Non-inferiority Study of Ocrelizumab and Rituximab in Active Multiple Sclerosis (DanNORMS)

Danish Non-inferiority Study of Ocrelizumab and Rituximab in MS (DanNORMS): A Randomized Study Comparing the Efficacy of Ocrelizumab and Rituximab in Active Multiple Sclerosis

Odense University Hospital, Aarhus University Hospital, Aalborg University Hospital, Herlev Hospital, Hillerod Hospital, Denmark, Kolding Sygehus, Gødstrup Hospital, Hvidovre University Hospital, Hospital of South West Jutland, Esbjerg, Denmark, GCP unit, Copenhagen University Hospital, GCP-unit at Aarhus University Hospital, Aarhus, Denmark, Hospital of Southern Jutland, Sønderborg, Denmark, Hospital of Central Denmark Region, Viborg, Denmark, Danske Regioner, Hospital of Southern Jutland, Aabenraa, Denmark

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.

Relapsing Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Primary Progressive Multiple Sclerosis

A prospective, 2:1 randomized, open-label, multi-centre, phase 3 non-inferiority clinical trial with blinded primary endpoint.

MRI scan data will be transfered to the MRI Reader Centre with pseudonymized identity and without any information regarding the treatment allocation of the patient.

Intravenous biosimilar rituximab (Ruxience®) 1000 mg given every 6th month (first 2 infusions 1000mg/1000 mg given 2 weeks apart).

Intravenous ocrelizumab (Ocrevus®) 600 mg every 6th month (first 2 infusions 300 mg/300 mg given 2 weeks apart).

Rituximab is a chimeric mouse/human monoclonal immunoglobulin gamma-1 (IgG1) antibody which depletes cluster of differentiation antigen 20 (CD20)-positive cells. Rituximab is approved for non-hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangitis and microscopic polyangitis, and pemphigus vulgaris.

Ocrelizumab is a recombinant humanised monoclonal IgG1 antibody which depletes CD20-positive cells. Ocrelizumab is approved for multiple sclerosis.

Premedication with oral fexofenadine 360 mg is given before every infusion to reduce frequency and intensity of infusion related reactions.

Premedication with oral. paracetamol 1000 mg is given before every infusion to reduce frequency and intensity of infusion related reactions.

Premedication with oral methylprednisolone 100 mg is given before every infusion to reduce frequency and intensity of infusion related reactions.

Percentage of patients with 6-month confirmed disability progression (CDP) in Expanded Disability Status Scale (EDSS)

Patient related outcome measure (PROM). A 29 item questionnaire with values ranging from 29 (good) to 145 (worse).

PROM. A 20 item questionnaire with values ranging from 20 (no fatigue at all) and 100 (severest grade of fatigue.

Genotyping of Fc gamma receptor type IIA and IIIA (FCRGIIA and FCGRIIIA), Complement C1q A Chain (C1QA) and low-density lipoprotein receptor-related protein 2 (LRP2)

Genotypes associated with rituximab efficacy and safety (FCRGIIA 131, FCGRIIIA 158, C1QA 276) and relapse frequency (LRP2)

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): ▪≥2 relapse previous 12 months OR 1 relapse previous 12 months with severe residual symptoms and EDSS ≥ 3.0 OR 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 relapse previous 12 months OR ≥1 contrast-enhancing lesion or ≥2 new/enlarging T2 lesions on brain and/or spinal cord MRI previous 12 months Progressive MS patients: ≥1 relapse previous 12 months OR ≥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 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 (measured with NF-Light® ELISA assay from Uman Diagnostics or Simoa): 18 to 40 years >560 ng/l 41 to 60 years >890 ng/l 61 to 65 years >1850 ng/l or (B) Serum NFL level (measured with Simoa™ NF-light® Advantage Kit) o Increased sNFL based on individual age-determined cut-off: >4.19 × 1.029^age ng/L OR o Increased sNFL based age-partitioned cut-offs: 18 to 20 years >7.4 ng/L 21 to 30 years >9.9 ng/L 31 to 40 years >13.1 ng/L 41 to 50 years >17.5 ng/L 51 to 60 years >23.3 ng/L 61 to 65 years >30.9 ng/L 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 symptoms or signs of active tuberculosis in a patient with a positive Quantiferon test. 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, siponimod or ozanimod lymphopenia is accepted at screening visit. Patients switching from dimethylfumarate who have persistent lymphopenia 5 to 6 weeks after stopping dimethylfumarate can be included if lymphopenia is grade 2 or lower, and treating phycisian judge CD20-depleting therapy safe. 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 month of baseline visit 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