Non-inferiority Study of Ocrelizumab and Rituximab in Active Multiple Sclerosis
Non-inferiority Study of Ocrelizumab and Rituximab in Active Multiple Sclerosis
The DanNORMS study is phase 3 non-inferiority clinical trial examining whether treatment of
 active multiple sclerosis with rituximab is non-inferior to ocrelizumab regarding efficacy
 and safety.
The DanNORMS study will include patients with active multiple sclerosis aged 18-65 years.
 Patients will be randomized in a 2:1 ratio to either rituximab or ocrelizumab. The study
 duration is 24 months, and patients can continue in an extension phase for additional 36
 month. The primary endpoint is the percentage of patients without new or enlarging T2 white
 matter lesions on brain MRI scans from month 6 to month 24, which will be assessed by
 radiologists blinded to the treatments status. The study will evaluate a number of efficacy
 and safety endpoints using clinical, MRI, routine blood samples and research biomarkers.
Inclusion Criteria:

 -  MS diagnosis and definition of disease course according to the 2017 McDonald criteria

 -  Expanded disability status scale (EDSS) ≤6.5

 -  Fulfilling criteria for active MS:

 -  Treatment naïve relapsing remitting multiple sclerosis (RRMS) patients (never
 treated, or no DMT the previous 2 years):

 1. ▪≥2 relapse previous 12 months OR

 2. 1 relapse previous 12 months with severe residual symptoms and EDSS ≥ 3.0 OR

 3. 1 relapse previous 12 months AND ≥9 T2 lesions on brain and/or spinal cord
 MRI AND

 -  1 contrast-enhancing lesion or ≥1 new or enlarging T2 lesion on brain
 and/or spinal cord MRI previous 12 month

 -  Previously treated RRMS patients:

 1. ≥1 relapse previous 12 months OR

 2. ≥1 contrast-enhancing lesion or ≥2 new/enlarging T2 lesions on brain and/or
 spinal cord MRI previous 12 months

 -  Progressive MS patients:

 1. ≥1 relapse previous 12 months OR

 2. ≥1 contrast-enhancing lesion previous 12 months or ≥1 new/enlarging T2
 lesions on brain and/or spinal cord MRI previous 12 months or ≥2 new or
 enlarging T2 lesion on brain and/or spinal cord MRI previous 24 months OR

 3. Increased levels of neurofilament light chain (NFL) in serum or
 cerebrospinal fluid (CSF) in sample collected previous 12 months.
 Progressive MS patients not fulfilling the clinical/MRI criteria for active
 disease, may qualify for inclusion in the study if:

 (A) CSF NFL level >600 ng/L (measured with NF-Light® ELISA assay from Uman
 Diagnostics) or serum NFL level >11.5 pg/ml (measured with Simoa™ NF-light®
 Advantage Kit)

 -  Signed written informed consent

 Exclusion Criteria:

 -  Pregnancy or breast feeding

 -  Lack of effective contraception for women of child-bearing potential (effective
 contraception include oral contraception, intrauterine devices and other forms of
 contraception with failure rate <1%)

 -  Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization

 -  Known active malignant disease

 -  Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled
 cardiac disease

 -  Positive test for HIV, hepatitis B or C, or tuberculosis

 -  Negative test for varicella zoster

 -  Lymphopenia grade 2 (0.5 to 0.8 × 10^9/L) or higher grades of lymphopenia (in case of
 switching from fingolimod lymphopenia grade 2 can be accepted if lymphocytes are
 rising markedly compared to on treatment levels)

 -  Neutropenia grade 2 (1.0 to 1.5 × 10^9/L) or higher grades

 -  Thrombocytopenia grade 2 (50 to 75 × 10^9/L) or higher grades

 -  Previous treatment with alemtuzumab or hematopoietic stem-cell transplantation

 -  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

 -  Methylprednisolone treatment within 1 months of inclusion

 -  Findings on the screening MRI judged to preclude participation by the treating
 physician

 -  Other diseases judged to be relevant by the treating physician

 -  Contraindication to MRI

 -  Known allergy or hypersensitivity to rituximab or ocrelizumab