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Active, not recruitingNCT04688788DanNORMSUpdated Aug 17, 2026

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

A Phase 3 interventional study of Rituximab and Ocrelizumab in Relapsing Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis and Primary Progressive Multiple Sclerosis, sponsored by Rigshospitalet, Denmark. Active, not recruiting at 11 sites in Denmark. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-08-17.

Sponsored by Rigshospitalet, Denmark · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
600
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Relapsing Remitting Multiple Sclerosis
  • Secondary Progressive Multiple Sclerosis
  • Primary Progressive Multiple Sclerosis

Keywords

  • Magnetic resonance imaging
  • Rituximab
  • Ocrelizumab
03

In context

Multiple Sclerosis, Relapsing-Remitting

602 studies on the registry are indexed under Multiple Sclerosis, Relapsing-Remitting; 80 are open to participants now.

This study's enrollment of 600 is above the median of 72 across 429 interventional studies indexed under Multiple Sclerosis, Relapsing-Remitting.

Browse Multiple Sclerosis, Relapsing-Remitting studies →

Lead sponsor

Rigshospitalet, Denmark is the lead sponsor of 1,017 studies on the registry; 183 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Single (Outcomes assessor)
Enrollment
600 participants (actual)

Study arms

  • Experimental
    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).

    Drug: Rituximab · Drug: Fexofenadine · Drug: Paracetamol · Drug: Methylprednisolone

  • Active comparator
    Ocrelizumab

    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

  • DrugRituximab

    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

  • DrugOcrelizumab

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

    Also known as: Ocrevus

  • DrugFexofenadine

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

  • DrugParacetamol

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

  • DrugMethylprednisolone

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

06

What researchers measure

Primary outcomes

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

    MRI outcome

    Time frame: Month 6 to month 24

Secondary outcomes

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

    Clinical outcome

    Time frame: Baseline to month 24

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

    Clinical outcome

    Time frame: Baseline to month 24

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

    Clinical outcome

    Time frame: Baseline to month 24

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

    Clinical outcome

    Time frame: Baseline to month 24

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

    Clinical outcome

    Time frame: Baseline to month 24

  6. Change in Multiple Sclerosis Impact Scale (MSIS-29)

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

    Time frame: Baseline to month 24

  7. Change in Fatigue Scale for Motor and Cognitive Functions (FSMC)

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

    Time frame: Baseline to month 24

  8. EuroQol- 5 Dimension (EQ-5D)

    PROM. A 5 item questionnaire with values ranging from 5 (good) to 15 (worse).

    Time frame: Baseline to month 24

  9. Percentage of patients without gadolinium-enhancing lesions (GdEL)

    MRI outcome

    Time frame: Month 6 and month 24 MRI scans

  10. Change in T2 white matter lesion volume

    MRI outcome

    Time frame: From month 6 to month 24

  11. Change in T1 white matter lesion volume

    MRI outcome

    Time frame: From month 6 to month 24

  12. Percentage brain volume change (PBVC) from month 6 to month 24

    MRI outcome

    Time frame: From month 6 to month 24

  13. Change in serum neurofilament light chain level

    Blood biomarker

    Time frame: From baseline to month 24

  14. Blood levels of cluster of differentiation antigen 19 (CD19)+ B cells

    Blood biomarker

    Time frame: At month 6 and month 24

Other outcomes

  1. Antidrug antibody frequency

    Anti drug antibodies against rituximab or ocrelizumab

    Time frame: Baseline, month 6 and month 24

  2. Drug concentration

    Rituximab or ocrelizumab drug concentration

    Time frame: Month 6 and month 24

  3. 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)

    Time frame: Baseline

07

Study locations

11 sites
  • Danish Multiple Sclerosis Center, Rigshospitalet
    Glostrup Municipality, Copenhagen 2600, Denmark
  • Department of Neurology, Aalborg University Hospital
    Aalborg, 9000, Denmark
  • Department of Neurology, Aarhus University Hospital
    Aarhus, 8200, Denmark
  • Department of Neurology, Hospital of South West Jutland, Esbjerg
    Esbjerg, 6700, Denmark
  • Department of Neurology, Herlev Hospital
    Herlev, 2730, Denmark
  • Department of Neurology, Nordsjællands Hospital i Hillerød
    Hillerød, 3400, Denmark
  • Department of Neurology, Regionshospitalet Holstebro
    Holstebro, 7500, Denmark
  • Department of Neurology, Kolding Hospital
    Kolding, 6000, Denmark
  • Department of Neurology, Odense University Hospital
    Odense, 5000, Denmark
  • Department of Neurology, Hospital of Southern Jutland, Sønderborg
    Sønderborg, 6400, Denmark
  • Department of neurology, Regionshospitalet Viborg
    Viborg, 8800, Denmark
08

References and documents

Individual participant data

Plan to share: No

No publications or documents are linked to this record.

09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Aug 17, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT04688788
Lead sponsor
Rigshospitalet, Denmark
Collaborators
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, University of Copenhagen, GCP-unit at Aarhus University Hospital, Aarhus, Denmark, Hospital of Southern Jutland, Hospital of Central Denmark Region, Viborg, Denmark, Danske Regioner, Sanquin Research & Blood Bank Divisions
Responsible party
Jeppe Romme Christensen (National coordinating principal investigator, Rigshospitalet, Denmark) — Principal investigator
First posted
Dec 30, 2020
Start date
Apr 28, 2021
Primary completion
Jun 10, 2026
Completion
Jun 10, 2029 (estimated)
Last update
Aug 17, 2026

Study contacts

Jeppe Romme Christensen, MD, PhD
principal investigator · Danish Multiple Sclerosis Center Rigshospitalet

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is active, not recruiting, as verified in Aug 2026. You cannot join it, but the record below documents what was studied.

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