RITUXIMAB for Multiple sclerosis

Stratification factors

• treatment (rituximab vs ocrelizumab)

Inclusion criteria

• {"criterion_text":"- Inclusion criteria for core study: • Age ≥18 and ≤65 years\n- MS diagnosis and definition of disease course according to the 2017 McDonald criteria\n- Expanded disability status scale (EDSS) ≤6.5\n- Fulfilling criteria for active MS: o Treatment naïve RRMS patients (never treated, or no DMT the previous 3 months):≥2 relapse previous 12 months OR ≥1 relapse previous 12 months AND ≥9 T2 lesions on brain and/or spinal MRI AND ≥1 contrast-enhancing lesion or ≥1 new or enlarging T2 lesion on brain and/or spinal MRI previous 12 month\n- Previously treated RRMS patients: ≥1 relapse previous 12 months OR ≥1 contrast-enhancing lesion or ≥2 new/enlarging T2 lesions on brain MRI previous 12 months\n- Progressive MS patients: ≥1 relapse previous 12 months OR ≥1 contrast-enhancing lesion previous 12 months or ≥1new/enlarging T2 lesions on brain MRI previous 12 months or ≥2 new or enlarging T2 lesion on brain MRI previous 24 months OR Increased levels of neurofilament light chain in serum or cerebrospinal on sample collected previous 12 months\n- Progressive MS patients not fulfilling the clinical/MRI criteria for active disease, may qualify for inclusion in the study if sNFL or CSF NFL levels is elevated\n- Signed written informed consent\n- long-term follow-up phase of the study: Inclusion criteria for extended interval dosing sub-study though randomisation: Completed the first 24 months of the study\n- No signs of active disease the previous 18 months\n- Signed written informed consent\n- Inclusion criteria for extended interval dosing outside the randomisation process: Completed the first 24 months of the study\n- Recommended by physician to switch to extended interval dosing due to Low IgG (<6,1 g/L) or Frequent infections\n- No signs of active disease the previous 18 months\n- Signed written informed consent"}

Exclusion criteria

• {"criterion_text":"- • Pregnancy or breast feeding\n- • Lack of effective contraception (failure rate <1%) for women of child-bearing potential\n- • Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization\n- • Active malignant disease in the previous 5 years\n- • Positive test for HIV, hepatitis B or C, or tuberculosis\n- • Negative test for varicella zoster\n- • Lymphopenia grade 2 (0.5 to 0.8 × 109/L) or higher grades of lymphopenia (in case of switching from fingolimod, siponimod or ozanimod lymphopenia is accepted at screening visit (note that treatment with interferon-beta can induce transient lymphopenia)\n- • Neutropenia grade 2 (1.0 to 1.5 × 109/L) or higher grades\n- • Thrombocytopenia grade 2 (50 to 75 × 109/L) or higher grades\n- • Previous treatment with alemtuzumab or hematopoietic stem-cell transplantation\n- • Previous treatment with cladribine, CD20-depleting antibodies, daclizumab or other immune suppressive treatment which is judged to still exert immune suppressive effect by treating physician\n- • Methylprednisolone treatment 4 weeks within baseline visit and baseline MRI scan\n- • Findings on the screening MRI (for patients without MRI scan of the brain the previous 12 months the baseline MRI scan is also used as screening MRI) judged to preclude participation by the treating physician\n- • Other diseases judged to be relevant by the treating physician\n- • Contraindication to MRI\n- • Known allergy or hypersensitivity to rituximab or ocrelizumab"}

Primary endpoints

• {"endpoint_text":"- Percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24","definition_or_measurement_approach":"Assessed on brain MRI scans from month 6 to month 24; MRI scans will be read by radiologists blinded to treatment"}

Secondary endpoints

• {"endpoint_text":"- Percentage of patients with 6-month confirmed disease worsening (CDW) in EDSS from baseline to month 24 (m24)","definition_or_measurement_approach":"6-month confirmed disability worsening on EDSS from baseline to month 24"}
• {"endpoint_text":"- ARR based on cumulative number of confirmed relapses from baseline to m24","definition_or_measurement_approach":"Annualised relapse rate calculated from cumulative confirmed relapses from baseline to month 24"}
• {"endpoint_text":"- Percentage of patients with 6-months CDW in T25FW, 9HPT and SDMT from baseline to m24","definition_or_measurement_approach":"6-month confirmed disease worsening measured by T25FW, 9HPT and SDMT from baseline to month 24"}
• {"endpoint_text":"- Change in MSIS-29, FSMC, EQ-5D from baseline to m24","definition_or_measurement_approach":"Change from baseline to month 24 in patient-reported outcome measures MSIS-29, FSMC and EQ-5D"}
• {"endpoint_text":"- Percentage of patients without GdEL on m6 and m24 scans","definition_or_measurement_approach":"Proportion without gadolinium-enhancing lesions on MRI at month 6 and month 24"}
• {"endpoint_text":"- Change in T2 and T1 white matter lesion volume from m6 to m24","definition_or_measurement_approach":"Change in MRI lesion volumes (T2 and T1) between month 6 and month 24"}
• {"endpoint_text":"- Difference in serum NFL from baseline to m24","definition_or_measurement_approach":"Change in serum neurofilament light chain (sNFL) from baseline to month 24"}

Other endpoints

• {"endpoint_text":"- blood flow cytometry (explorative/tertiary endpoint)","definition_or_measurement_approach":"Explorative immunophenotyping by blood flow cytometry during 24-month core study period"}
• {"endpoint_text":"- whole blood gene expression (explorative/tertiary endpoint)","definition_or_measurement_approach":"Explorative assessment of whole blood gene expression during 24-month core study period"}
• {"endpoint_text":"- genotyping of Fcγ-receptor or complement genes (explorative/tertiary endpoint)","definition_or_measurement_approach":"Genotyping of Fcγ-receptor and complement genes as exploratory endpoints in the 24-month core period"}
• {"endpoint_text":"- serum NFL (explorative/tertiary endpoint)","definition_or_measurement_approach":"Serial serum neurofilament light chain measurements as exploratory endpoints"}
• {"endpoint_text":"- IgG concentrations (explorative/tertiary endpoint)","definition_or_measurement_approach":"Measurement of IgG concentrations as exploratory safety/efficacy endpoints"}

Denmark

Earliest CTIS Part Ii Submission Date

29-07-2024

Latest Decision Or Authorization Date

09-04-2026

Processing Time Days

619

Number Of Sites

11

Number Of Participants

600

Primary sponsor

Full Name

Rigshospitalet

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Denmark

Third parties

• {"country":"Denmark","full_name":"Danish Research Centre for Magnetic Resonance","duties_or_roles":"MR analysis (primary endpoint) - blinded","organisation_type":"Health care"}
• {"country":"Denmark","full_name":"Aalborg University Hospital","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Denmark","full_name":"Odense University Hospital","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Denmark","full_name":"Aarhus Universitet","duties_or_roles":"1","organisation_type":"Educational Institution"}
• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Netherlands","full_name":"Sanquin Blood Supply Foundation","duties_or_roles":"4","organisation_type":"Patient organisation/association"}