Ocrelizumab VErsus Rituximab Off-Label at the Onset of Relapsing MS Disease
Ocrelizumab VErsus Rituximab Off-Label at the Onset of Relapsing MS Disease
This is a multicenter non-inferiority study, designed to establish non-inferiority of the
 study treatment rituximab compared with the comparator ocrelizumab for consecutively included
 patients (male or female) with active relapsing-remitting multiple sclerosis aged 18-60
 years.
The objective of the study is to demonstrate if rituximab is non-inferior to ocrelizumab with
 regards to efficacy and safety in treatment naïve RRMS patients, diagnosed within the last 12
 months.

 To test this hypothesis, the investigators aim to perform a 30-months (24 + 6 months)
 prospective randomized double blinded multicenter non-inferiority study to compare rituximab
 to ocrelizumab in RRMS.

 MS disease activity as measured by brain MRI is more sensitive as compared to clinical
 disease activity as measured by number of relapses or disability progression. New or
 enlarging MRI T2 lesions is regarded an acceptable marker of disease activity, and is
 routinely used in clinical practice by annual examinations (Thompson, Baranzini et al. 2018)
 (Thompson, Banwell et al. 2018). The investigators will therefore use the proportion of
 patients with no new or enlarging T2-weighted brain MRI lesions from month 6 to month 24 as
 the primary endpoint of this study.

 Secondary objectives are included to further evaluate potential the difference or
 similarities in effectiveness between the treatments (disability progression, relapse rate,
 T25FW, 9-HPT, SDMT), to evaluate the difference in safety issues (most notably hematological
 complications, infections, malignancies, infusion reactions and other serious adverse events)
 and to evaluate the difference in patient reported outcomes by evaluation of working status,
 fatigue, anxiety and depressive symptoms, quality of life and treatment satisfaction (EQ-5D,
 MSIS-29, FSMC, and SDMT). The exploratory outcomes are included to evaluate specific blood
 samples and plasma biomarkers for treatment response (sNFL and CD19+ cell counts) and side
 effects (hypogammaglobulinemia and neutropenia) of the two treatments, differences in
 vaccination status (pneumococcus and/or influenza) and to determine the predictive value of
 BICAMS for the individual patient.
Inclusion Criteria:

 1. Male and female patients, treatment naïve, and aged between 18 and 60 years included

 2. Women of childbearing potential1 (WOCBP) able and willing to use highly effective
 methods of birth control2 per ICH M3 (R2) that result in a low failure rate of less
 than 1% per year when used consistently and correctly for the duration of the study OR
 until 3 months after last dose administered.

 3. A diagnosis of RRMS according to the 2017 revised diagnostic criteria of McDonald
 (Thompson, Banwell et al. 2018) within the last 12 months.

 4. Disease activity defined as ≥ 1 relapse3 or ≥ 1 new MRI lesion during the last 12
 months

 5. EDSS score ≤ 4.0

 6. Absence of comorbidity or drug abuse that preclude study participation

 7. Able to complete treatment or follow-up visits in the study (e.g. no contraindications
 for MRI or plans of moving)

 8. Able to understand written and spoken Norwegian or English

 9. Capable of giving signed informed consent as described in Appendix 1.2 which includes
 compliance with the requirements and restrictions listed in the informed consent form
 (ICF) and in this protocol.

 Exclusion Criteria:

 1. Known hypersensitivity or other known side effects for any of the study medications,
 including co-medications such as high glucocorticosteroids

 2. A diagnosis of primary progressive MS according to the revised diagnostic criteria of
 McDonald (Thompson, Banwell et al. 2018)

 3. A disease course of secondary progressive MS (Lublin, Reingold et al. 2014)

 4. Any ongoing infection, including tuberculosis, hepatitis virus or HIV, as well as
 hepatitis B surface antigen positivity and/or hepatitis C PCR positivity verified at
 screening visit.

 5. Prior or current psychiatric illness, mental deficiency or cognitive dysfunction
 influencing the patient ability to make an informed consent or comply with the
 treatment and follow-up phases of this protocol.

 6. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhythmia, unstable or
 advanced ischemic heart disease (NYHA III or IV)

 7. Active malignancy or prior history of malignancy except localized basal cell, squamous
 skin cancer or carcinoma in situ of the cervix.

 8. WBC < 1.5 x 109/L if not caused by a reversible effect of documented ongoing
 medication. If WBC < 1.5 x 109/L is caused by a reversible effect of documented
 ongoing medication the WBC count must be > 1,5 x 109/L before start of study
 treatment.

 9. Platelet (thrombocyte) count < 100 x 109/L

 10. ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)

 11. Serum creatinine > 200 µmol/L

 12. Serum bilirubin > ULN

 13. Pregnancy or lactating female patients

 14. Any disease that can influence the patient safety and compliance, or the evaluation of
 disability

 15. History of serious or life-threatening infusion reaction to ocrelizumab or rituximab,
 if previously treated with these medications for other diseases than MS

 16. Previous use of MS-therapies such as natalizumab, fingolimod, interferons, glatiramer
 acetate, dimethyl fumarate, teriflunomide, cladribine, rituximab, alemtuzumab,
 ocrelizumab, hematopoietic stem cell therapy (HSCT) or other immunosuppression
 therapies with long lasting effects, or any other disease modifying therapy (DMT) for
 MS. If any of these medications have been used against other diseases than MS,
 patients can be included if the medications have not been used the previous year
 before enrollment.

 17. Currently enrolled in another investigational device or drug study, or less than 30
 days since ending another investigational device or drug study (s), or receiving other
 investigational treatment(s). Patients participating in a purely observational trial
 will not be excluded.

 18. Presence of metallic objects implanted in the body, or allergy to MRI contrast that
 would preclude the ability of the patient to safely have MRI exams

 19. Current alcohol or drug dependencies