|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Remitting Relapsing Multiple Sclerosis
|Medical condition in easily understood language
|Relapsing Remitting Multiple Sclerosis
|Diseases [C] - Nervous System Diseases [C10]
|E.1.2 Medical condition or disease under investigation
|Relapsing-remitting multiple sclerosis
|System Organ Class
|10029205 - Nervous system disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To demonstrate non-inferiority of rituximab compared to ocrelizumab with regards to efficacy and safety in treatment of naïve RRMS patients, diagnosed within the last 12 months.
|Secondary objectives of the trial
|Trial contains a sub-study
|Principal 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 12 months after last dose administered to comply with CTFG Contraception guidance version 1.1 (CTFG 21/09/2020).
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 lesion4 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 Swedish.
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.
|Principal 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 seropositivity.
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 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.
|E.5 End points
|Primary end point(s)
|The primary endpoint is to determine the difference in efficacy and safety between rituximab and ocrelizumab according to the following criteria:
•Proportion of patients with no new or enlarging T2-weighted brain MRI lesions from month 6 (re-baseline) to month 24
|Timepoint(s) of evaluation of this end point
|From re-baseline at 6 months to 24 months.
|Secondary end point(s)
|•Proportion of patients with 6-months confirmed disability progression (6M-CDP) as measured by the Expanded disability status scale (EDSS) from baseline to month 24. CDP-EDSS defined as an increase of one point in the EDSS score confirmed after 6 months, with an absence of relapse at the time of assessment.
•Proportion of patients with 6-months confirmed disability improvement (6M-CDI) as measured by the Expanded disability status scale (EDSS) from baseline to month 24. CDI-EDSS is defined as a decrease of one point in the EDSS score, confirmed after 6 months, with an absence of relapse at the time of assessment.
•The annual relapse rate from baseline to month 24
•Proportion of patients without relapses from baseline to month 24
•Proportion of patients with 6M-CDP in T25FW from baseline to month 24. 6M-CDP in T25FW is defined as patients experiencing an increase of ≥20% from baseline which is confirmed after 6 months
•Proportion of patients with 6M-CDP in 9-HPT from baseline to month 24. 6M-CDP in 9HPT is defined as patients experiencing an increase of ≥20% from baseline which is confirmed after 6 months
•Proportion of patients with 6M-CDP in SDMT from baseline to month 24. 6-month CDP in SDMT is defined as patients experiencing a reduction of 15% from baseline which is confirmed after 6 months
•Proportion of patients with no new or enlarging T2-weighted brain MRI lesions from baseline to month 6, and from baseline to month 24
•Proportion of patients without new gadolinium enhancing T1-weighted brain MRI lesions at month 6, month 12 and month 24
•Change in brain volumes from baseline to month 24 and from month 6 to month 24
•Overall safety during 24 months of treatment
•The frequency of immediate and delayed infusion reactions during 24 months of treatment
•The frequency of infections during 24 months of treatment
•The frequency any malignancies during 24 months of treatment
•Change in the quality of life as measured by MS impact scale 29 (MSIS-29) from baseline to month 24
•Change in Health related Anxiety and Depression as measured by HADS from baseline to month 24
•Change in the fatigue as measured by fatigue scale for motor and cognitive functions (FSMC)
•Change in EQ-5D score from baseline to month 24
•Change in employment status from baseline to month 24
•The frequency of anti-drug-antibodies during 24 months of treatment
|Timepoint(s) of evaluation of this end point
|From baseline (month 0) or re-baseline (month 6) to month 12 and/or month 24.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days