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

NCT04688788 | Active Not Recruiting Phase 3

• 1 other identifier: DanNORMS_version 3.2
• Study Type: interventional
• Target: 600
• Locations: 1 country
• Sites: 11

Brief Summary

The DanNORMS study is a phase 3, non-inferiority clinical trial examining whether treatment of active multiple sclerosis with rituximab is non-inferior to ocrelizumab regarding efficacy and safety.

Conditions

Relapsing Remitting Multiple Sclerosis; Secondary Progressive Multiple Sclerosis; Primary Progressive Multiple Sclerosis

Keywords

Magnetic resonance imaging; Rituximab; Ocrelizumab

Outcome Measures

Primary Outcomes (1)

• Percentage of patients without new or enlarging T2 white matter lesions on brain MRI scans

  MRI outcome

  Month 6 to month 24

Secondary Outcomes (14)

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

  Baseline to month 24

• Annualised relapse rate based on cumulative number of confirmed relapses from baseline to months 24

  Baseline to month 24

• Percentage of patients with 6-months CDP in Timed 25 Foot Walk (T25FW)

  Baseline to month 24

• Percentage of patients with 6-months CDP in 9-Hole-Peg Test (9HPT)

  Baseline to month 24

• Percentage of patients with 6-months CDP in Symbol Digit Modalities Test (SDMT)

  Baseline to month 24

Other Outcomes (3)

• Antidrug antibody frequency

  Baseline, month 6 and month 24

• Drug concentration

  Month 6 and month 24

• 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)

  Baseline

Study Arms (2)

Rituximab

EXPERIMENTAL

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

Drug: Rituximab; Drug: Fexofenadine; Drug: Paracetamol; Drug: Methylprednisolone

Ocrelizumab

ACTIVE COMPARATOR

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

Drug: Ocrelizumab; Drug: Fexofenadine; Drug: Paracetamol; Drug: Methylprednisolone

Interventions

Rituximab DRUG

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.

Also known as: Ruxience, Rixathon® or other biosimilar rituximab

Rituximab

Ocrelizumab DRUG

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

Also known as: Ocrevus

Ocrelizumab

Fexofenadine DRUG

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

Ocrelizumab; Rituximab

Paracetamol DRUG

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

Ocrelizumab; Rituximab

Methylprednisolone DRUG

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

Ocrelizumab; Rituximab

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• relapse previous 12 months with severe residual symptoms and EDSS ≥ 3.0 OR
• relapse previous 12 months AND ≥9 T2 lesions on brain and/or spinal cord MRI AND
• 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
• (A) CSF NFL level (measured with NF-Light® ELISA assay from Uman Diagnostics or Simoa):

You may not qualify if:

• 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

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Odense University Hospital: collaborator
• Aarhus University Hospital: collaborator
• Aalborg University Hospital: collaborator
• Herlev Hospital: collaborator
• Hillerod Hospital, Denmark: collaborator
• Kolding Sygehus: collaborator
• Gødstrup Hospital: collaborator
• Hvidovre University Hospital: collaborator
• Hospital of South West Jutland, Esbjerg, Denmark: collaborator
• GCP unit, Copenhagen University Hospital: collaborator
• GCP-unit at Aarhus University Hospital, Aarhus, Denmark: collaborator
• Hospital of Southern Jutland, Sønderborg, Denmark: collaborator
• Hospital of Central Denmark Region, Viborg, Denmark: collaborator
• Danske Regioner: collaborator
• Hospital of Southern Jutland, Aabenraa, Denmark: collaborator
• Sanquin Research & Blood Bank Divisions: collaborator

Study Sites (11)

Danish Multiple Sclerosis Center, Rigshospitalet

Glostrup Municipality, Copenhagen, 2600, Denmark

Location

Department of Neurology, Aalborg University Hospital

Aalborg, 9000, Denmark

Location

Department of Neurology, Aarhus University Hospital

Aarhus, 8200, Denmark

Location

Department of Neurology, Hospital of South West Jutland, Esbjerg

Esbjerg, 6700, Denmark

Location

Department of Neurology, Herlev Hospital

Herlev, 2730, Denmark

Location

Department of Neurology, Nordsjællands Hospital i Hillerød

Hillerød, 3400, Denmark

Location

Department of Neurology, Regionshospitalet Holstebro

Holstebro, 7500, Denmark

Location

Department of Neurology, Kolding Hospital

Kolding, 6000, Denmark

Location

Department of Neurology, Odense University Hospital

Odense, 5000, Denmark

Location

Department of Neurology, Hospital of Southern Jutland, Sønderborg

Sønderborg, 6400, Denmark

Location

Department of neurology, Regionshospitalet Viborg

Viborg, 8800, Denmark

Location

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive

Interventions

Rituximab; ocrelizumab; fexofenadine; Acetaminophen; Methylprednisolone

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Jeppe Romme Christensen, MD, PhD

  Danish Multiple Sclerosis Center Rigshospitalet

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: National coordinating principal investigator

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

Study Record Dates

• First Submitted: December 22, 2020
• First Posted: December 30, 2020
• Study Start: April 28, 2021
• Primary Completion: May 5, 2026
• Study Completion (Estimated): May 5, 2029
• Last Updated: July 28, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

DK (11)