Relapsing-remitting Multiple Sclerosis
Conditions
Keywords
Immunomodulating treatment, Cohort study, Dimethyl fumarate, Fingolimod, Interferon-beta, Natalizumab, Rituximab, Glatiramer acetate
Brief summary
The overarching goal of this study is to determine whether rituximab (RTX) offers effectiveness and safety advantages over other commonly used approved Disease-Modifying Drugs (DMT) in the largest real-world population-based structured prospective follow-up cohort of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. The study will include both treatment naïve patients starting their first DMT and patients switching from a previous first line DMT (escalation/second-line).
Detailed description
This is a prospective non-intervention observational prospective cohort study assessing the long-term safety and efficacy of RTX treatment in MS compared with other common MS DMTs regarding both clinical and radiological parameters in a real-life population of patients with MS. A number of parameters will be assessed annually. These include baseline demographics, previous drug history and reasons for discontinuation, disability status (expanded disability status scale), relapses, safety and adverse events (AE), contrast enhancing T1 and newly appearing T2 lesions on magnetic resonance imaging, as well as a panel of patient reported outcome measures: Symbol Digit Modalities Test (SDMT); MS impact scale-29 (MSIS-29) Fatigue Scale for Motor and Cognitive Functions (FSMC), EuroQol-5 Dimensions (EQ-5D), the MS check scale and Treatment Satisfaction Questionnaire 9 (TSQM-9). Retrospective data entered in medical charts and the Swedish MS registry will be included together with prospective annual structured follow up from inclusion into the study for a minimum of three years (three to nine years). In a substudy - Covid Enhancement study - analyses will be performed regarding the effect of COVID-19 on people with MS as compared to non-MS individuals and also if there is any indication that a particular DMD is associated with a risk to contract a more severe COVID-19. The analyses will primarily be performed in official health care databases.
Interventions
DRUGRituximab
Comparisons of efficacy and safety between rituximab and all other frequently used immunomodulating drugs against multiple sclerosis
Sponsors
Patient-Centered Outcomes Research Institute
Kaiser Foundation Research Institute
Karolinska Institutet
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The study population consists of all patients with Clinically Isolated Syndrome (CIS) or RRMS who; * Initiate a first MS DMT (treatment naïve), or Initiate a second ever DMT, of a different drug class than the first, regardless of time between drugs or reason for discontinuation(switchers) from 1st Jan 2011 to 30st June 2018, and * Are followed at any of the University clinics of Sweden, and * Consent to participation in COMBAT-MS core, and * Are expected to be capable to follow study assessments.
Exclusion criteria
\- Patients with progressive forms of MS at start of therapy are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | 3 years | Proportion of patients with baseline EDSS \<2.5 progressing to 12 months confirmed EDSS ≥3 among those over 3 years of follow up. Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability). |
| Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | 3 years | \- 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 Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability). |
| Disease-related Impact on Daily Life, Physical | 3 years | \- Change in the MSIS-29 physical subscale (change from baseline; mean value) The Multiple Sclerosis Impact Scale (MSIS-29) physical subscale measures patient-reported physical impact of multiple sclerosis. Scale range: Minimum score: 1 (least impact). Maximum score: 5 (highest impact). Lower scores indicate better outcomes. Higher scores indicate worse outcomes. |
| Disease-related Impact on Daily Life, Psychological | 3 years | \- Change in the MSIS-29 psychological subscale (change from baseline; mean value) The Multiple Sclerosis Impact Scale (MSIS-29) psychological subscale measures patient-reported psychological impact of multiple sclerosis. Scale range: Minimum score: 1 (least impact). Maximum score: 5 (highest impact). Lower scores indicate better outcomes. Higher scores indicate worse outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | 3 years | \- 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. Lower NEDA-2 scores indicate better outcomes. Higher NEDA-2 scores indicate worse outcomes. |
| Proportion of Patients With NEDA-3 | 3 years | \- Comparison of yearly proportion of patients with NEDA-3 (NEDA-2 plus no confirmed worsening of EDSS from baseline). Lower NEDA-3 scores indicate better outcomes. Higher NEDA-3 scores indicate worse outcomes. |
| Quality of Life Assessments | 3 years | Comparison of health-related quality of life measured by the European Quality of Life Five Dimensions (EQ-5D). Higher values indicate better health, and lower values indicate poorer health. The maximum theoretical value is 1. While there is no fixed minimum, scores can fall below 0, indicating health states worse than death. In this study, scores ranged from -0.59 to 1, which represent clinically relevant ranges of values. |
| Fatigue | 3 years | Comparison of fatigue measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC). The fatigue scale for motor and cognitive functions (FSMC) scale range: Minimum score: 20. Maximum score: 100. Lower scores indicate better outcomes. Higher scores indicate worse outcomes. |
| Annualized Relapse Rate | 3 years | \- Comparison of mean number of relapses per year between the different treatments |
| Rate of Serious Infections | 3 years | \- 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 |
| Rate of Major Adverse Cardiovascular Events (MACE) | 3 years | \- 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 |
| Rate of Invasive Cancer | 3 years | \- 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. |
| Treatment Satisfaction | 3 years | 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. The Treatment Satisfaction Questionnaire (TSQ), items 1-9 scale range: Minimum score: 0. Maximum score: 100. Lower scores indicate worse outcomes. Higher scores indicate better outcomes. |
| Remaining on Drug | 3 years | \- Proportion remaining on the index DMT after 3 years |
| Increase in EDSS | 3 years | \- Comparison of yearly increase in mean EDSS between the different treatments Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability). |
| Proportion of Patients With at Least 1 Step Increase in EDSS | 3 years | \- Comparison of yearly proportion of patients with at least 1 step increase in EDSS between the different treatments Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability). |
Countries
Sweden
Participant flow
Recruitment details
Note that unique 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, as based on baseline characteristics. The 'total' automatically summed across groups should be interpreted as the total number of participants in first line DMT and second line DMT, respectively.
Participants by arm
| Arm | Count |
|---|---|
| RTX (First Line) Rituximab (First line) | 591 |
| RTX (First Line) Rituximab (First line) | 591 |
| IFN (First Line) Interferons, first line DMT | 992 |
| IFN (First Line) Interferons, first line DMT | 992 |
| GA (First Line) Glatiramer acetate, first line DMT | 116 |
| GA (First Line) Glatiramer acetate, first line DMT | 116 |
| DMF (First Line) Dimethyl fumarate, first line DMT | 416 |
| DMF (First Line) Dimethyl fumarate, first line DMT | 416 |
| NTZ (First Line) Natalizumab, first line DMT | 334 |
| NTZ (First Line) Natalizumab, first line DMT | 334 |
| RTX (Second Line) Rituximab, as first second line DMT | 748 |
| RTX (Second Line) Rituximab, as first second line DMT | 748 |
| DMF (Second Line) Dimethyl fumarate, as first second line DMT | 570 |
| DMF (Second Line) Dimethyl fumarate, as first second line DMT | 570 |
| NTZ (Second Line) Natalizumab, as first second line DMT | 541 |
| NTZ (Second Line) Natalizumab, as first second line DMT | 541 |
| FGL (Second Line) Fingolimod, as first second line DMT | 443 |
| FGL (Second Line) Fingolimod, as first second line DMT | 443 |
| TFL (Second Line) Teriflunomide, as first second line DMT | 161 |
| TFL (Second Line) Teriflunomide, as first second line DMT | 161 |
| Total | 9,824 |
Baseline characteristics
| Characteristic | Total | IFN (First Line) | GA (First Line) | RTX (First Line) | DMF (First Line) | NTZ (First Line) | RTX (Second Line) | DMF (Second Line) | NTZ (Second Line) | FGL (Second Line) | TFL (Second Line) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous First line | 35.3 years STANDARD_DEVIATION 10.6 | 35.8 years STANDARD_DEVIATION 10.5 | 36.9 years STANDARD_DEVIATION 11.7 | 36.9 years STANDARD_DEVIATION 11.3 | 34.4 years STANDARD_DEVIATION 9.7 | 31.6 years STANDARD_DEVIATION 9.2 | — | — | — | — | — |
| Age, Continuous Second line | 38.7 years STANDARD_DEVIATION 10.5 | — | — | — | — | — | 39.0 years STANDARD_DEVIATION 10.5 | 40.6 years STANDARD_DEVIATION 10.6 | 35.1 years STANDARD_DEVIATION 9.6 | 37.3 years STANDARD_DEVIATION 9.4 | 46.3 years STANDARD_DEVIATION 9.8 |
| Antidepressant use First line | 310 Participants | 98 Participants | 25 Participants | 88 Participants | 64 Participants | 35 Participants | — | — | — | — | — |
| Antidepressant use Second line | 447 Participants | — | — | — | — | — | 124 Participants | 92 Participants | 108 Participants | 81 Participants | 42 Participants |
| Any relapse last year First line | 1594 Participants | 648 Participants | 62 Participants | 367 Participants | 265 Participants | 252 Participants | — | — | — | — | — |
| Any relapse last year Second line | 864 Participants | — | — | — | — | — | 254 Participants | 120 Participants | 288 Participants | 172 Participants | 30 Participants |
| Arrhythmia First line | 21 Participants | 7 Participants | 0 Participants | 10 Participants | 2 Participants | 2 Participants | — | — | — | — | — |
| Arrhythmia Second line | 31 Participants | — | — | — | — | — | 11 Participants | 5 Participants | 8 Participants | 6 Participants | 1 Participants |
| Born in Sweden First line | 1989 Participants | 782 Participants | 98 Participants | 494 Participants | 337 Participants | 278 Participants | — | — | — | — | — |
| Born in Sweden Second line | 2031 Participants | — | — | — | — | — | 605 Participants | 466 Participants | 460 Participants | 361 Participants | 139 Participants |
| Cancer First line | 24 Participants | 10 Participants | 3 Participants | 4 Participants | 4 Participants | 3 Participants | — | — | — | — | — |
| Cancer Second line | 35 Participants | — | — | — | — | — | 10 Participants | 10 Participants | 2 Participants | 6 Participants | 7 Participants |
| Diabetes First line | 43 Participants | 17 Participants | 2 Participants | 13 Participants | 4 Participants | 7 Participants | — | — | — | — | — |
| Diabetes Second line | 42 Participants | — | — | — | — | — | 17 Participants | 12 Participants | 6 Participants | 5 Participants | 2 Participants |
| EDSS First line | 1.7 units on a scale STANDARD_DEVIATION 1.2 | 1.6 units on a scale STANDARD_DEVIATION 1.2 | 1.4 units on a scale STANDARD_DEVIATION 1.2 | 2.0 units on a scale STANDARD_DEVIATION 1.3 | 1.5 units on a scale STANDARD_DEVIATION 1.1 | 2.1 units on a scale STANDARD_DEVIATION 1.3 | — | — | — | — | — |
| EDSS Second line | 1.9 units on a scale STANDARD_DEVIATION 1.4 | — | — | — | — | — | 2.0 units on a scale STANDARD_DEVIATION 1.3 | 1.6 units on a scale STANDARD_DEVIATION 1.3 | 2.2 units on a scale STANDARD_DEVIATION 1.4 | 1.8 units on a scale STANDARD_DEVIATION 1.3 | 1.8 units on a scale STANDARD_DEVIATION 1.6 |
| Education, 12+ years First line | 1303 Participants | 545 Participants | 61 Participants | 310 Participants | 226 Participants | 161 Participants | — | — | — | — | — |
| Education, 12+ years Second line | 1307 Participants | — | — | — | — | — | 403 Participants | 309 Participants | 272 Participants | 234 Participants | 89 Participants |
| MACE First line | 28 Participants | 10 Participants | 4 Participants | 9 Participants | 2 Participants | 3 Participants | — | — | — | — | — |
| MACE Second line | 22 Participants | — | — | — | — | — | 6 Participants | 6 Participants | 5 Participants | 1 Participants | 4 Participants |
| MSIS-29 physical First line | 1.8 units on a scale STANDARD_DEVIATION 0.8 | 1.6 units on a scale STANDARD_DEVIATION 0.7 | 1.7 units on a scale STANDARD_DEVIATION 0.6 | 1.8 units on a scale STANDARD_DEVIATION 0.8 | 1.7 units on a scale STANDARD_DEVIATION 0.8 | 2.0 units on a scale STANDARD_DEVIATION 0.9 | — | — | — | — | — |
| MSIS-29 physical Second line | 1.8 units on a scale STANDARD_DEVIATION 0.8 | — | — | — | — | — | 1.7 units on a scale STANDARD_DEVIATION 0.8 | 1.6 units on a scale STANDARD_DEVIATION 0.7 | 1.9 units on a scale STANDARD_DEVIATION 0.9 | 1.7 units on a scale STANDARD_DEVIATION 0.8 | 1.7 units on a scale STANDARD_DEVIATION 0.7 |
| MSIS-29 psychological First line | 2.4 units on a scale STANDARD_DEVIATION 1 | 2.2 units on a scale STANDARD_DEVIATION 0.9 | 2.6 units on a scale STANDARD_DEVIATION 0.9 | 2.4 units on a scale STANDARD_DEVIATION 1 | 2.3 units on a scale STANDARD_DEVIATION 1 | 2.6 units on a scale STANDARD_DEVIATION 1 | — | — | — | — | — |
| MSIS-29 psychological Second line | 2.2 units on a scale STANDARD_DEVIATION 1 | — | — | — | — | — | 2.2 units on a scale STANDARD_DEVIATION 1 | 2.0 units on a scale STANDARD_DEVIATION 0.9 | 2.4 units on a scale STANDARD_DEVIATION 1 | 2.2 units on a scale STANDARD_DEVIATION 0.9 | 2.1 units on a scale STANDARD_DEVIATION 1 |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — | — | — | — | — | — | — | — |
| Region of Enrollment Sweden | 2449 participants | 992 participants | 116 participants | 591 participants | 416 participants | 334 participants | 748 participants | 570 participants | 541 participants | 443 participants | 161 participants |
| Serious infection First line | 60 Participants | 21 Participants | 1 Participants | 15 Participants | 7 Participants | 16 Participants | — | — | — | — | — |
| Serious infection Second line | 77 Participants | — | — | — | — | — | 21 Participants | 17 Participants | 21 Participants | 12 Participants | 6 Participants |
| Sex: Female, Male First line Female | 1719 Participants | 705 Participants | 90 Participants | 399 Participants | 283 Participants | 242 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male First line Male | 730 Participants | 287 Participants | 26 Participants | 192 Participants | 133 Participants | 92 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Second line Female | 1792 Participants | — | — | — | — | — | 560 Participants | 418 Participants | 406 Participants | 292 Participants | 116 Participants |
| Sex: Female, Male Second line Male | 671 Participants | — | — | — | — | — | 188 Participants | 152 Participants | 135 Participants | 151 Participants | 45 Participants |
| Year of DMT start First line | 2014 year | 2013 year | 2013 year | 2016 year | 2015 year | 2014 year | — | — | — | — | — |
| Year of DMT start Second line | 2014 year | — | — | — | — | — | 2016 year | 2015 year | 2013 year | 2013 year | 2015 year |
| Years since MS diagnosis First line | 0.9 years STANDARD_DEVIATION 3.2 | 0.9 years STANDARD_DEVIATION 3.1 | 1.7 years STANDARD_DEVIATION 4.5 | 1.3 years STANDARD_DEVIATION 4 | 0.6 years STANDARD_DEVIATION 2.3 | 0.5 years STANDARD_DEVIATION 1.9 | — | — | — | — | — |
| Years since MS diagnosis Second line | 6.0 years STANDARD_DEVIATION 5.6 | — | — | — | — | — | 5.6 years STANDARD_DEVIATION 5.5 | 7.1 years STANDARD_DEVIATION 5.9 | 4.7 years STANDARD_DEVIATION 4.8 | 5.6 years STANDARD_DEVIATION 4.8 | 9.3 years STANDARD_DEVIATION 6.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1,184 | 0 / 884 | 0 / 97 | 0 / 870 | 0 / 767 | 0 / 384 | 1 / 138 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 43 / 1,184 | 1 / 884 | 0 / 97 | 1 / 870 | 3 / 767 | 3 / 384 | 3 / 138 |
Outcome results
Primary
Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline
\- 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 Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RTX (First Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | First line | 50 Participants |
| IFN (First Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | First line | 111 Participants |
| GA (First Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | First line | 9 Participants |
| DMF (First Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | First line | 30 Participants |
| NTZ (First Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | First line | 32 Participants |
| RTX (Second Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | Second line | 50 Participants |
| DMF (Second Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | Second line | 57 Participants |
| NTZ (Second Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | Second line | 47 Participants |
| FGL (Second Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | Second line | 37 Participants |
| TFL (Second Line) | Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline | Second line | 9 Participants |
Comparison: 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.95% CI: [-7.5, 8.8]
Comparison: 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.95% CI: [-18.5, 12.8]
Comparison: 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.95% CI: [-8.8, 8.6]
Comparison: 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.95% CI: [-8.1, 7.2]
Comparison: 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.95% CI: [-5.7, 8.9]
Comparison: 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.95% CI: [-4.7, 8]
Comparison: 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.95% CI: [-6.2, 7.9]
Comparison: 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.95% CI: [-10.8, 7.5]
Primary
Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline
Proportion of patients with baseline EDSS \<2.5 progressing to 12 months confirmed EDSS ≥3 among those over 3 years of follow up. Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RTX (First Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 20 Participants |
| IFN (First Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 50 Participants |
| GA (First Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 5 Participants |
| DMF (First Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 14 Participants |
| NTZ (First Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 7 Participants |
| RTX (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | Second line | 18 Participants |
| RTX (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 0 Participants |
| DMF (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 0 Participants |
| DMF (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | Second line | 25 Participants |
| NTZ (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 0 Participants |
| NTZ (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | Second line | 19 Participants |
| FGL (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 0 Participants |
| FGL (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | Second line | 19 Participants |
| TFL (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | Second line | 8 Participants |
| TFL (Second Line) | Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline | First line | 0 Participants |
Comparison: 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.95% CI: [-1.8, 4.9]
Comparison: 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.95% CI: [-6.8, 6.5]
Comparison: 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.95% CI: [-1.7, 4.3]
Comparison: 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.95% CI: [-4.3, 2.4]
Comparison: 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.95% CI: [-1.3, 4.6]
Comparison: 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.95% CI: [-2.7, 3.3]
Comparison: 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.95% CI: [-2, 4.4]
Comparison: 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.95% CI: [-3.2, 7.1]
Primary
Disease-related Impact on Daily Life, Physical
\- Change in the MSIS-29 physical subscale (change from baseline; mean value) The Multiple Sclerosis Impact Scale (MSIS-29) physical subscale measures patient-reported physical impact of multiple sclerosis. Scale range: Minimum score: 1 (least impact). Maximum score: 5 (highest impact). Lower scores indicate better outcomes. Higher scores indicate worse outcomes.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTX (First Line) | Disease-related Impact on Daily Life, Physical | First line | -1.4 units on a scale | Standard Deviation 16.6 |
| IFN (First Line) | Disease-related Impact on Daily Life, Physical | First line | 1.1 units on a scale | Standard Deviation 16.2 |
| GA (First Line) | Disease-related Impact on Daily Life, Physical | First line | -4.8 units on a scale | Standard Deviation 17.7 |
| DMF (First Line) | Disease-related Impact on Daily Life, Physical | First line | -1.2 units on a scale | Standard Deviation 16.1 |
| NTZ (First Line) | Disease-related Impact on Daily Life, Physical | First line | -6.3 units on a scale | Standard Deviation 18 |
| RTX (Second Line) | Disease-related Impact on Daily Life, Physical | Second line | -0.3 units on a scale | Standard Deviation 14.5 |
| DMF (Second Line) | Disease-related Impact on Daily Life, Physical | Second line | -0.5 units on a scale | Standard Deviation 13.3 |
| NTZ (Second Line) | Disease-related Impact on Daily Life, Physical | Second line | -2.1 units on a scale | Standard Deviation 16.4 |
| FGL (Second Line) | Disease-related Impact on Daily Life, Physical | Second line | -1.3 units on a scale | Standard Deviation 14.3 |
| TFL (Second Line) | Disease-related Impact on Daily Life, Physical | Second line | 2.9 units on a scale | Standard Deviation 16.5 |
Comparison: 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.95% CI: [-2.5, 3.3]
Comparison: 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.95% CI: [-12.5, 3.4]
Comparison: 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.95% CI: [-2.5, 1.8]
Comparison: 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.95% CI: [-4.9, -0.1]
Comparison: 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.95% CI: [-2.6, 1.1]
Comparison: 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.95% CI: [-4.2, 0.3]
Comparison: 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.95% CI: [-4, 0.3]
Comparison: 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.95% CI: [-0.6, 5.8]
Primary
Disease-related Impact on Daily Life, Psychological
\- Change in the MSIS-29 psychological subscale (change from baseline; mean value) The Multiple Sclerosis Impact Scale (MSIS-29) psychological subscale measures patient-reported psychological impact of multiple sclerosis. Scale range: Minimum score: 1 (least impact). Maximum score: 5 (highest impact). Lower scores indicate better outcomes. Higher scores indicate worse outcomes.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTX (First Line) | Disease-related Impact on Daily Life, Psychological | First line | -8.5 units on a scale | Standard Deviation 21.3 |
| IFN (First Line) | Disease-related Impact on Daily Life, Psychological | First line | -5.1 units on a scale | Standard Deviation 20.7 |
| GA (First Line) | Disease-related Impact on Daily Life, Psychological | First line | -23.1 units on a scale | Standard Deviation 23.8 |
| DMF (First Line) | Disease-related Impact on Daily Life, Psychological | First line | -6.8 units on a scale | Standard Deviation 20.7 |
| NTZ (First Line) | Disease-related Impact on Daily Life, Psychological | First line | -12.2 units on a scale | Standard Deviation 22.3 |
| RTX (Second Line) | Disease-related Impact on Daily Life, Psychological | Second line | -3.7 units on a scale | Standard Deviation 19.5 |
| DMF (Second Line) | Disease-related Impact on Daily Life, Psychological | Second line | -1.7 units on a scale | Standard Deviation 19.3 |
| NTZ (Second Line) | Disease-related Impact on Daily Life, Psychological | Second line | -6.1 units on a scale | Standard Deviation 20.5 |
| FGL (Second Line) | Disease-related Impact on Daily Life, Psychological | Second line | -4.7 units on a scale | Standard Deviation 19.5 |
| TFL (Second Line) | Disease-related Impact on Daily Life, Psychological | Second line | -0.3 units on a scale | Standard Deviation 21.8 |
Comparison: 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.95% CI: [-2.2, 6.8]
Comparison: 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.95% CI: [-20.3, 3.7]
Comparison: 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.95% CI: [-2.6, 3.5]
Comparison: 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.95% CI: [-5.8, 0.9]
Comparison: 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.95% CI: [-2.9, 2.7]
Comparison: 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.95% CI: [-4.5, 1.6]
Comparison: 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.95% CI: [-4.7, 1.5]
Comparison: 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.95% CI: [-1.7, 6.4]
Secondary
Annualized Relapse Rate
\- Comparison of mean number of relapses per year between the different treatments
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTX (First Line) | Annualized Relapse Rate | First line | 0.08 percentage of relapses | Standard Deviation 0.31 |
| IFN (First Line) | Annualized Relapse Rate | First line | 0.59 percentage of relapses | Standard Deviation 0.94 |
| GA (First Line) | Annualized Relapse Rate | First line | 0.47 percentage of relapses | Standard Deviation 0.73 |
| DMF (First Line) | Annualized Relapse Rate | First line | 0.26 percentage of relapses | Standard Deviation 0.53 |
| NTZ (First Line) | Annualized Relapse Rate | First line | 0.26 percentage of relapses | Standard Deviation 0.63 |
| RTX (Second Line) | Annualized Relapse Rate | Second line | 0.09 percentage of relapses | Standard Deviation 0.34 |
| DMF (Second Line) | Annualized Relapse Rate | Second line | 0.22 percentage of relapses | Standard Deviation 0.54 |
| NTZ (Second Line) | Annualized Relapse Rate | Second line | 0.30 percentage of relapses | Standard Deviation 0.67 |
| FGL (Second Line) | Annualized Relapse Rate | Second line | 0.30 percentage of relapses | Standard Deviation 0.72 |
| TFL (Second Line) | Annualized Relapse Rate | Second line | 0.25 percentage of relapses | Standard Deviation 0.61 |
Comparison: 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.95% CI: [0.3, 0.48]
Comparison: 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.95% CI: [0.11, 0.42]
Comparison: 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.95% CI: [0.1, 0.23]
Comparison: 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.95% CI: [-0.03, 0.13]
Comparison: 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.95% CI: [0.08, 0.19]
Comparison: 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.95% CI: [0.01, 0.16]
Comparison: 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.95% CI: [0.06, 0.21]
Comparison: 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.95% CI: [0.13, 0.33]
Secondary
Fatigue
Comparison of fatigue measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC). The fatigue scale for motor and cognitive functions (FSMC) scale range: Minimum score: 20. Maximum score: 100. Lower scores indicate better outcomes. Higher scores indicate worse outcomes.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTX (First Line) | Fatigue | First line | 55.1 units on a scale | Standard Deviation 22.9 |
| IFN (First Line) | Fatigue | First line | 52.1 units on a scale | Standard Deviation 23 |
| GA (First Line) | Fatigue | First line | 55.7 units on a scale | Standard Deviation 22.2 |
| DMF (First Line) | Fatigue | First line | 48.3 units on a scale | Standard Deviation 23 |
| NTZ (First Line) | Fatigue | First line | 53.2 units on a scale | Standard Deviation 23.2 |
| RTX (Second Line) | Fatigue | Second line | 53.5 units on a scale | Standard Deviation 23 |
| DMF (Second Line) | Fatigue | Second line | 49.7 units on a scale | Standard Deviation 21.6 |
| NTZ (Second Line) | Fatigue | Second line | 55.9 units on a scale | Standard Deviation 23 |
| FGL (Second Line) | Fatigue | Second line | 49.3 units on a scale | Standard Deviation 22.8 |
| TFL (Second Line) | Fatigue | Second line | 53.1 units on a scale | Standard Deviation 22.7 |
Comparison: 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.95% CI: [-3.3, 5.2]
Comparison: 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.95% CI: [-9.4, 6.4]
Comparison: 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.95% CI: [-4.2, 1.4]
Comparison: 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.95% CI: [-5.9, 0.8]
Comparison: 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.95% CI: [-2.9, 2.5]
Comparison: 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.95% CI: [-4, 1.8]
Comparison: 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.95% CI: [-7, 0.9]
Comparison: 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.95% CI: [-2.9, 5.4]
Secondary
Increase in EDSS
\- Comparison of yearly increase in mean EDSS between the different treatments Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTX (First Line) | Increase in EDSS | First line | -0.2 units on a scale | Standard Deviation 1.2 |
| IFN (First Line) | Increase in EDSS | First line | 0.1 units on a scale | Standard Deviation 1.2 |
| GA (First Line) | Increase in EDSS | First line | 0.2 units on a scale | Standard Deviation 1.2 |
| DMF (First Line) | Increase in EDSS | First line | -0.2 units on a scale | Standard Deviation 1.1 |
| NTZ (First Line) | Increase in EDSS | First line | -0.4 units on a scale | Standard Deviation 1.2 |
| RTX (Second Line) | Increase in EDSS | Second line | -0.0 units on a scale | Standard Deviation 0.9 |
| DMF (Second Line) | Increase in EDSS | Second line | 0.1 units on a scale | Standard Deviation 0.9 |
| NTZ (Second Line) | Increase in EDSS | Second line | -0.1 units on a scale | Standard Deviation 1.1 |
| FGL (Second Line) | Increase in EDSS | Second line | 0.1 units on a scale | Standard Deviation 1 |
| TFL (Second Line) | Increase in EDSS | Second line | 0.3 units on a scale | Standard Deviation 0.9 |
Comparison: 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.95% CI: [-0.1, 0.3]
Comparison: 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.95% CI: [-0.3, 0.4]
Comparison: 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.95% CI: [-0.2, 0.1]
Comparison: 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.95% CI: [-0.3, 0.1]
Comparison: 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.95% CI: [-0.1, 0.1]
Comparison: 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.95% CI: [-0.2, 0.1]
Comparison: 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.95% CI: [-0.1, 0.2]
Comparison: 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.95% CI: [-0.1, 0.3]
Secondary
Proportion of Patients With at Least 1 Step Increase in EDSS
\- Comparison of yearly proportion of patients with at least 1 step increase in EDSS between the different treatments Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RTX (First Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | First line | 108 Participants |
| IFN (First Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | First line | 272 Participants |
| GA (First Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | First line | 43 Participants |
| DMF (First Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | First line | 83 Participants |
| NTZ (First Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | First line | 44 Participants |
| RTX (Second Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | Second line | 135 Participants |
| DMF (Second Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | Second line | 114 Participants |
| NTZ (Second Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | Second line | 117 Participants |
| FGL (Second Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | Second line | 93 Participants |
| TFL (Second Line) | Proportion of Patients With at Least 1 Step Increase in EDSS | Second line | 39 Participants |
Comparison: 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.95% CI: [-2.2, 11.9]
Comparison: 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.95% CI: [-2.6, 20.6]
Comparison: 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.95% CI: [-7.6, 6.2]
Comparison: 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.95% CI: [-9.4, 4.1]
Comparison: 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.95% CI: [-8.6, 3.4]
Comparison: 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.95% CI: [-4.7, 12.2]
Comparison: 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.95% CI: [-6.9, 8.1]
Comparison: 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.95% CI: [-6.3, 14.1]
Secondary
Proportion of Patients With NEDA-3
\- Comparison of yearly proportion of patients with NEDA-3 (NEDA-2 plus no confirmed worsening of EDSS from baseline). Lower NEDA-3 scores indicate better outcomes. Higher NEDA-3 scores indicate worse outcomes.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RTX (First Line) | Proportion of Patients With NEDA-3 | First line | 467 Participants |
| IFN (First Line) | Proportion of Patients With NEDA-3 | First line | 340 Participants |
| GA (First Line) | Proportion of Patients With NEDA-3 | First line | 43 Participants |
| DMF (First Line) | Proportion of Patients With NEDA-3 | First line | 232 Participants |
| NTZ (First Line) | Proportion of Patients With NEDA-3 | First line | 204 Participants |
| RTX (Second Line) | Proportion of Patients With NEDA-3 | Second line | 619 Participants |
| DMF (Second Line) | Proportion of Patients With NEDA-3 | Second line | 339 Participants |
| NTZ (Second Line) | Proportion of Patients With NEDA-3 | Second line | 314 Participants |
| FGL (Second Line) | Proportion of Patients With NEDA-3 | Second line | 220 Participants |
| TFL (Second Line) | Proportion of Patients With NEDA-3 | Second line | 94 Participants |
Comparison: 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.95% CI: [-39.4, -27]
Comparison: 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.95% CI: [-41.4, -19.8]
Comparison: 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.95% CI: [-27, -14.7]
Comparison: 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.95% CI: [-13.6, -0.3]
Comparison: 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.95% CI: [-29.2, -18.3]
Comparison: 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.95% CI: [-18.6, -6.1]
Comparison: 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.95% CI: [-31.7, -19]
Comparison: 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.95% CI: [-38.2, -20.8]
Secondary
Proportion of Patients With No Evidence of Disease Activity (NEDA) -2
\- 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. Lower NEDA-2 scores indicate better outcomes. Higher NEDA-2 scores indicate worse outcomes.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RTX (First Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | First line | 483 Participants |
| IFN (First Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | First line | 348 Participants |
| GA (First Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | First line | 44 Participants |
| DMF (First Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | First line | 235 Participants |
| NTZ (First Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | First line | 208 Participants |
| RTX (Second Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | Second line | 638 Participants |
| DMF (Second Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | Second line | 356 Participants |
| NTZ (Second Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | Second line | 326 Participants |
| FGL (Second Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | Second line | 226 Participants |
| TFL (Second Line) | Proportion of Patients With No Evidence of Disease Activity (NEDA) -2 | Second line | 95 Participants |
Comparison: 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.95% CI: [-40.3, -27.9]
Comparison: 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.95% CI: [-43, -21.5]
Comparison: 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.95% CI: [-27.9, -15.7]
Comparison: 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.95% CI: [-14.5, -1.2]
Comparison: 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.95% CI: [-28.9, -18.3]
Comparison: 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.95% CI: [-18.9, -6.5]
Comparison: 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.95% CI: [-32.8, -20.2]
Comparison: 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.95% CI: [-40.1, -23.2]
Secondary
Quality of Life Assessments
Comparison of health-related quality of life measured by the European Quality of Life Five Dimensions (EQ-5D). Higher values indicate better health, and lower values indicate poorer health. The maximum theoretical value is 1. While there is no fixed minimum, scores can fall below 0, indicating health states worse than death. In this study, scores ranged from -0.59 to 1, which represent clinically relevant ranges of values.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTX (First Line) | Quality of Life Assessments | First line | 0.77 units on a scale | Standard Deviation 0.24 |
| IFN (First Line) | Quality of Life Assessments | First line | 0.77 units on a scale | Standard Deviation 0.24 |
| GA (First Line) | Quality of Life Assessments | First line | 0.74 units on a scale | Standard Deviation 0.26 |
| DMF (First Line) | Quality of Life Assessments | First line | 0.81 units on a scale | Standard Deviation 0.22 |
| NTZ (First Line) | Quality of Life Assessments | First line | 0.76 units on a scale | Standard Deviation 0.26 |
| RTX (Second Line) | Quality of Life Assessments | Second line | 0.76 units on a scale | Standard Deviation 0.24 |
| DMF (Second Line) | Quality of Life Assessments | Second line | 0.81 units on a scale | Standard Deviation 0.22 |
| NTZ (Second Line) | Quality of Life Assessments | Second line | 0.74 units on a scale | Standard Deviation 0.27 |
| FGL (Second Line) | Quality of Life Assessments | Second line | 0.79 units on a scale | Standard Deviation 0.22 |
| TFL (Second Line) | Quality of Life Assessments | Second line | 0.76 units on a scale | Standard Deviation 0.24 |
Comparison: 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.95% CI: [-0.07, 0]
Comparison: 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.95% CI: [-0.09, 0.06]
Comparison: 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.95% CI: [-0.03, 0.03]
Comparison: 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.95% CI: [-0.03, 0.05]
Comparison: 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.95% CI: [-0.02, 0.04]
Comparison: 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.95% CI: [-0.01, 0.06]
Comparison: 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.95% CI: [0, 0.06]
Comparison: 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.95% CI: [-0.06, 0.03]
Secondary
Rate of Invasive Cancer
\- 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.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RTX (First Line) | Rate of Invasive Cancer | First line | 0.6 invasive cancer per 1000 person-years |
| IFN (First Line) | Rate of Invasive Cancer | First line | 2.4 invasive cancer per 1000 person-years |
| GA (First Line) | Rate of Invasive Cancer | First line | 2.9 invasive cancer per 1000 person-years |
| DMF (First Line) | Rate of Invasive Cancer | First line | 0.0 invasive cancer per 1000 person-years |
| NTZ (First Line) | Rate of Invasive Cancer | First line | 3.0 invasive cancer per 1000 person-years |
| RTX (Second Line) | Rate of Invasive Cancer | Second line | 1.3 invasive cancer per 1000 person-years |
| DMF (Second Line) | Rate of Invasive Cancer | Second line | 3.0 invasive cancer per 1000 person-years |
| NTZ (Second Line) | Rate of Invasive Cancer | Second line | 1.2 invasive cancer per 1000 person-years |
| FGL (Second Line) | Rate of Invasive Cancer | Second line | 4.6 invasive cancer per 1000 person-years |
| TFL (Second Line) | Rate of Invasive Cancer | Second line | 0.0 invasive cancer per 1000 person-years |
Secondary
Rate of Major Adverse Cardiovascular Events (MACE)
\- 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
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RTX (First Line) | Rate of Major Adverse Cardiovascular Events (MACE) | First line | 1.7 MACE per 1000 person-years |
| IFN (First Line) | Rate of Major Adverse Cardiovascular Events (MACE) | First line | 1.4 MACE per 1000 person-years |
| GA (First Line) | Rate of Major Adverse Cardiovascular Events (MACE) | First line | 0.0 MACE per 1000 person-years |
| DMF (First Line) | Rate of Major Adverse Cardiovascular Events (MACE) | First line | 0.8 MACE per 1000 person-years |
| NTZ (First Line) | Rate of Major Adverse Cardiovascular Events (MACE) | First line | 0.0 MACE per 1000 person-years |
| RTX (Second Line) | Rate of Major Adverse Cardiovascular Events (MACE) | Second line | 1.3 MACE per 1000 person-years |
| DMF (Second Line) | Rate of Major Adverse Cardiovascular Events (MACE) | Second line | 0.6 MACE per 1000 person-years |
| NTZ (Second Line) | Rate of Major Adverse Cardiovascular Events (MACE) | Second line | 1.2 MACE per 1000 person-years |
| FGL (Second Line) | Rate of Major Adverse Cardiovascular Events (MACE) | Second line | 0.0 MACE per 1000 person-years |
| TFL (Second Line) | Rate of Major Adverse Cardiovascular Events (MACE) | Second line | 4.2 MACE per 1000 person-years |
Secondary
Rate of Serious Infections
\- 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
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RTX (First Line) | Rate of Serious Infections | First line | 12.7 infections per 1000 person-years |
| IFN (First Line) | Rate of Serious Infections | First line | 6.8 infections per 1000 person-years |
| GA (First Line) | Rate of Serious Infections | First line | 5.8 infections per 1000 person-years |
| DMF (First Line) | Rate of Serious Infections | First line | 9.8 infections per 1000 person-years |
| NTZ (First Line) | Rate of Serious Infections | First line | 12.2 infections per 1000 person-years |
| RTX (Second Line) | Rate of Serious Infections | Second line | 20.2 infections per 1000 person-years |
| DMF (Second Line) | Rate of Serious Infections | Second line | 5.9 infections per 1000 person-years |
| NTZ (Second Line) | Rate of Serious Infections | Second line | 6.2 infections per 1000 person-years |
| FGL (Second Line) | Rate of Serious Infections | Second line | 10.7 infections per 1000 person-years |
| TFL (Second Line) | Rate of Serious Infections | Second line | 14.9 infections per 1000 person-years |
Secondary
Remaining on Drug
\- Proportion remaining on the index DMT after 3 years
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RTX (First Line) | Remaining on Drug | First line | 527 Participants |
| IFN (First Line) | Remaining on Drug | First line | 300 Participants |
| GA (First Line) | Remaining on Drug | First line | 40 Participants |
| DMF (First Line) | Remaining on Drug | First line | 191 Participants |
| NTZ (First Line) | Remaining on Drug | First line | 167 Participants |
| RTX (Second Line) | Remaining on Drug | Second line | 662 Participants |
| DMF (Second Line) | Remaining on Drug | Second line | 307 Participants |
| NTZ (Second Line) | Remaining on Drug | Second line | 299 Participants |
| FGL (Second Line) | Remaining on Drug | Second line | 260 Participants |
| TFL (Second Line) | Remaining on Drug | Second line | 76 Participants |
Comparison: 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.95% CI: [-76.6, -66.6]
Comparison: 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.95% CI: [-76.3, -56.4]
Comparison: 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.95% CI: [-53, -41.7]
Comparison: 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.95% CI: [-49.6, -36.6]
Comparison: 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.95% CI: [-46.4, -36.2]
Comparison: 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.95% CI: [-39.8, -28]
Comparison: 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.95% CI: [-39.7, -28]
Comparison: 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.95% CI: [-58, -41.6]
Secondary
Treatment Satisfaction
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. The Treatment Satisfaction Questionnaire (TSQ), items 1-9 scale range: Minimum score: 0. Maximum score: 100. Lower scores indicate worse outcomes. Higher scores indicate better outcomes.
Time frame: 3 years
Population: First line and Second line reported in separate rows
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RTX (First Line) | Treatment Satisfaction | First line | 50.1 units on a scale | Standard Deviation 6.8 |
| IFN (First Line) | Treatment Satisfaction | First line | 44.3 units on a scale | Standard Deviation 7.7 |
| GA (First Line) | Treatment Satisfaction | First line | 42.8 units on a scale | Standard Deviation 8.3 |
| DMF (First Line) | Treatment Satisfaction | First line | 48.3 units on a scale | Standard Deviation 7.1 |
| NTZ (First Line) | Treatment Satisfaction | First line | 49.5 units on a scale | Standard Deviation 6.7 |
| RTX (Second Line) | Treatment Satisfaction | Second line | 49.5 units on a scale | Standard Deviation 7.2 |
| DMF (Second Line) | Treatment Satisfaction | Second line | 49.0 units on a scale | Standard Deviation 6.7 |
| NTZ (Second Line) | Treatment Satisfaction | Second line | 49.5 units on a scale | Standard Deviation 6.7 |
| FGL (Second Line) | Treatment Satisfaction | Second line | 51.8 units on a scale | Standard Deviation 6.3 |
| TFL (Second Line) | Treatment Satisfaction | Second line | 51.6 units on a scale | Standard Deviation 6.3 |
Comparison: 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.95% CI: [-8.1, -2.9]
Comparison: 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.95% CI: [-10.9, -1]
Comparison: 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.95% CI: [-4, -0.8]
Comparison: 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.95% CI: [-2.1, 1.5]
Comparison: 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.95% CI: [-2.2, 0.6]
Comparison: 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.95% CI: [-0.3, 2.8]
Comparison: 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.95% CI: [0.9, 4.6]
Comparison: 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.95% CI: [0.2, 4]