Vitamin D deficiency
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2019
    • Inclusion and exclusion criteria were amended. All MS prior therapies were permitted. Nevertheless, time interval between a prior therapy and administration of Mavenclad had to be observed. • The procedure of patient screening regarding the prescription of Mavenclad was amended.
    03 Mar 2020
    • Inclusion and exclusion criteria were amended. The time intervals to be observed for certain prior therapies were updated. • The adjusted shelf life of Mavenclad was updated.
    09 Jul 2021
    • It was planned to enrol 30 patients in the study. The study was terminated early after the enrolment of 24 patients. The patients included were examined in accordance with the study protocol until their individual end of the study.
    20 Apr 2022
    • Administrative changes in the study were implemented. New safety data on Mavenclad regarding side effects, precautions and warnings were added.

    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/38084102
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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