Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS)

Study Overview
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Brief Summary
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The main aim and overall objective of the study is to assess whether rituximab is non-inferior to cladribine for the treatment of relapsing MS. Secondly, the investigators will test specific blood and MRI biomarkers that may contribute to future personalized treatment for MS patients. Furthermore, the investigators want to evaluate the health economic consequences of the two therapies.

Detailed Description
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Multiple sclerosis (MS) is a demyelinating and neurodegenerative inflammatory disease of the central nervous system, affecting more than 12 000 patients in Norway and more than 2.2 mill patients worldwide. Oral cladribine is one of the first choices for highly efficient disease modulatory treatment (DMT), while Rituximab is used off-label as DMT in relapsing MS. Large observational studies indicate good tolerance and treatment effect of rituximab in MS and studies from other diseases indicate a good safety profile. However, no phase 3 studies have been performed to test whether rituximab is as efficient as established MS treatments. Formal safety data is also lacking for the treatment with rituximab in MS. The investigators will perform a prospective randomized open-label blinded endpoint multicenter non-inferiority study. The primary objective is to test whether rituximab is non-inferior to oral cladribine in the treatment of relapsing MS. 264 MS patients aged 18-65 years with relapsing MS will be recruited from 10 centers and followed for 96 weeks. The primary endpoint is difference in new T2 lesions between the groups. Furthermore, the investigators will test novel blood sample and MRI biomarkers to provide tools for personalized MS treatments. Finally, the health economic consequences of these treatment options will be evaluated. This study will guide clinicians and patients in the future treatment choice for MS and can potentially make a huge impact on the costs of future MS treatment.

Official Title
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Norwegian Study of Oral Cladribine and Rituximab in Multiple Sclerosis (NOR-MS) A Prospective Randomized Open-label Blinded Endpoint (PROBE) Multicenter Non-inferiority Study

Conditions
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Relapsing Multiple Sclerosis, Multiple Sclerosis

Intervention / Treatment
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* Biological: Rituximab
* Drug: Cladribine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 65 years A diagnosis of relapsing MS according to the 2017 McDonald criteria Disease activity seen as either a clinical relapse or MRI activity during the last 12 months EDSS between 0 and 5.5 Thrombocytes and leukocytes within normal range, and lymphocytes above 0.8 x10 9/L before first dose of study medication A) For women of childbearing potential: accepting to use adequate contraception in the trial period. If randomized to cladribine, women who use systemic hormonal contraception must accept to use additional barrier contraception during each treatment cycle and for four weeks after each treatment cycle. B) For men: If randomized to cladribine, accepting to use adequate contraception in the safety period of 6 months after each treatment cycle. Able to understand written and spoken Norwegian or English Able to complete treatment or follow-ups in the study (e.g. no contraindications for MRI, severe psychiatric disease, drug abuse or plans of moving) Signed informed consent Exclusion Criteria: Any contraindication or increased risk of side-effects from rituximab or cladribine (such as ongoing acute or chronic infection, live vaccination less than 4 weeks before start of treatment or planned live vaccination, immunocompromised, previous or active malignant disease, ongoing glucocorticoid treatment or allergy against any products of the medication) Previous use of any of cladribine, rituximab, alemtuzumab, ocrelizumab, hematopoietic stem cell therapy (HSCT) or other immunosuppression with long lasting effects Fingolimod or natalizumab treatment within the last six months before inclusion Current pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A prospective randomized open-label blinded endpoint (PROBE) multicenter non-inferiority study, designed to establish non-inferiority of the test treatment rituximab compared with the comparator oral cladribine for consecutively included patients with active RMS. Randomization rituximab:cladribine is 1:1.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab<br>Biosimilar rituximab concentrate for solution for infusion | Biological: Rituximab<br>* Biosimilar rituximab concentrate for solution for infusion<br>|
| Active Comparator: Cladribine<br>Mavenclad oral cladribine tablets | Drug: Cladribine<br>* Mavenclad oral cladribine tablets<br>* Other names: Mavenclad;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of new or enlarging cerebral MRI T2 lesions | The primary outcome is the number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 96 | Week 12-96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T2 lesions after 48 weeks | Number of new or enlarging cerebral MRI T2 lesions per patient from week 12 to week 48 | Week 12-48 | 
| Annual clinical relapse rate (ARR) | Annual clinical relapse rate (ARR) at 24, 48 and 96 weeks | Week -2 to 96 | 
| Relapse-free patients | Proportion of relapse-free patients at 24, 48 and 96 weeks | Week -2 to 96 | 
| Disability progression | Proportion of patients with 24 weeks confirmed disability progression (24-CDP) on EDSS at 48 and 96 weeks | Week -2 to 96 | 
| Change in disability | Change in disability on the Expanded Disability Status Scale (EDSS) from week -2 to 48 and 96 weeks. Disability progression is defined as an increase in EDSS of at least 1.5 points if baseline EDSS was 0, 1 point with baseline EDSS 0.5-4.5 and 0.5 point with baseline EDSS 5-5.5. EDSS is a scale from 0-10 measuring neurological disability. | Week -2 to 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, ms, rms, rituximab, cladribine, probe