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    Clinical Trial Results:
    A Randomised, Controlled, Open-Label, Rater-Blinded, Phase 3b Study of the Efficacy, Safety, and Tolerability of 6-Week Extended Interval Dosing (EID) of Natalizumab (BG00002) in Subjects With Relapsing-Remitting Multiple Sclerosis Switching From Treatment With 4-Week Natalizumab Standard Interval Dosing (SID) in Relation to Continued SID Treatment - Followed by an Open-Label Crossover Extension Study Comprising Subcutaneous and Intravenous Natalizumab Administration

    Summary
    EudraCT number
    		 2018-002145-11
    Trial protocol
    		 GB   DE   FR   NL   ES   IT  
    Global end of trial date
    24 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2024
    First version publication date
    13 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    101MS329
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03689972
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    22 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.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
    24 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1:Primary objective=evaluate efficacy of natalizumab extended interval dosing(EID)(every 6 weeks[Q6W])in participants who have previously been treated with natalizumab standard interval dosing(SID)(every 4 weeks[Q4W])for at least 12 months,in relation to continued Q4W treatment.Secondary objectives=evaluate relapse-based clinical efficacy measures,disability worsening,additional magnetic resonance imaging(MRI)-lesion efficacy measures & safety of Q6W in participants who have previously been treated with natalizumab Q4W for at least 12 months,in relation to continued Q4W treatment.Part 2:Primary objective=evaluate participant preference for subcutaneous(SC)/intravenous(IV) route of natalizumab administration.Secondary objectives=evaluate treatment satisfaction,drug preparation & administration time,safety & immunogenicity,efficacy & characterise pharmacokinetic(PK) & pharmacodynamic(PD) drug preparation and administration time of SC versus IV routes of natalizumab administration.
    Protection of trial subjects
    Written informed consent was obtained from each participant or participant`s legally authorised representative, as applicable, prior to evaluations performed for eligibility. Participants or the participant`s legally authorised representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    27 Nov 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
    United States: 237
    Country: Number of subjects enrolled
    Spain: 65
    Country: Number of subjects enrolled
    Germany: 61
    Country: Number of subjects enrolled
    Israel: 41
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    Italy: 37
    Country: Number of subjects enrolled
    Australia: 31
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    585
    EEA total number of subjects
    227
    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)
    585
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at the investigative sites in Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, the United Kingdom, and the United States from 27 November 2018 to 20 June 2021.

    Pre-assignment
    Screening details
    		 585 participants were enrolled in the study,out of which 499 participants were randomised in Part 1.A total of 396 participants completed Part 1 of the study,out of which 67 participants entered Part 2 of the study. A total of 153 participants (including 86 new participants) entered Part 2 crossover period and 123 participants completed the study.

    Period 1
    Period 1 title
    Part 1 (Day 1 up to Week 72)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: IV Q4W
    Arm description
    		 Participants received natalizumab 300 mg IV infusion Q4W up to Week 72.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    Other name
    BG00002, AN100226
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 Part 1: IV Q6W
    Arm description
    		 Participants received natalizumab 300 mg IV infusion Q6W up to Week 72.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    Other name
    BG00002, AN100226
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 1 [1]
    		Part 1: IV Q4W Part 1: IV Q6W
    Started
    248
    251
    Completed
    194
    202
    Not completed
    54
    49
         Randomised but not Dosed
    1
    1
         Adverse event, non-fatal
    1
    3
         Pregnancy
    5
    1
         Protocol-Defined Rescue Criteria
    -
    6
         Developed Persistent Anti-Natalizumab Antibodies
    1
    3
         Unwilling to Comply With Protocol
    3
    2
         Investigator Decision
    9
    6
         Lost to follow-up
    -
    2
         Reason not Specified
    20
    16
         Consent Withdrawn
    14
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 585 participants were enrolled in the study, out of which 499 participants were randomised in Part 1.
    Period 2
    Period 2 title
    Part 2:Run-in Period(Week 73-Week 107)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part 2: Run-in Period: IV Q6W
    Arm description
    		 Participants who completed Part 1 or were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 72 through Week 102.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    Other name
    BG00002, AN100226
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 2
    		Part 2: Run-in Period: IV Q6W
    Started
    158
    Completed
    153
    Not completed
    5
         Reason not Specidfied
    2
         Pregnancy
    1
         Consent Withdrawn
    2
    Period 3
    Period 3 title
    Part 2:Crossover Period(Week108-Week156)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 2: Crossover Period: IV Q6W then SC Q6W
    Arm description
    		 Participants who completed run-in period of Part 2 were randomised to receive natalizumab 300 mg IV infusion Q6W from Week 108 through Week 126 followed by natalizumab 300 mg SC injection Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant`s choice at Week 156.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    Other name
    BG00002, AN100226
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 Part 2: Crossover Period: SC Q6W then IV Q6W
    Arm description
    		 Participants who completed run-in period of Part 2 were randomised to receive natalizumab 300 mg SC injection Q6W from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant`s choice at Week 156.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    Other name
    BG00002, AN100226
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 3
    		Part 2: Crossover Period: IV Q6W then SC Q6W Part 2: Crossover Period: SC Q6W then IV Q6W
    Started
    75
    78
    Completed
    63
    60
    Not completed
    12
    18
         Randomised but not Dosed
    -
    12
         Adverse event, non-fatal
    1
    1
         Pregnancy
    -
    1
         Investigator Decision
    2
    2
         Reason not Specified
    2
    1
         Consent Withdrawn
    7
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: IV Q4W
    Reporting group description
    		 Participants received natalizumab 300 mg IV infusion Q4W up to Week 72.

    Reporting group title
    Part 1: IV Q6W
    Reporting group description
    		 Participants received natalizumab 300 mg IV infusion Q6W up to Week 72.

    Reporting group values
    		 Part 1: IV Q4W Part 1: IV Q6W Total
    Number of subjects
    		 248 251
    Age Categorical
    Units: Subjects
    Age continuous
    Part 1: All randomised population included all the randomised participants in Part 1 of the study. Part 2: Included all the newly enrolled randomised participants in the crossover period of Part 2 of the study.
    Units: years
        arithmetic mean (standard deviation)
    		 40.5 ( 10.03 ) 41.0 ( 9.66 ) -
    Gender categorical
    Units: Subjects
        Male
    		 67 73 140
        Female
    		 181 178 359
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 10 9 19
        Not Hispanic or Latino
    		 223 224 447
        Unknown or Not Reported
    		 15 18 33
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 1 4 5
        Black or African American
    		 23 14 37
        White
    		 211 211 422
        Not reported due to confidentiality regulations
    		 11 15 26
        Other
    		 1 6 7
    Subject analysis sets

    Subject analysis set title
    Part 2: Crossover Period
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants who were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 108 through Week 126 followed by natalizumab 300 mg SC injection Q6W from Week 132 through Week 150, or natalizumab 300 mg SC injection Q6W from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion Q6W from Week 132 through Week 150, along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant`s choice at Week 156.

    Subject analysis set title
    Part 2: Crossover Period: IV Q6W
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received natalizumab 300 mg IV infusion Q6W for 24 weeks.

    Subject analysis set title
    Part 2: Crossover Period: SC Q6W
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received natalizumab 300 mg SC injection Q6W for 24 weeks.

    Subject analysis sets values
    		 Part 2: Crossover Period Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects
    86
    153
    153
    Age Categorical
    Units: Subjects
    Age continuous
    Part 1: All randomised population included all the randomised participants in Part 1 of the study. Part 2: Included all the newly enrolled randomised participants in the crossover period of Part 2 of the study.
    Units: years
        arithmetic mean (standard deviation)
    37.6 ( 9.85 )
    0 ( 0 )
    0 ( 0 )
    Gender categorical
    Units: Subjects
        Male
    28
    0
    0
        Female
    58
    0
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1
    0
    0
        Not Hispanic or Latino
    67
    0
    0
        Unknown or Not Reported
    18
    0
    0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0
    0
    0
        Asian
    0
    0
    0
        Black or African American
    0
    0
    0
        White
    71
    0
    0
        Not reported due to confidentiality regulations
    14
    0
    0
        Other
    1
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Part 1: IV Q4W
    Reporting group description
    		 Participants received natalizumab 300 mg IV infusion Q4W up to Week 72.

    Reporting group title
    Part 1: IV Q6W
    Reporting group description
    		 Participants received natalizumab 300 mg IV infusion Q6W up to Week 72.
    Reporting group title
    Part 2: Run-in Period: IV Q6W
    Reporting group description
    		 Participants who completed Part 1 or were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 72 through Week 102.
    Reporting group title
    Part 2: Crossover Period: IV Q6W then SC Q6W
    Reporting group description
    		 Participants who completed run-in period of Part 2 were randomised to receive natalizumab 300 mg IV infusion Q6W from Week 108 through Week 126 followed by natalizumab 300 mg SC injection Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant`s choice at Week 156.

    Reporting group title
    Part 2: Crossover Period: SC Q6W then IV Q6W
    Reporting group description
    		 Participants who completed run-in period of Part 2 were randomised to receive natalizumab 300 mg SC injection Q6W from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant`s choice at Week 156.

    Subject analysis set title
    Part 2: Crossover Period
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants who were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 108 through Week 126 followed by natalizumab 300 mg SC injection Q6W from Week 132 through Week 150, or natalizumab 300 mg SC injection Q6W from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion Q6W from Week 132 through Week 150, along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant`s choice at Week 156.

    Subject analysis set title
    Part 2: Crossover Period: IV Q6W
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received natalizumab 300 mg IV infusion Q6W for 24 weeks.

    Subject analysis set title
    Part 2: Crossover Period: SC Q6W
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received natalizumab 300 mg SC injection Q6W for 24 weeks.

    Primary: Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72

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    End point title
    		 Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72
    End point description
    T2 hyperintense lesions were analysed by magnetic resonance imaging (MRI) scans of brain. New MRI scans were compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions at Week 72 relative to baseline. Modified intent to treat (mITT) population included all randomised participants who received at least one dose of study treatment and had at least 1 postbaseline result in Part 1. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis.
    End point type
    Primary
    End point timeframe
    Week 72
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    197
    211
    Units: number of T2 lesions
        arithmetic mean (confidence interval 95%)
    0.05 (0.01 to 0.22)
    0.20 (0.07 to 0.63)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 1: IV Q4W v Part 1: IV Q6W
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0755 [1]
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Ratio of Mean
    Point estimate
    4.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 20.85
    Notes
    [1] - The model included treatment as classification variable & baseline body weight, duration of natalizumab exposure at baseline, & region as covariates.

    Primary: Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Periof ofPart 2

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    End point title
    		 Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Periof ofPart 2
    End point description
    mITT population included all randomised participants who received at least one dose of SC natalizumab after randomisation in Part 2 and who completed at least the first question in the Patient Preference Questionnaire (PPQ) on one occasion. Here, ‘subjects analysed’ signifies the number of participants with data available for endpoint analysis. (Confidence interval=CI)
    End point type
    Primary
    End point timeframe
    Week 150
    End point values
    		 Part 2: Crossover Period: IV Q6W then SC Q6W Part 2: Crossover Period: SC Q6W then IV Q6W
    Number of subjects analysed
    62
    61
    Units: percentage of participants
    number (not applicable)
        SC
    83.9
    91.8
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Part 2: Crossover Period: IV Q6W then SC Q6W v Part 2: Crossover Period: SC Q6W then IV Q6W
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Exact Binomial Method
    Parameter type
    		 Percentage
    Point estimate
    87.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 80.68
         upper limit
    		 93.01

    Secondary: Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC)

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    End point title
    		 Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC)
    End point description
    Relapse is defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination. Only relapses confirmed by an INEC were included in the analysis. Time to First Relapse was estimated by Kaplan-Meier method. mITT population included all randomised participants who received at least one dose of study treatment and had at least 1 postbaseline result in Part 1. 99999= Median, Q1 and Q3 were not reached in the Kaplan-Meier curve due to insufficient number of relapses.
    End point type
    Secondary
    End point timeframe
    Up to Week 72
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    242
    247
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Part 1: Annualised Relapse Rate at Week 72

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    End point title
    		 Part 1: Annualised Relapse Rate at Week 72
    End point description
    Annualised relapse rate is calculated as the total number of INEC-confirmed relapses that occurred during the treatment period divided by the total number of participant-years followed in the period. mITT population included all randomised participants who received at least one dose of study treatment and had at least 1 postbaseline result in Part 1.
    End point type
    Secondary
    End point timeframe
    Week 72
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    242
    247
    Units: relapses per participant-year
        number (confidence interval 95%)
    0.00010 (0.00004 to 0.00024)
    0.00013 (0.00006 to 0.00027)
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Part 1: IV Q4W v Part 1: IV Q6W
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6312 [2]
    Method
    		 Poisson Regression
    Parameter type
    		 Ratio of annualised relapse rate
    Point estimate
    1.32481
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42016
         upper limit
    		 4.17725
    Notes
    [2] - Poisson regression model was adjusted for baseline body weight (<= 80 kg versus >80 kg), duration of natalizumab exposure at baseline (<= 3 years versus > 3 years), and region.

    Secondary: Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening

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    End point title
    		 Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening
    End point description
    Confirmed EDSS worsening is defined as an increase of at least 1.0 point from a baseline EDSS score ≥ 1.0 or an increase of at least 1.5 points from a baseline EDSS score of 0 that is confirmed after at least 24 weeks. Time to EDSS worsening is estimated by Kaplan-Meier method. mITT population included all randomised participants who received at least one dose of study treatment and had at least 1 postbaseline result in Part 1. 99999= Median, Q1 and Q3 were not reached in the Kaplan-Meier curve due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to Week 72
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    242
    247
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72

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    End point title
    		 Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72
    End point description
    T1 hypointense lesions on brain were analysed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyse the number of new T1 hypointense lesions at Weeks 24, 48, and 72 relative to baseline. mITT population included all randomised participants who received at least one dose of study treatment and had at least 1 postbaseline result in Part 1. ‘Subjects analysed’ signifies the number of participants with data available for endpoint analysis. Here, 'number analysed (n)' signifies the number of participants with data available for analysis at specified time point.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48, and 72
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    227
    241
    Units: number of T1 lesions
    arithmetic mean (standard deviation)
        Week 24 (n=227,241)
    0.0 ( 0.13 )
    0.0 ( 0.06 )
        Week 48 (n=202,218)
    0.0 ( 0.16 )
    0.0 ( 0.07 )
        Week 72 (n=191,209)
    0.0 ( 0.16 )
    0.0 ( 0.32 )
    No statistical analyses for this end point

    Secondary: Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48

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    End point title
    		 Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48
    End point description
    T2 hyperintense lesions were analysed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions at Weeks 24 and 48 relative to baseline. mITT population included all randomised participants who received at least one dose of study treatment and had at least 1 postbaseline result in Part 1. ‘Subjects analysed’ signifies the number of participants with data available for endpoint analysis Here, 'number analysed (n)' signifies the number of participants with data available for analysis at specified time point.
    End point type
    Secondary
    End point timeframe
    Weeks 24 and 48
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    229
    242
    Units: number of T2 lesions
    arithmetic mean (standard deviation)
        Week 24 (n=229,242)
    0.0 ( 0.16 )
    0.0 ( 0.35 )
        Week 48 (n=206,221)
    0.0 ( 0.21 )
    0.1 ( 1.03 )
    No statistical analyses for this end point

    Secondary: Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72

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    End point title
    		 Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72
    End point description
    Gd enhancing lesions on brain were analysed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyse the number of new Gd enhancing lesions at Weeks 24, 48, and 72 relative to baseline. mITT population included all randomised participants who received at least one dose of study treatment and had at least 1 postbaseline result in Part 1. ‘Subjects analysed’ signifies the number of participants with data available for endpoint analysis Here, 'number analysed' signifies the number of participants with data available for analysis at specified time point.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48, and 72
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    227
    241
    Units: number of Gd lesions
    arithmetic mean (standard deviation)
        Week 24 (n=227,241)
    0.0 ( 0.07 )
    0.0 ( 0.00 )
        Week 48 (n=203,218)
    0.0 ( 0.07 )
    0.0 ( 0.00 )
        Week 72 (n=191,210)
    0.0 ( 0.07 )
    0.1 ( 0.83 )
    No statistical analyses for this end point

    Secondary: Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    AE is any untoward medical occurrence in participant/clinical investigation participant administered a pharmaceutical product & that does not necessarily have causal relationship with this treatment.It can therefore be any unfavorable & unintended sign(including an abnormal laboratory finding),symptom/disease temporally associated with use of medicinal(investigational)product,whether or not related to medicinal(investigational)product.TEAE is any event occurring on/after first dose after randomisation up to 12 weeks(or 24 weeks for PML[progressive multifocal leukoencephalopathy]events)following last dose on study.SAE is any untoward medical occurrence that at any dose results in death,is life-threatening event,requires inpatient hospitalization/prolongation of existing hospitalization,results in significant disability/incapacity/congenital anomaly,is medically important event.Safety population=all randomised participants who received at least one dose of study treatment in Part 1.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Part 1: IV Q4W Part 1: IV Q6W
    Number of subjects analysed
    247
    250
    Units: percentage of participants
    number (not applicable)
        TEAEs
    76.9
    77.6
        SAEs
    6.9
    6.8
    No statistical analyses for this end point

    Secondary: Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period

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    End point title
    		 Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period
    End point description
    TSQM has 14 questions that assesses participants' global satisfaction level with their treatment in 4 domains:side effects(5 questions in the side effects domain,1of them is Yes/No question & there are 4 sub-components,hence maximum score of 20),effectiveness(3 questions),global satisfaction(3 questions),convenience(3 questions).All questions are scored from 1(least satisfied) to 5/7(most satisfied).Total score is summed for each domain to obtain:side effects(1-20),effectiveness(1-21),global satisfaction(1-17),convenience(1-21),using transformed scores between 0 & 100 for effectiveness.Lower total scores in each domain indicate dissatisfaction with study medication & higher total scores indicate satisfaction.Full analysis set(FAS)=all randomised participants who received at least one dose of study treatment during at least one study period & had at least 1 baseline assessment in Part 2.Here,subjects analysed'=number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Part 2 Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    127
    127
    Units: Score on a scale
        least squares mean (standard error)
    0.17 ( 0.899 )
    0.64 ( 0.902 )
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Part 2: Crossover Period: IV Q6W v Part 2: Crossover Period: SC Q6W
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.764 [3]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 Difference
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.61
         upper limit
    		 3.54
    Notes
    [3] - Performed with factors:route of administration,period,sequence,body weight,duration of natalizumab exposure,stratification factor,baseline TSQM score.

    Secondary: Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period

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    End point title
    		 Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period
    End point description
    FAS included all randomised participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2.
    End point type
    Secondary
    End point timeframe
    Week 108 up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    136
    132
    Units: Minutes
    arithmetic mean (standard deviation)
        Drug Preparation Time
    4.9 ( 3.86 )
    0 ( 0 )
        Drug Administration Time
    62.6 ( 10.45 )
    4.3 ( 5.11 )
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any event occurring on or after first dose after randomisation up to and including 12 weeks (or 24 weeks for PML events) following the last dose on the study.Safety population included all randomised participants who received at least one dose of study treatment during the crossover period of Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline (Week 108) up to Week 180
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    136
    132
    Units: percentage of participants
        number (not applicable)
    57.4
    62.9
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period

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    End point title
    		 Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period
    End point description
    Immunogenicity population included all participants who received at least one dose of SC or IV natalizumab and had at least one assessment for anti-drug antibody during crossover period of Part 2.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    136
    132
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period

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    End point title
    		 Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period
    End point description
    T2 hyperintense lesions were analysed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions during the crossover period of Part 2 relative to baseline. FAS included all randomised participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, ‘subjects analysed' signifies the number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    131
    128
    Units: number of T2 lesions
        arithmetic mean (standard deviation)
    0.0 ( 0.09 )
    0.0 ( 0.22 )
    No statistical analyses for this end point

    Secondary: Part 2: Time to First Relapse During the Crossover Period

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    End point title
    		 Part 2: Time to First Relapse During the Crossover Period
    End point description
    Relapse is defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours. The time to first relapse was defined as the time from the first randomised dose in Part 2 up to the first relapse.Time to First Relapse is estimated by Kaplan-Meier method. FAS:all randomised participants receiving ≥1 dose of study treatment during at least one study period;had ≥1 baseline assessment in Part 2.Overall number analysed:participants without any relapse at beginning of crossover period of Part 2.As pre-specified in Statistical Analysis Plan(SAP),time to event analyses was planned by ‘per treatment sequence’ rather than ‘per intervention' in Part 2 as protocol-specified analysis does not account for correlation of within participant effect.9999= Median, Q1 and Q3 were not reached in the Kaplan-Meier curve due to one relapse. 99999= Data is not available as no participant in this group had a relapse.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W then SC Q6W Part 2: Crossover Period: SC Q6W then IV Q6W
    Number of subjects analysed
    71
    63
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    9999 (9999 to 9999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Part 2: Annualized Relapse Rate During the Crossover Period

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    End point title
    		 Part 2: Annualized Relapse Rate During the Crossover Period
    End point description
    Annualised relapse rate is calculated as the total number of relapses that occurred during the treatment period divided by the total number of participant-years followed in the period.
    End point type
    Secondary
    End point timeframe
    Part 2 Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W then SC Q6W Part 2: Crossover Period: SC Q6W then IV Q6W
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: relapses per-participant year
        number (not applicable)
    Notes
    [4] - Data was not analysed for this endpoint as only 1 relapse was observed in Part 2 crossover period.
    [5] - Data was not analysed for this endpoint as only 1 relapse was observed in 1 Part 2 crossover period.
    No statistical analyses for this end point

    Secondary: Part 2: Change From Baseline in EDSS Score During the Crossover Period

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    End point title
    		 Part 2: Change From Baseline in EDSS Score During the Crossover Period
    End point description
    The EDSS is a scale based on standardised neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory and cerebral functions, as well as walking ability. It measures the MS disability status on a scale ranging from 0 (normal) to 10 (death due to MS), with higher scores indicating more disability. FAS included all randomised participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, ’subjects analysed' signifies the number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Part 2 Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    135
    132
    Units: Score on a scale
        least squares mean (standard error)
    0.02 ( 0.055 )
    0.10 ( 0.056 )
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Part 2: Crossover Period: IV Q6W v Part 2: Crossover Period: SC Q6W
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.357 [6]
    Method
    		 Linear Mixed Effects Model
    Parameter type
    		 Difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.25
    Notes
    [6] - Performed with factors:route of administration,period,sequence,body weight,duration of natalizumab exposure,stratification factor,baseline TSQM score.

    Secondary: Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period

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    End point title
    		 Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period
    End point description
    Gd enhancing lesions on brain were analysed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyse the number of new Gd enhancing lesions during the crossover period of Part 2 relative to baseline. FAS included all randomised participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, ’subjects analysed' signifies the number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Week 108 up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    131
    128
    Units: number of Gd lesions
        arithmetic mean (standard deviation)
    0.0 ( 0.00 )
    0.0 ( 0.00 )
    No statistical analyses for this end point

    Secondary: Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period

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    End point title
    		 Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period
    End point description
    T1 hypointense lesions on brain were analysed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyse the number of new T1 hypointense lesions during the crossover period of Part 2 relative to baseline. FAS included all randomised participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, ’subjects analysed' signifies the number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Week 108 up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    131
    128
    Units: number of T1 lesions
        arithmetic mean (standard deviation)
    0.0 ( 0.09 )
    0.0 ( 0.00 )
    No statistical analyses for this end point

    Secondary: Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period

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    End point title
    		 Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period
    End point description
    FAS included all randomised participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, ’subjects analysed' signifies the number of participants with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Part 2 Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    112
    108
    Units: percent change
        least squares mean (standard error)
    -0.11 ( 0.042 )
    -0.10 ( 0.042 )
    No statistical analyses for this end point

    Secondary: Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period

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    End point title
    		 Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period
    End point description
    FAS included all randomised participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. ‘Subjects analysed’ signifies the number of participants with data available for endpoint analysis. Here ‘number analysed (n)’ signifies the number of participants with data available for analysis at specified categories.
    End point type
    Secondary
    End point timeframe
    Part 2 Baseline (Week 108) up to Week 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    111
    107
    Units: cubic centimetres (cm^3)
    least squares mean (standard error)
        Cortical Brain Region (n=111,107)
    -1478.82 ( 363.714 )
    -881.34 ( 367.155 )
        Thalamic Brain Region (n=108,104)
    -25.98 ( 14.582 )
    -17.96 ( 14.796 )
    No statistical analyses for this end point

    Secondary: Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period

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    End point title
    		 Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period
    End point description
    Pharmacokinetic (PK) population included all participants who received at least one dose of SC or IV natalizumab and had at least one assessment for the concentration of natalizumab in serum during the crossover period of Part 2.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    136
    132
    Units: micrograms per millilitre (µg/mL)
        arithmetic mean (standard deviation)
    11.9 ( 11.50 )
    10.3 ( 10.94 )
    No statistical analyses for this end point

    Secondary: Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period

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    End point title
    		 Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period
    End point description
    Pharmacodynamic (PD) population included all participants who received at least 1 dose of SC or IV natalizumab after randomisation in Part 2 and had at least 1 post-baseline assessment of the PD parameter. Here ‘subjects analysed’ indicates the number of participants without any relapse at the beginning of the crossover period of Part 2.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156
    End point values
    		 Part 2: Crossover Period: IV Q6W Part 2: Crossover Period: SC Q6W
    Number of subjects analysed
    135
    132
    Units: percentage
        arithmetic mean (standard deviation)
    71.2 ( 15.31 )
    67.2 ( 17.80 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to Week 180
    Adverse event reporting additional description
    Safety population included all randomised participants who received at least one dose of study treatment. MedDRA version 24.0 applied for Part 1 and MedDRA version 26.0 applied for Part 2.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0, 26.0
    Reporting groups
    Reporting group title
    Part 1: IV Q4W
    Reporting group description
    		 Participants received natalizumab 300 mg IV infusion Q4W up to Week 72.

    Reporting group title
    Part 2: Crossover Period: SC Q6W
    Reporting group description
    		 Participants received natalizumab 300 mg SC injection Q6W for 24 weeks.

    Reporting group title
    Part 2: Crossover Period: IV Q6W
    Reporting group description
    		 Participants received natalizumab 300 mg IV infusion Q6W for 24 weeks.

    Reporting group title
    Part 1: IV Q6W
    Reporting group description
    		 Participants received natalizumab 300 mg IV infusion Q6W up to Week 72.

    Reporting group title
    Part 2: Run-in period: IV Q6W
    Reporting group description
    		 Participants who completed Part 1 or were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 72 through Week 102.

    Serious adverse events
    		 Part 1: IV Q4W Part 2: Crossover Period: SC Q6W Part 2: Crossover Period: IV Q6W Part 1: IV Q6W Part 2: Run-in period: IV Q6W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 247 (6.88%)
    4 / 132 (3.03%)
    2 / 136 (1.47%)
    17 / 250 (6.80%)
    3 / 158 (1.90%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign lung neoplasm
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    1 / 136 (0.74%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 132 (0.76%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 132 (0.76%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hyperventilation
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract procedural complication
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery dissection
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis pseudo relapse
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Papilloedema
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    1 / 136 (0.74%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    2 / 250 (0.80%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 132 (0.76%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cholangitis infective
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 132 (0.76%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 pneumonia
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    0 / 250 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 247 (0.00%)
    0 / 132 (0.00%)
    0 / 136 (0.00%)
    1 / 250 (0.40%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: IV Q4W Part 2: Crossover Period: SC Q6W Part 2: Crossover Period: IV Q6W Part 1: IV Q6W Part 2: Run-in period: IV Q6W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 247 (42.11%)
    56 / 132 (42.42%)
    48 / 136 (35.29%)
    105 / 250 (42.00%)
    42 / 158 (26.58%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    13 / 247 (5.26%)
    2 / 132 (1.52%)
    2 / 136 (1.47%)
    13 / 250 (5.20%)
    5 / 158 (3.16%)
         occurrences all number
    14
    2
    2
    18
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 247 (9.31%)
    4 / 132 (3.03%)
    7 / 136 (5.15%)
    26 / 250 (10.40%)
    4 / 158 (2.53%)
         occurrences all number
    45
    7
    7
    43
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 247 (3.24%)
    2 / 132 (1.52%)
    3 / 136 (2.21%)
    25 / 250 (10.00%)
    4 / 158 (2.53%)
         occurrences all number
    8
    2
    6
    30
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 247 (1.62%)
    1 / 132 (0.76%)
    2 / 136 (1.47%)
    14 / 250 (5.60%)
    4 / 158 (2.53%)
         occurrences all number
    4
    1
    2
    14
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 247 (3.64%)
    8 / 132 (6.06%)
    2 / 136 (1.47%)
    18 / 250 (7.20%)
    1 / 158 (0.63%)
         occurrences all number
    11
    8
    2
    24
    1
    Pain in extremity
         subjects affected / exposed
    7 / 247 (2.83%)
    1 / 132 (0.76%)
    1 / 136 (0.74%)
    14 / 250 (5.60%)
    4 / 158 (2.53%)
         occurrences all number
    7
    1
    1
    14
    4
    Infections and infestations
    Covid-19
         subjects affected / exposed
    6 / 247 (2.43%)
    31 / 132 (23.48%)
    28 / 136 (20.59%)
    5 / 250 (2.00%)
    19 / 158 (12.03%)
         occurrences all number
    6
    32
    28
    5
    19
    Nasopharyngitis
         subjects affected / exposed
    32 / 247 (12.96%)
    13 / 132 (9.85%)
    3 / 136 (2.21%)
    27 / 250 (10.80%)
    4 / 158 (2.53%)
         occurrences all number
    44
    13
    3
    31
    5
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 247 (6.88%)
    4 / 132 (3.03%)
    2 / 136 (1.47%)
    12 / 250 (4.80%)
    1 / 158 (0.63%)
         occurrences all number
    21
    5
    2
    14
    1
    Urinary tract infection
         subjects affected / exposed
    19 / 247 (7.69%)
    2 / 132 (1.52%)
    7 / 136 (5.15%)
    24 / 250 (9.60%)
    6 / 158 (3.80%)
         occurrences all number
    24
    4
    9
    42
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2019
    1. Updated the timing of the primary efficacy endpoint to Week 72. 2. Updated time to EDSS worsening as a secondary endpoint. 3. Specified and clarified the study’s statistical analysis plan within the protocol. 4. Extended the screening period from Day -42 to Day -1. 5. Added Week 84 EDSS and neurological examination assessments and Week 60 assessments for anti-natalizumab antibodies. 6. Clarified stratification on the factor ‘country/region’ and used a lower cut-off for body weight. 7. Clarified the screening assessments’ timing.
    08 Jul 2020
    Added an open-label extension (OLE) part (Part 2) comprising a crossover analysis of natalizumab administered by IV infusion and SC injection under every 6 weeks (Q6W).
    20 Aug 2020
    1. Added details regarding the Screening visit for new participants who did not participate in Part 1 of the study and were being enrolled in Part 2. 2. Revised instructions for postdosing observation requirements. 3. Revised the nominal study day for the screening visit.

    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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