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    Clinical Trial Results:
    COMBAT-MS (COMparison Between All immunoTherapies for Multiple Sclerosis) A prospective long-term cohort study of safety, efficacy and patient’s satisfaction of MS disease modulatory treatments in relapsing-remitting multiple sclerosis

    Summary
    EudraCT number
    		 2016-003587-39
    Trial protocol
    		 SE  
    Global end of trial date
    31 Mar 2022

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    COMBAT-MS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Nobels väg 6, Stockholm, Sweden, 17177
    Public contact
    Dept of Clinial Neuroscience, Karoloinska Institutet, 0046 08517 737 57, fredrik.piehl@ki.se
    Scientific contact
    Dept of Clinial Neuroscience, Karoloinska Institutet, 0046 08517 737 57, fredrik.piehl@ki.se
    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
    25 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overarching goal of the study was to describe the effectiveness and safety of rituximab in comparison to other commonly used approved disease-modulatory therapies for relapsing-remitting MS in the setting of a population-based structured prospective follow-up cohort of patients being either treatment naïve or switching from a previous first MS therapy (escalation/second-line). In keeping with the non-interventional design and real-world setting, the main focus was to present point estimates and confidence limits for different outcome measures, with particular focus on long-term disability, quality of life scales and risk of serious adverse events.
    Protection of trial subjects
    The study design was developed together with a Stakeholder Advisory Group (SAG) consisting of people with MS (PwMS), relatives to PwMS, patients’ organization representatives, clinicians, and senior scientific consultants. They were selected to represent pwMS and caregivers from both USA and Sweden, advocacy and patient organizations (National MS Society, Neuro Sweden) and professional societies (American Academy of Neurology, Swedish MS Society). Quarterly conference calls with the SAG were held throughout the study to discuss study progress, provide feedback and address arising issues. To provide an additional communication channel for questions arising among study participants and provide consensus responses from the research team, our stakeholders initiated a Facebook COMBAT-MS group. The study design endorsed by the SAG was in the form of a prospective non-intervention cohort study where only additional patient-reported outcomes and a yearly biobanked blood sample deviated from clinical routine. No issues relating to safety or discomfort of participants due to the study itself were recorded during the study. Only two out of 3,522 participants initially consenting to participate chose to withdraw their consent and asked for their data to be deleted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jun 2017
    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
    Sweden: 3764
    Worldwide total number of subjects
    3764
    EEA total number of subjects
    3764
    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)
    3730
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were recruited for prospective data collection between June 2, 2017 and June 30, 2019. Annual assessment of disability status and patient-reported outcomes were registered in the Swedish MS register, from the date of recruitment until March 31, 2022.

    Pre-assignment
    Screening details
    		 CIS or RRMS; first or second ever MS DMT (2011–2018); followed at a Swedish university clinic; written consent; age 18–75; capacity to consent; if fertile, informed about DMT risks and contraception; no interfering conditions; no contraindications to trial drugs; no participation in other trials with blinded medication or conflicting protocols

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Rituximab (First DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    RITUXIMAB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 to 1000 mg

    Arm title
    		 Interferon (First DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    INTERFERON BETA-1B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.25 mg, 30 mg, 44 mg, 125 mg;

    Arm title
    		 Glatiramer acetate (First DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GLATIRAMER ACETATE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20 to 40 mg

    Arm title
    		 Dimethyl fumarate (First DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    DIMETHYL FUMARATE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg

    Arm title
    		 Natalizumab (First DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NATALIZUMAB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    300 mg

    Arm title
    		 Rituximab (Switch DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    RITUXIMAB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 to 1000 mg

    Arm title
    		 Dimethyl fumarate (Switch DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    DIMETHYL FUMARATE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    240 mg

    Arm title
    		 Natalizumab (Switch DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NATALIZUMAB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    300 mg

    Arm title
    		 Fingolimod (Switch DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FINGOLIMOD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg

    Arm title
    		 Teriflunomide (Switch DMT Cohort)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TERIFLUNOMIDE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    14 mg

    Number of subjects in period 1
    		Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Started
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Completed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Rituximab (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Interferon (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Glatiramer acetate (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Dimethyl fumarate (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Natalizumab (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Rituximab (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Dimethyl fumarate (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Natalizumab (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Fingolimod (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Teriflunomide (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort) Total
    Number of subjects
    		 591 992 116 416 334 748 570 541 443 161
    Age categorical
    Units: Subjects
    Age continuous
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: years
        arithmetic mean (standard deviation)
    		 36.9 ( 11.3 ) 35.8 ( 10.5 ) 36.9 ( 11.7 ) 34.4 ( 9.7 ) 31.6 ( 9.2 ) 39.0 ( 10.5 ) 40.6 ( 10.6 ) 35.1 ( 9.6 ) 37.3 ( 9.4 ) 46.3 ( 9.8 ) -
    Gender categorical
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        Female
    		 399 705 90 283 242 560 418 406 292 116 3511
        Male
    		 192 287 26 133 92 188 152 135 151 45 1401
    Born in Sweden
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        born in Sweden (n)
    		 494 782 98 337 278 605 466 460 361 139 4020
        not born in Sweden (n)
    		 97 210 18 79 56 143 104 81 82 22 892
    Education 12+ years
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        has 12+ years education (n)
    		 310 545 61 226 161 403 309 272 234 89 2610
        does not have 12+ years education (n)
    		 281 447 55 190 173 345 261 269 209 72 2302
    Any relapse last year
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        relapse last year (n)
    		 367 648 62 265 252 254 120 288 172 30 2458
        no relapse last year (n)
    		 224 344 54 151 82 494 450 253 271 131 2454
    Medical history - serious infection
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        serious infection reported (n)
    		 15 21 1 7 16 21 17 21 12 6 137
        no serious infection reported (n)
    		 576 971 115 409 318 727 553 520 431 155 4775
    Medical history - cancer
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        cancer reported (n)
    		 4 10 3 4 3 10 10 2 6 7 59
        no cancer reported (n)
    		 587 982 113 412 331 738 560 539 437 154 4853
    Medical history - major adverse cardiovascular event (MACE)
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        MACE reported (n)
    		 9 10 4 2 3 6 6 5 1 4 50
        no MACE reported (n)
    		 582 982 112 414 331 742 564 536 442 157 4862
    Medical history - arrhythmia
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        Arrhythmia reported (n)
    		 10 7 0 2 2 11 5 8 6 1 52
        no Arrhythmia reported (n)
    		 581 985 116 414 332 737 565 533 437 160 4860
    Medical history - diabetes
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        Diabetes reported (n)
    		 13 17 2 4 7 17 12 6 5 2 85
        no Diabetes reported (n)
    		 578 975 114 412 327 731 558 535 438 159 4827
    Medical history - antidepressant use
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Subjects
        Antidepressant use (n)
    		 88 98 25 64 35 124 92 108 81 42 757
        no Antidepressant use (n)
    		 503 894 91 352 299 624 478 433 362 119 4155
    Year of DMT start
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: Year
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 2016 (2015 to 2017) 2013 (2012 to 2014) 2013 (2012 to 2014) 2015 (2014 to 2017) 2014 (2013 to 2016) 2016 (2014 to 2017) 2015 (2014 to 2016) 2013 (2012 to 2014) 2013 (2012 to 2014) 2015 (2015 to 2017) -
    Years since MS diagnosis
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: mean (SD)
        arithmetic mean (standard deviation)
    		 1.3 ( 4.0 ) 0.9 ( 3.1 ) 1.7 ( 4.5 ) 0.6 ( 2.3 ) 0.5 ( 1.9 ) 5.6 ( 5.5 ) 7.1 ( 5.9 ) 4.7 ( 4.8 ) 5.6 ( 4.8 ) 9.3 ( 6.9 ) -
    EDSS mean
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: mean (SD)
        arithmetic mean (standard deviation)
    		 2.0 ( 1.3 ) 1.6 ( 1.2 ) 1.4 ( 1.2 ) 1.5 ( 1.1 ) 2.1 ( 1.3 ) 2.0 ( 1.3 ) 1.6 ( 1.3 ) 2.2 ( 1.4 ) 1.8 ( 1.3 ) 1.8 ( 1.6 ) -
    MSIS-29 physical mean
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: mean (SD)
        arithmetic mean (standard deviation)
    		 1.8 ( 0.8 ) 1.6 ( 0.7 ) 1.7 ( 0.6 ) 1.7 ( 0.8 ) 2.0 ( 0.9 ) 1.7 ( 0.8 ) 1.6 ( 0.7 ) 1.9 ( 0.9 ) 1.7 ( 0.8 ) 1.7 ( 0.7 ) -
    MSIS-29 psychological mean
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: mean (SD)
        arithmetic mean (standard deviation)
    		 2.4 ( 1.0 ) 2.2 ( 0.9 ) 2.6 ( 0.9 ) 2.3 ( 1.0 ) 2.6 ( 1.0 ) 2.2 ( 1.0 ) 2.0 ( 0.9 ) 2.4 ( 1.0 ) 2.2 ( 0.9 ) 2.1 ( 1.0 ) -
    SDMT mean
    Note that individual patients could contribute to more than one treatment group, both with their first line and second line DMT, or exclusively in the first line or second line DMT group. The 'Total' column automatically sums observations across the first line and second line DMT groups. Therefore, the total number of participants reported in the total column of the descriptive table does not represent the number of unique patients.
    Units: mean (SD)
        arithmetic mean (standard deviation)
    		 52.0 ( 11.4 ) 55.2 ( 12.3 ) 54.4 ( 11.4 ) 53.4 ( 12.5 ) 50.6 ( 13.3 ) 51.5 ( 11.5 ) 52.8 ( 11.8 ) 52.1 ( 11.9 ) 53.3 ( 12.6 ) 53.3 ( 9.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Rituximab (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Interferon (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Glatiramer acetate (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Dimethyl fumarate (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Natalizumab (First DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Rituximab (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Dimethyl fumarate (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Natalizumab (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Fingolimod (Switch DMT Cohort)
    Reporting group description
    		 -

    Reporting group title
    Teriflunomide (Switch DMT Cohort)
    Reporting group description
    		 -

    Primary: Confirmed Disease Progression in Patients with Expanded Disability Status Scale (EDSS) <2.5 at Baseline

    		 Close Top of page
    End point title
    		 Confirmed Disease Progression in Patients with Expanded Disability Status Scale (EDSS) <2.5 at Baseline
    End point description
    Data shown are adjusted difference in proportion, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Primary
    End point timeframe
    Proportion of patients with baseline EDSS <2.5 progressing to 12 months confirmed EDSS ≥3 among those over 3 years of follow up.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    3.6
    4.9
    3.9
    3.1
    1.6
    2.6
    4.4
    3.9
    4.4
    4.6
    Statistical analysis title
    		 Rituximab vs. Natalizumabh (First DMT Cohort)
    Statistical analysis description
    Mean difference between Natalizumab to Rituximab at follow-up.
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.43
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [1] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.43
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [2] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs. Glatiramer acetate (First DMT Cohort
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.88
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [3] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.57
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [4] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.35
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [5] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.76
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [6] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.51
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [7] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.66
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [8] - Comparative effectiveness analysis;

    Primary: Confirmed Disease Progression in Patients with EDSS ≥2.5 at Baseline

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    End point title
    		 Confirmed Disease Progression in Patients with EDSS ≥2.5 at Baseline
    End point description
    Data shown are adjusted difference in proportion, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Primary
    End point timeframe
    Proportion of patients with baseline EDSS ≥2.5 experiencing 12 months confirmed EDSS increase of 1 point among those over 3 years of follow up.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    8.8
    11.4
    9.4
    6.5
    9.6
    6.7
    9.2
    8.9
    7.9
    5.0
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.99
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [9] - Comparative effectiveness analysis;
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.83
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [10] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.7
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [11] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.78
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [12] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.82
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [13] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.49
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [14] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.85
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [15] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.64
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [16] - Comparative effectiveness analysis

    Primary: Disease-related Impact on Daily Life, Physical

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    End point title
    		 Disease-related Impact on Daily Life, Physical
    End point description
    Change in the MSIS-29 physical subscale (change from baseline; mean value). Data shown are adjusted mean difference, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Primary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    -1.5
    1.3
    -5.0
    -1.1
    -6.2
    -0.3
    -0.5
    -1.9
    -1.4
    2.7
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.57
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [17] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.23
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [18] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.96
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [19] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.05
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [20] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.5
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [21] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.11
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [22] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.07
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [23] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.13
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [24] - Comparative effectiveness analysis

    Primary: Disease-related Impact on Daily Life, Psychological

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    End point title
    		 Disease-related Impact on Daily Life, Psychological
    End point description
    Data shown are adjusted mean differences, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Primary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    -8.4
    -5.3
    -16.8
    -6.6
    -12.1
    -3.9
    -1.8
    -6.0
    -4.7
    -0.8
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value).
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.37
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [25] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.31
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [26] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value).
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.65
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [27] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value).
    Comparison groups
    Natalizumab (First DMT Cohort) v Rituximab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 0.14
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [28] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value).
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.98
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [29] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Natalizumab (Switch DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value).
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.3
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [30] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value).
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.28
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [31] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Statistical analysis description
    Change in the MSIS-29 psychological subscale (change from baseline; mean value).
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.26
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [32] - Comparative effectiveness analysis

    Secondary: Annualized Relapse Rate

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    End point title
    		 Annualized Relapse Rate
    End point description
    Data shown are adjusted mean differences, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Comparison of mean number of relapses per year between the different treatments.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    0.08
    0.59
    0.47
    0.26
    0.26
    0.09
    0.22
    0.30
    0.30
    0.25
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [33] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 0.0005
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [34] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [35] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    P-value
    		 = 0.23
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [36] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [37] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    P-value
    		 = 0.02
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [38] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.0002
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [39] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [40] - Comparative effectiveness analysis

    Secondary: Remaining on Therapy

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    End point title
    		 Remaining on Therapy
    End point description
    Proportion remaining on the index DMT after 3 years. Data shown are adjusted differences in percentage points, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: percentage
        number (not applicable)
    89.1
    30.2
    34.5
    45.8
    50.0
    88.5
    53.9
    55.2
    58.7
    47.5
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [41] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [42] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [43] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [44]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [44] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [45] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [46] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [47]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [47] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [48]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [48] - Comparative effectiveness analysis

    Secondary: Change in EDSS

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    End point title
    		 Change in EDSS
    End point description
    Comparison of yearly increase in mean EDSS between the different treatments. Data shown are adjusted mean differences, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    -0.2
    0.1
    0.2
    -0.2
    -0.4
    -0.0
    0.1
    -0.1
    0.1
    0.3
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Interferon (First DMT Cohort) v Rituximab (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [49]
    P-value
    		 = 0.2
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [49] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [50]
    P-value
    		 = 0.81
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [50] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [51]
    P-value
    		 = 0.36
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [51] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [52]
    P-value
    		 = 0.6
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [52] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [53]
    P-value
    		 = 0.98
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [53] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [54]
    P-value
    		 = 0.53
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [54] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [55]
    P-value
    		 = 0.94
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [55] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [56]
    P-value
    		 = 0.19
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [56] - Comparative effectiveness analysis

    Secondary: Proportion of Patients With at Least 1 Step Increase in EDSS

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    End point title
    		 Proportion of Patients With at Least 1 Step Increase in EDSS
    End point description
    Comparison of yearly proportion of patients with at least 1 step increase in EDSS between the different treatments. Data shown are adjusted differences in proportion, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    17.6
    28.1
    35.9
    19.3
    13.4
    18.1
    20.5
    21.3
    20.7
    25.2
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [57]
    P-value
    		 = 0.046
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [57] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [58]
    P-value
    		 = 0.13
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [58] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Dimethyl fumarate (First DMT Cohort) v Rituximab (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [59]
    P-value
    		 = 0.92
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [59] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [60]
    P-value
    		 = 0.74
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [60] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [61]
    P-value
    		 = 0.44
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [61] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [62]
    P-value
    		 = 0.37
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [62] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [63]
    P-value
    		 = 0.94
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [63] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [64]
    P-value
    		 = 0.28
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [64] - Comparative effectiveness analysis

    Secondary: Proportion of Patients With No Evidence of Disease Activity (NEDA) -2

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    End point title
    		 Proportion of Patients With No Evidence of Disease Activity (NEDA) -2
    End point description
    Comparison of yearly proportion of patients with No Evidence of Disease Activity (NEDA) -2 (free of exacerbations, new/enlarged T2-lesions and occurrence of CEL) between the treatments. Data shown are adjusted differences in proportion, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    77.6
    33.8
    34.1
    52.6
    58.5
    81.4
    60.6
    58.4
    48.6
    58.5
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [65]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [65] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [66]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [66] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [67]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [67] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [68]
    P-value
    		 = 0.048
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [68] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [69]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [69] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [70]
    P-value
    		 = 0.0004
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [70] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [71]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [71] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [72]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [72] - Comparative effectiveness analysis

    Secondary: Proportion of Patients With NEDA-3

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    End point title
    		 Proportion of Patients With NEDA-3
    End point description
    Comparison of yearly proportion of patients with NEDA-3 (NEDA-2 plus no confirmed worsening of EDSS from baseline). Data shown are adjusted differences in proportion, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    75.1
    33.1
    33.2
    51.7
    57.2
    78.9
    57.5
    56.0
    47.6
    57.0
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [73]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [73] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [74]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [74] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [75]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [75] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [76]
    P-value
    		 = 0.07
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [76] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [77]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [77] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [78]
    P-value
    		 = 0.0007
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [78] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [79]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [79] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Teriflunomide (Switch DMT Cohort) v Rituximab (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [80]
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [80] - Comparative effectiveness analysis

    Secondary: Quality of Life Assessments

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    End point title
    		 Quality of Life Assessments
    End point description
    Comparison of health related quality of life measured by EQ-5D. European Quality of Life Five Dimension (EQ-5D) measures health-related quality of life. Data shown are adjusted mean differences, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    0.77
    0.77
    0.74
    0.81
    0.76
    0.76
    0.80
    0.74
    0.79
    0.77
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [81]
    P-value
    		 = 0.1
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [81] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [82]
    P-value
    		 = 0.52
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [82] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [83]
    P-value
    		 = 0.997
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [83] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [84]
    P-value
    		 = 0.66
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [84] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [85]
    P-value
    		 = 0.46
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [85] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [86]
    P-value
    		 = 0.13
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [86] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [87]
    P-value
    		 = 0.04
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [87] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [88]
    P-value
    		 = 0.69
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [88] - Comparative effectiveness analysis

    Secondary: Fatigue

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    End point title
    		 Fatigue
    End point description
    Comparison of fatigue measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC). Data shown are adjusted mean differences, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Observed treatment effectiveness and adjusted difference compared to RTX, among Swedish MS patients 3 years after starting a first ever DMT (groups 1-5) and first DMT switch (groups 6-10) 2011-2018.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    55.3
    51.7
    55.2
    48.4
    53.1
    53.3
    49.6
    56.0
    48.7
    53.2
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [89]
    P-value
    		 = 0.98
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [89] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [90]
    P-value
    		 = 0.79
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [90] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [91]
    P-value
    		 = 0.35
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [91] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [92]
    P-value
    		 = 0.19
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [92] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [93]
    P-value
    		 = 0.82
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [93] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [94]
    P-value
    		 = 0.55
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [94] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [95]
    P-value
    		 = 0.04
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [95] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Teriflunomide (Switch DMT Cohort) v Rituximab (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [96]
    P-value
    		 = 0.45
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [96] - Comparative effectiveness analysis

    Secondary: Treatment Satisfaction

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    End point title
    		 Treatment Satisfaction
    End point description
    Data shown are adjusted mean differences, stratified by DMT line with rituximab as reference, from multivariable linear regression adjusted for age, sex, year of treatment start, country of birth, geographical region, education level, duration since MS diagnosis, baseline EDSS and MSIS-29 scores, history of serious infection, malignancy, major adverse cardiovascular event, arrhythmia, use of antidepressants, diabetes. Confidence intervals are based on robust (Huber-White) standard errors.
    End point type
    Secondary
    End point timeframe
    Comparison of patient satisfaction with their treatment using the Treatment Satisfaction Questionnaire (TSQ), items 1-9, restricted to patients remaining on index DMT at 3 years.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: mean
        number (not applicable)
    50.0
    44.5
    42.3
    48.3
    49.6
    49.4
    49.0
    49.8
    51.7
    51.6
    Statistical analysis title
    		 Rituximab vs. Interferon (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Interferon (First DMT Cohort)
    Number of subjects included in analysis
    1583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [97]
    P-value
    		 = 0.0008
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [97] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Glatiramer acetate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Glatiramer acetate (First DMT Cohort)
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 other [98]
    P-value
    		 = 0.09
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [98] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Dimethyl fumarate (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Dimethyl fumarate (First DMT Cohort)
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 other [99]
    P-value
    		 = 0.004
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [99] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (First DMT Cohort)
    Comparison groups
    Rituximab (First DMT Cohort) v Natalizumab (First DMT Cohort)
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 other [100]
    P-value
    		 = 0.88
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [100] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs Dimethyl fumarate (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Dimethyl fumarate (Switch DMT Cohort)
    Number of subjects included in analysis
    1318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [101]
    P-value
    		 = 0.31
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [101] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Natalizumab (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Natalizumab (Switch DMT Cohort)
    Number of subjects included in analysis
    1289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [102]
    P-value
    		 = 0.08
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [102] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Fingolimod (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Fingolimod (Switch DMT Cohort)
    Number of subjects included in analysis
    1191
    Analysis specification
    Pre-specified
    Analysis type
    		 other [103]
    P-value
    		 = 0.0018
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [103] - Comparative effectiveness analysis
    Statistical analysis title
    		 Rituximab vs. Teriflunomide (Switch DMT Cohort)
    Comparison groups
    Rituximab (Switch DMT Cohort) v Teriflunomide (Switch DMT Cohort)
    Number of subjects included in analysis
    909
    Analysis specification
    Pre-specified
    Analysis type
    		 other [104]
    P-value
    		 = 0.04
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [104] - Comparative effectiveness analysis

    Secondary: Rate of Serious Infections

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    End point title
    		 Rate of Serious Infections
    End point description
    Descriptive analysis (Regression, Cox)
    End point type
    Secondary
    End point timeframe
    Rate of serious infections, defined as hospitalizations where the main diagnosis included an ICD-10 diagnosis code in the national patient register in the 3 years after initiating index DMT
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: Incident rate (IR) per 1000 pyrs
        number (not applicable)
    12.7
    6.8
    5.8
    9.8
    12.2
    20.2
    5.9
    6.2
    10.7
    14.9
    No statistical analyses for this end point

    Secondary: Rate of Major Adverse Cardiovascular Events (MACE)

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    End point title
    		 Rate of Major Adverse Cardiovascular Events (MACE)
    End point description
    Descriptive analysis (Regression, Cox)
    End point type
    Secondary
    End point timeframe
    Rate of MACE, defined as acute coronary syndrome, stroke or death from any cardiovascular cause based on corresponding ICD-codes in the national patient and cause of death registries in the 3 years after initiating index DMT.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: Incident Rate (IR) per 1000 Pyrs
        number (not applicable)
    1.7
    1.4
    0.0
    0.81
    0.0
    1.3
    0.6
    1.2
    0.0
    4.2
    No statistical analyses for this end point

    Secondary: Rate of Invasive Cancer

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    End point title
    		 Rate of Invasive Cancer
    End point description
    Descriptive analysis (Regression, Cox)
    End point type
    Secondary
    End point timeframe
    Rate of incident invasive cancer, defined as invasive cancers based on corresponding ICD-codes in the national cancer registry in the 3 years after initiating index DMT.
    End point values
    		 Rituximab (First DMT Cohort) Interferon (First DMT Cohort) Glatiramer acetate (First DMT Cohort) Dimethyl fumarate (First DMT Cohort) Natalizumab (First DMT Cohort) Rituximab (Switch DMT Cohort) Dimethyl fumarate (Switch DMT Cohort) Natalizumab (Switch DMT Cohort) Fingolimod (Switch DMT Cohort) Teriflunomide (Switch DMT Cohort)
    Number of subjects analysed
    591
    992
    116
    416
    334
    748
    570
    541
    443
    161
    Units: Incident Rate (IR) per 1000 Pyrs
        number (not applicable)
    0.6
    2.4
    2.9
    0.0
    3.0
    1.3
    3.0
    1.2
    4.6
    0.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    3 years.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 N/A
    Dictionary version
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Serious and non-serious Adverse Events were not monitored. Other safety outcomes, collected retrospectively from national registers, are presented under secondary endpoints.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2021
    Update in the informed consent to indicate that the last date for clinical visits is set to 2022, and the database will be locked on 2022-09-01.

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

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