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

NCT ID: NCT04688788

Last Updated: 2025-07-28

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-28
• Study Completion Date: 2029-05-05

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.

Detailed Description

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 for the core-phase, and patients can continue in a long-term follow-up phase for additional 36 months with possibility for extended interval dosing guided by CD19+ B cell count.

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Rituximab

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).

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: 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.

Fexofenadine

Intervention Type: DRUG

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

Paracetamol

Intervention Type: DRUG

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

Methylprednisolone

Intervention Type: DRUG

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

Ocrelizumab

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

Group Type: ACTIVE_COMPARATOR

Ocrelizumab

Intervention Type: DRUG

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

Fexofenadine

Intervention Type: DRUG

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

Paracetamol

Intervention Type: DRUG

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

Methylprednisolone

Intervention Type: DRUG

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

Interventions

Rituximab

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.

Intervention Type: DRUG

Ocrelizumab

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

Intervention Type: DRUG

Fexofenadine

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

Intervention Type: DRUG

Paracetamol

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

Intervention Type: DRUG

Methylprednisolone

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

Intervention Type: DRUG

Other Intervention Names

Ruxience, Rixathon® or other biosimilar rituximab; Ocrevus

Eligibility Criteria

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 (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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Odense University Hospital

OTHER

Sponsor Role: collaborator

Aarhus University Hospital

OTHER

Sponsor Role: collaborator

Aalborg University Hospital

OTHER

Sponsor Role: collaborator

Herlev Hospital

OTHER

Sponsor Role: collaborator

Hillerod Hospital, Denmark

OTHER

Sponsor Role: collaborator

Kolding Sygehus

OTHER

Sponsor Role: collaborator

Gødstrup Hospital

OTHER

Sponsor Role: collaborator

Hvidovre University Hospital

OTHER

Sponsor Role: collaborator

Hospital of South West Jutland, Esbjerg, Denmark

UNKNOWN

Sponsor Role: collaborator

GCP unit, Copenhagen University Hospital

UNKNOWN

Sponsor Role: collaborator

GCP-unit at Aarhus University Hospital, Aarhus, Denmark

OTHER

Sponsor Role: collaborator

Hospital of Southern Jutland, Sønderborg, Denmark

UNKNOWN

Sponsor Role: collaborator

Hospital of Central Denmark Region, Viborg, Denmark

UNKNOWN

Sponsor Role: collaborator

Danske Regioner

OTHER

Sponsor Role: collaborator

Hospital of Southern Jutland, Aabenraa, Denmark

UNKNOWN

Sponsor Role: collaborator

Sanquin Research & Blood Bank Divisions

OTHER

Sponsor Role: collaborator

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Jeppe Romme Christensen

National coordinating principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jeppe Romme Christensen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Danish Multiple Sclerosis Center Rigshospitalet

Locations

Danish Multiple Sclerosis Center, Rigshospitalet

Glostrup Municipality, Copenhagen, Denmark

Department of Neurology, Aalborg University Hospital

Aalborg, , Denmark

Department of Neurology, Aarhus University Hospital

Aarhus, , Denmark

Department of Neurology, Hospital of South West Jutland, Esbjerg

Esbjerg, , Denmark

Department of Neurology, Herlev Hospital

Herlev, , Denmark

Department of Neurology, Nordsjællands Hospital i Hillerød

Hillerød, , Denmark

Department of Neurology, Regionshospitalet Holstebro

Holstebro, , Denmark

Department of Neurology, Kolding Hospital

Kolding, , Denmark

Department of Neurology, Odense University Hospital

Odense, , Denmark

Department of Neurology, Hospital of Southern Jutland, Sønderborg

Sønderborg, , Denmark

Department of neurology, Regionshospitalet Viborg

Viborg, , Denmark

Countries

Denmark

Other Identifiers

DanNORMS_version 3.2

Identifier Type: -

Identifier Source: org_study_id