Ocrelizumab VErsus Rituximab Off-Label at the Onset of Relapsing

Official Summary

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.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 60 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 214 participants

Study Arms

• Rituximab (EXPERIMENTAL)
  Rituximab will be given as infusion at week 0, week 26, week 52, week 78, and week 104 unless there is a reason for schedule modifications (see Section 6.3). Each infusion is given over approximately 4 hours and follow local guidelines for infusion. Initial dose; 1000 mg Subsequent doses; 500 mg
• Ocrelizumab (ACTIVE_COMPARATOR)
  Ocrelizumab will be given as infusion at week 0, week 26, week 52, week 78, and week 104 unless there is a reason for schedule modifications (see Section 6.3). Each infusion is given over approximately 4 hours and follow local guidelines for infusion. Initial and subsequent doses; 600 mg

Interventions

• DRUG: Rituximab — A prospective randomized double blinded 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. Active substance is biosimilar rituximab iv infusion and comparator is ocrelizumab (Ocrevus ®) iv infusion. Both treatments are given as infusion at month 0, month 6, month 12, month 18 and mo
• DRUG: Ocrelizumab — A prospective randomized double blinded 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. Active substance is biosimilar rituximab iv infusion and comparator is ocrelizumab (Ocrevus ®) iv infusion. Both treatments are given as infusion at month 0, month 6, month 12, month 18 and mo

Primary Outcomes

• Proportion without new MRI activity (From month 6 (re-baseline) to month 24)

Secondary Outcomes

• Proportion of patients with 6-months confirmed disability progression (6M-CDP) (From baseline to month 24)
• Proportion of patients with 6-months confirmed disability improvement (6M-CDI) (From baseline to month 24)
• 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)

Eligibility Criteria

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

Trial Locations

• Haukeland University Hospital, Bergen, Norway
• Nordlandsykehuset HF, Bodø, Norway
• Vestre Viken sykehus, Drammen, Norway
• Sørlandet Sykehus, Kristiansand, Norway
• Molde sjukehus, Molde, Norway
• Sykehuset Namsos, Namsos, Norway
• Oslo University Hospital HF, Oslo, Norway
• Akershus University Hospital, Oslo, Norway
• Sykehuset Telemark, Skien, Norway
• Stavanger University Hospital HF, Stavanger, Norway
• ...and 2 more locations

Study Officials

• Kjell-Morten Myhr, MD — STUDY_DIRECTOR
  Haukeland University Hospital
• Øivind Torkildsen, MD — PRINCIPAL_INVESTIGATOR
  Haukeland University Hospital

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