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    Clinical Trial Results:
    A 2-year prospective study to evaluate the onset of action of Mavenclad® in subjects with highly active relapsing multiple sclerosis

    Summary
    EudraCT number
    		 2017-002631-42
    Trial protocol
    		 SE   GB   HU   AT   CZ   ES   FR   BE   FI   IT  
    Global end of trial date
    21 Feb 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Mar 2023
    First version publication date
    11 Oct 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MS700568_0022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03364036
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Healthcare KGaA, Darmstadt, Germany
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Center, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of the study was to determine the onset of Mavenclad® action by frequent magnetic resonance imaging (MRI) assessment of the combined unique active (CUA) lesions in subjects with highly active relapsing multiple sclerosis (MS).
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2018
    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
    Czechia: 89
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Finland: 4
    Worldwide total number of subjects
    270
    EEA total number of subjects
    225
    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)
    270
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 270 subjects were enrolled in the study from different trial sites across14 countries (Austria, Germany, Hungary, Poland, Czechia, Italy, Spain, France, United Kingdom of Great Britain and Northern Ireland, Finland, Sweden, Israel, Australia and Canada).

    Pre-assignment
    Screening details
    		 A total of 313 subjects were screened for eligibility and 270 subjects were enrolled and randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Experimental: Mavenclad®
    Arm description
    		 Participants received Mavenclad® 3.5 milligram per kilogram (mg/kg) of body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mavenclad®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Mavenclad® 3.5 milligram per kilogram (mg/kg) of body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year.

    Number of subjects in period 1
    		Experimental: Mavenclad®
    Started
    270
    Full Analysis Set (FAS)
    270
    Completed
    270

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental: Mavenclad®
    Reporting group description
    		 Participants received Mavenclad® 3.5 milligram per kilogram (mg/kg) of body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year.

    Reporting group values
    		 Experimental: Mavenclad® Total
    Number of subjects
    		 270 270
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 270 270
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 37.7 ( 9.75 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 180 180
        Male
    		 90 90
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 2 2
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 225 225
        More than one race
    		 0 0
        Unknown or Not Reported
    		 30 30
        Other
    		 12 12
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 7
        Not Hispanic or Latino
    		 246 246
        Unknown or Not Reported
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Experimental: Mavenclad®
    Reporting group description
    		 Participants received Mavenclad® 3.5 milligram per kilogram (mg/kg) of body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year.

    Primary: Change From Baseline Period (Period Screening to Baseline) in Counts of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions at Period 1 (Month 1-6)

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    End point title
    		 Change From Baseline Period (Period Screening to Baseline) in Counts of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions at Period 1 (Month 1-6) [1]
    End point description
    CUA lesions were measured by using MRI scans. FAS included all subjects from the Intent to Treat (ITT) set who received at least one dose of the study treatment. Here, "Number of subjects analyzed" signifies those subjects who were evaluable for this outcome measure and "Number Analyzed" signifies those subjects who were evaluable at specified categories.
    End point type
    Primary
    End point timeframe
    Baseline period (the period screening to Baseline), Period 1 (Month 1-6)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical and comparison analysis were performed in single arm for this endpoint.
    End point values
    		 Experimental: Mavenclad®
    Number of subjects analysed
    252
    Units: lesions
        arithmetic mean (standard deviation)
    -1.211 ( 3.4413 )
    No statistical analyses for this end point

    Primary: Change From Baseline Period (Period Screening to Baseline) in Counts of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions at Period 2 (Month 2-6)

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    End point title
    		 Change From Baseline Period (Period Screening to Baseline) in Counts of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions at Period 2 (Month 2-6) [2]
    End point description
    CUA lesions were measured by using MRI scans. FAS included all subjects from the ITT set who received at least one dose of the study treatment. Here, "Number of subjects analyzed" signifies those subjects who were evaluable for this outcome measure and "Number Analyzed" signifies those subjects who were evaluable at specified categories.
    End point type
    Primary
    End point timeframe
    Baseline period (the period screening to Baseline), Period 2 (Month 2-6)
    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: No statistical and comparison analysis were performed in single arm for this endpoint.
    End point values
    		 Experimental: Mavenclad®
    Number of subjects analysed
    252
    Units: lesions
        arithmetic mean (standard deviation)
    -1.521 ( 4.0558 )
    No statistical analyses for this end point

    Primary: Change From Baseline Period (Period Screening to Baseline) in Counts of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions at Period 3 (Month 3-6)

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    End point title
    		 Change From Baseline Period (Period Screening to Baseline) in Counts of Combined Unique Active (CUA) Magnetic Resonance Imaging (MRI) Lesions at Period 3 (Month 3-6) [3]
    End point description
    CUA lesions were measured by using MRI scans. FAS included all subjects from the ITT set who received at least one dose of the study treatment. Here, "Number of subjects analyzed" signifies those subjects who were evaluable for this outcome measure and "Number Analyzed" signifies those subjects who were evaluable at specified categories.
    End point type
    Primary
    End point timeframe
    Baseline period (the period screening to Baseline), Period 3 (Month 3-6)
    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: No statistical and comparison analysis were performed in single arm for this endpoint.
    End point values
    		 Experimental: Mavenclad®
    Number of subjects analysed
    246
    Units: lesions
        arithmetic mean (standard deviation)
    -1.499 ( 3.4244 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Counts of Immune Cell Subsets - B Cells at Month 3, 6, 12, 15, 18 and 24

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    End point title
    		 Percent Change From Baseline in Counts of Immune Cell Subsets - B Cells at Month 3, 6, 12, 15, 18 and 24
    End point description
    B cell population counts are: CD19 B cells (TBNK panel), CD20 B cells (B cell panel), Memory B cells (B cell panel), Activated B cells (B cell panel), Total plasma cells (B cell panel), Short-lived plasma cells (B cell panel), Naïve B cells (B cell panel), Transitional B cells (B cell panel), and Regulatory B cells (B cell panel). FAS included all subjects from the ITT set who received at least one dose of the study treatment. Here, "Number of subjects analyzed" signifies those subjects who were evaluable for this outcome measure and "n" signifies those subjects who were evaluable at specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, 6, 12, 15, 18 and 24.
    End point values
    		 Experimental: Mavenclad®
    Number of subjects analysed
    204
    Units: Percent change
    median (inter-quartile range (Q1-Q3))
        CD19 B cells(TBNK panel),Month 3:n=204
    -80.14 (-85.85 to -73.65)
        CD19 B cells(TBNK panel),Month 6:n=200
    -60.60 (-72.43 to -45.62)
        CD19 B cells(TBNK panel),Month 12:n=195
    -26.88 (-46.67 to -3.70)
        CD19 B cells(TBNK panel),Month 15:n=161
    -77.24 (-85.64 to -65.59)
        CD19 B cells(TBNK panel),Month 18:n=163
    -55.30 (-69.55 to -39.30)
        CD19 B cells(TBNK panel),Month 24:n=172
    -27.65 (-46.11 to 1.77)
        CD20 B cells(B cell panel),Month 3: n=200
    -80.50 (-86.46 to -74.23)
        CD20 B cells(B cell panel),Month 6: n=196
    -60.32 (-71.94 to -43.77)
        CD20 B cells(B cell panel),Month 12: n=191
    -24.56 (-45.77 to -2.54)
        CD20 B cells(B cell panel),Month 15: n=159
    -77.11 (-85.54 to -65.25)
        CD20 B cells(B cell panel),Month 18: n=163
    -54.21 (-68.62 to -36.91)
        CD20 B cells(B cell panel),Month 24: n= 169
    -24.77 (-43.43 to 8.84)
        Memory B cells(B cell panel),Month 3: n= 200
    -92.69 (-95.56 to -88.52)
        Memory B cells(B cell panel), Month 6: n= 196
    -91.56 (-94.14 to -86.80)
        Memory B cells(B cell panel), Month 12: n= 189
    -86.90 (-91.57 to -80.14)
        Memory B cells(B cell panel), Month 15: n= 159
    -96.47 (-97.75 to -93.25)
        Memory B cells(B cell panel), Month 18: n= 162
    -94.67 (-96.70 to -91.41)
        Memory B cells(B cell panel), Month 24: n= 169
    -89.29 (-93.61 to -84.91)
        Activated B cells(B cell panel), Month 3: n= 200
    -74.02 (-83.29 to -61.45)
        Activated B cells(B cell panel), Month 6: n= 196
    -60.91 (-74.77 to -38.25)
        Activated B cells(B cell panel), Month 12: n= 190
    -28.82 (-52.68 to -1.85)
        Activated B cells(B cell panel), Month 15: n= 159
    -73.02 (-83.81 to -62.22)
        Activated B cells(B cell panel), Month 18: n= 163
    -51.87 (-65.00 to -28.54)
        Activated B cells(B cell panel), Month 24: n= 169
    -15.95 (-40.82 to 29.33)
        Total plasma cells(B cell panel), Month 3: n= 200
    -66.62 (-82.38 to -33.69)
        Total plasma cells(B cell panel), Month 6: n= 196
    -59.00 (-78.63 to -28.51)
        Total plasma cells (B cell panel),Month 12:n= 190
    -54.75 (-71.43 to -19.03)
        Total plasma cells(B cell panel), Month 15: n= 155
    -78.02 (-89.68 to -60.13)
        Total plasma cells(B cell panel), Month 18: n= 158
    -72.39 (-84.71 to -57.31)
        Total plasma cells(B cell panel), Month 24: n= 167
    -62.47 (-80.79 to -36.26)
        Short-lived plasma cells(BCell panel)Month3:n=200
    -68.18 (-84.72 to -43.46)
        Short-lived plasma cells(BCell panel)Month6:n=195
    -56.55 (-77.83 to -31.98)
        Short-lived plasma cells(BCell panel)Month12:n=188
    -56.70 (-76.20 to -23.22)
        Short-lived plasma cells(BCell panel)Month15:n=158
    -82.96 (-93.23 to -69.90)
        Short-lived plasma cells(BCell panel)Month18:n=161
    -79.54 (-90.76 to -65.70)
        Short-lived plasma cells(BCell panel)Month24:n=168
    -70.10 (-83.17 to -45.12)
        Naïve B cells (B cell panel), Month 3: n= 200
    -75.87 (-84.21 to -66.18)
        Naïve B cells (B cell panel), Month 6: n=196
    -45.87 (-61.72 to -24.82)
        Naïve B cells (B cell panel), Month 12: n=189
    1.63 (-20.85 to 35.59)
        Naïve B cells (B cell panel), Month 15: n=159
    -69.17 (-79.40 to -51.59)
        Naïve B cells (B cell panel), Month 18: n=162
    -39.73 (-57.61 to -5.27)
        Naïve B cells (B cell panel), Month 24: n=169
    10.85 (-21.00 to 45.19)
        Transitional B cells(B cell panel), Month3:n=200
    -4.06 (-38.65 to 56.25)
        Transitional B cells(B cell panel) Month6:n=196
    14.82 (-26.68 to 63.34)
        Transitional B cells(B cell panel)Month12:n=191
    11.92 (-26.75 to 64.99)
        Transitional B cells(B cell panel)Month15:n=159
    28.69 (-29.88 to 92.02)
        Transitional B cells(B cell panel)Month18:n=163
    11.27 (-22.94 to 67.22)
        Transitional B cells (B cell panel)Month24:n=170
    6.30 (-27.06 to 69.12)
        Regulatory B cells(B cell panel), Month3:n=200
    110.73 (17.78 to 290.50)
        Regulatory B cells(B cell panel), Month6:n=196
    92.95 (19.07 to 231.41)
        Regulatory B cells(B cell panel), Month12:n= 191
    30.64 (-18.33 to 134.17)
        Regulatory B cells(B cell panel), Month15:n=159
    91.57 (15.05 to 288.71)
        Regulatory B cells(B cell panel), Month18:n=163
    33.83 (-21.55 to 150.29)
        Regulatory B cells(B cell panel), Month24:n=170
    1.62 (-36.85 to 98.81)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Counts of Immune Cell Subsets - T Cells at Month 3, 6, 12, 15, 18 and 24

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    End point title
    		 Percent Change From Baseline in Counts of Immune Cell Subsets - T Cells at Month 3, 6, 12, 15, 18 and 24
    End point description
    T cell population counts are: Total CD4 T cells (TBNK panel), CD4 Th1 cells (T cell panel), CD4 Th17 T cells (T cell panel), CD4 Regulatory T cells (T cell panel), and Total CD8 T cells (TBNK panel). FAS included all subjects from the ITT set who received at least one dose of the study treatment. Here, "Number of subjects analyzed" signifies those subjects who were evaluable for this outcome measure and "n" signifies those subjects who were evaluable at specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, 6, 12, 15, 18 and 24.
    End point values
    		 Experimental: Mavenclad®
    Number of subjects analysed
    204
    Units: Percent change
    median (inter-quartile range (Q1-Q3))
        Total CD4 T cells (TBNK panel), Month 3: n= 204
    -48.60 (-62.55 to -37.05)
        Total CD4 T cells (TBNK panel), Month 6: n= 200
    -47.18 (-59.72 to -34.68)
        Total CD4 T cells (TBNK panel), Month 12: n= 195
    -40.16 (-55.59 to -27.74)
        Total CD4 T cells (TBNK panel), Month 15: n= 161
    -69.04 (-79.78 to -58.61)
        Total CD4 T cells (TBNK panel), Month 18: n= 163
    -66.98 (-75.03 to -55.24)
        Total CD4 T cells (TBNK panel), Month 24: n= 172
    -57.51 (-67.54 to -47.47)
        CD4 Th1 cells (T cell panel), Month 3: n= 203
    -44.35 (-61.62 to -30.01)
        CD4 Th1 cells (T cell panel), Month 6: n= 197
    -43.20 (-56.95 to -28.94)
        CD4 Th1 cells (T cell panel), Month 12: n= 192
    -35.55 (-50.76 to -17.71)
        CD4 Th1 cells (T cell panel), Month 15: n= 159
    -63.68 (-77.41 to -51.43)
        CD4 Th1 cells (T cell panel), Month 18: n= 163
    -63.01 (-74.41 to -49.62)
        CD4 Th1 cells (T cell panel), Month 24: n= 170
    -52.86 (-62.71 to -40.22)
        CD4 Th17 T cells (T cell panel), Month 3: n= 200
    -33.09 (-53.72 to -15.56)
        CD4 Th17 T cells (T cell panel), Month 6: n= 193
    -30.26 (-46.84 to -10.70)
        CD4 Th17 T cells (T cell panel), Month 12: n= 185
    -18.39 (-38.10 to 10.51)
        CD4 Th17 T cells (T cell panel), Month 15: n= 152
    -44.77 (-59.51 to -28.43)
        CD4 Th17 T cells (T cell panel), Month 18: n= 157
    -42.77 (-55.47 to -18.37)
        CD4 Th17 T cells (T cell panel), Month 24: n= 164
    -31.74 (-46.81 to -3.84)
        CD4 Regulatory T cells(T cell panel),Month3:n=203
    -25.98 (-42.82 to -11.42)
        CD4 Regulatory T cells(T cell panel),Month6:n=197
    -29.84 (-41.82 to -11.66)
        CD4 Regulatory T cells(T cell panel),Month12:n=192
    -25.60 (-38.18 to -10.45)
        CD4 Regulatory T cells(T cell panel),Month15:n=159
    -48.40 (-59.80 to -35.82)
        CD4 Regulatory T cells(T cell panel),Month18:n=163
    -48.73 (-60.71 to -34.86)
        CD4 Regulatory T cells(T cell panel)Month24:n=169
    -40.30 (-52.78 to -27.15)
        Total CD8 T cells(TBNK panel), Month3:n=204
    -42.33 (-54.55 to -22.17)
        Total CD8 T cells(TBNK panel), Month6:n=200
    -39.42 (-52.98 to -19.88)
        Total CD8 T cells (TBNK panel), Month 12: n= 195
    -36.28 (-51.42 to -15.79)
        Total CD8 T cells (TBNK panel), Month 15: n= 161
    -57.08 (-69.20 to -38.74)
        Total CD8 T cells (TBNK panel), Month 18: n= 163
    -54.44 (-67.77 to -35.12)
        Total CD8 T cells (TBNK panel), Month 24: n= 172
    -45.93 (-58.41 to -30.17)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Counts of Immune Cell Subsets - NK Cells at Month 3, 6, 12, 15, 18 and 24

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    End point title
    		 Percent Change From Baseline in Counts of Immune Cell Subsets - NK Cells at Month 3, 6, 12, 15, 18 and 24
    End point description
    NK cell population counts are: CD16+ CD56-, NK Cells, CD16+ NK Cells, NK p46 cells, CD16lowCD56bright, and CD16brightCD56dim. FAS included all subjects from the ITT set who received at least one dose of the study treatment. Here, "Number of subjects analyzed" signifies those subjects who were evaluable for this outcome measure and "n" signifies those subjects who were evaluable at specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, 6, 12, 15, 18 and 24.
    End point values
    		 Experimental: Mavenclad®
    Number of subjects analysed
    203
    Units: Percent change
    median (inter-quartile range (Q1-Q3))
        CD16+ CD56- NK cells, Month 3: n= 203
    3.08 (-32.82 to 48.59)
        CD16+ CD56- NK cells, Month 6: n= 197
    -8.88 (-35.60 to 40.41)
        CD16+ CD56- NK cells, Month 12: n= 192
    9.44 (-38.02 to 65.90)
        CD16+ CD56- NK cells, Month 15: n= 159
    27.70 (-24.44 to 104.4)
        CD16+ CD56- NK cells, Month 18: n= 163
    7.89 (-31.60 to 55.64)
        CD16+ CD56- NK cells, Month 24: n= 170
    -21.64 (-50.92 to 38.15)
        CD16+ NK cells, Month 3: n= 203
    -32.50 (-49.49 to -12.61)
        CD16+ NK cells, Month 6: n= 197
    -21.78 (-44.93 to 1.81)
        CD16+ NK cells, Month 12: n= 192
    -8.10 (-33.88 to 14.37)
        CD16+ NK cells, Month 15: n= 159
    -28.56 (-48.73 to -4.90)
        CD16+ NK cells, Month 18: n= 163
    -21.47 (-40.28 to 2.74)
        CD16+ NK cells, Month 24: n= 170
    -13.76 (-35.92 to 12.58)
        NK p46 cells, Month 3: n= 203
    -20.85 (-47.77 to 17.63)
        NK p46 cells, Month 6: n= 197
    -22.38 (-45.67 to 21.71)
        NK p46 cells, Month 12: n= 192
    29.49 (-18.73 to 116.77)
        NK p46 cells, Month 15: n= 158
    28.42 (-11.69 to 97.64)
        NK p46 cells, Month 18: n= 163
    71.73 (2.68 to 154.75)
        NK p46 cells, Month 24: n= 170
    77.70 (18.42 to 175.01)
        CD16low CD56bright, Month 3: n= 203
    -8.94 (-36.65 to 31.46)
        CD16low CD56bright, Month 6: n= 197
    3.72 (-26.06 to 42.24)
        CD16low CD56bright, Month 12: n= 192
    2.56 (-20.62 to 41.41)
        CD16low CD56bright, Month 15: n= 159
    4.77 (-23.35 to 49.22)
        CD16low CD56bright, Month 18: n= 163
    30.13 (-8.52 to 75.67)
        CD16low CD56bright, Month 24: n= 170
    17.21 (-20.09 to 82.09)
        CD16bright CD56dim, Month 3: n= 203
    -36.13 (-55.16 to -14.13)
        CD16bright CD56dim, Month 6: n= 197
    -25.61 (-46.87 to 1.97)
        CD16bright CD56dim, Month 12: n= 192
    -11.05 (-38.53 to 16.63)
        CD16bright CD56dim, Month 15: n= 159
    -35.05 (-55.45 to -8.85)
        CD16bright CD56dim, Month 18: n= 163
    -24.99 (-45.87 to -0.29)
        CD16bright CD56dim, Month 24: n= 170
    -12.94 (-37.36 to 10.95)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to Month 45
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Experimental: Mavenclad®
    Reporting group description
    		 Participants received Mavenclad® 3.5 milligram per kilogram (mg/kg) of body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year.

    Serious adverse events
    		 Experimental: Mavenclad®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 270 (5.19%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Carotid endarterectomy
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 270 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Interspinous osteoarthritis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Vestibular neuronitis
         subjects affected / exposed
    1 / 270 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental: Mavenclad®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    225 / 270 (83.33%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 270 (7.41%)
         occurrences all number
    20
    Headache
         subjects affected / exposed
    87 / 270 (32.22%)
         occurrences all number
    87
    Paraesthesia
         subjects affected / exposed
    15 / 270 (5.56%)
         occurrences all number
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    31 / 270 (11.48%)
         occurrences all number
    31
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    28 / 270 (10.37%)
         occurrences all number
    28
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    26 / 270 (9.63%)
         occurrences all number
    26
    Nausea
         subjects affected / exposed
    31 / 270 (11.48%)
         occurrences all number
    31
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    21 / 270 (7.78%)
         occurrences all number
    21
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    16 / 270 (5.93%)
         occurrences all number
    16
    Insomnia
         subjects affected / exposed
    16 / 270 (5.93%)
         occurrences all number
    16
    Musculoskeletal and connective tissue disorders
    Pain in extrimity
         subjects affected / exposed
    22 / 270 (8.15%)
         occurrences all number
    22
    Arthralgia
         subjects affected / exposed
    19 / 270 (7.04%)
         occurrences all number
    19
    Back pain
         subjects affected / exposed
    30 / 270 (11.11%)
         occurrences all number
    30
    Muscle Spasm
         subjects affected / exposed
    17 / 270 (6.30%)
         occurrences all number
    17
    Neck Pain
         subjects affected / exposed
    14 / 270 (5.19%)
         occurrences all number
    14
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    57 / 270 (21.11%)
         occurrences all number
    57
    Urinary tract infection
         subjects affected / exposed
    32 / 270 (11.85%)
         occurrences all number
    32
    Oral herpes
         subjects affected / exposed
    20 / 270 (7.41%)
         occurrences all number
    20
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 270 (10.00%)
         occurrences all number
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2019
    • Revised the primary endpoint analyses and the primary population for analyses from the ITT Set to the FAS. • Updated to include a risk-benefit evaluation for subjects with prior malignancy. • Inclusion criterion was added to include subjects with previous exposure and immunity to varicella virus. • Section 8 (including several sub-sections) was amended to provide more detail on the planned analyses.

    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
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