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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04688788
Recruitment Status : Active, not recruiting
First Posted : December 30, 2020
Last Update Posted : May 16, 2024
Sponsor:
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
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
Sanquin Research & Blood Bank Divisions
Information provided by (Responsible Party):
Jeppe Romme Christensen, Rigshospitalet, Denmark

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.

Condition or disease Intervention/treatment Phase
Relapsing Remitting Multiple Sclerosis Secondary Progressive Multiple Sclerosis Primary Progressive Multiple Sclerosis Drug: Rituximab Drug: Ocrelizumab Drug: Fexofenadine Drug: Paracetamol Drug: Methylprednisolone Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A prospective, 2:1 randomized, open-label, multi-centre, phase 3 non-inferiority clinical trial with blinded primary endpoint.
Masking: Single (Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 28, 2021
Estimated Primary Completion Date : May 5, 2026
Estimated Study Completion Date : May 5, 2028


Arm Intervention/treatment
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
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.
Other Name: Ruxience, Rixathon® or other biosimilar rituximab

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

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

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

Active Comparator: Ocrelizumab
Intravenous ocrelizumab (Ocrevus®) 600 mg every 6th month (first 2 infusions 300 mg/300 mg given 2 weeks apart).
Drug: Ocrelizumab
Ocrelizumab is a recombinant humanised monoclonal IgG1 antibody which depletes CD20-positive cells. Ocrelizumab is approved for multiple sclerosis.
Other Name: Ocrevus

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

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

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




Primary Outcome Measures :
  1. Percentage of patients without new or enlarging T2 white matter lesions on brain MRI scans [ Time Frame: Month 6 to month 24 ]
    MRI outcome


Secondary Outcome Measures :
  1. Percentage of patients with 6-month confirmed disability progression (CDP) in Expanded Disability Status Scale (EDSS) [ Time Frame: Baseline to month 24 ]
    Clinical outcome

  2. Annualised relapse rate based on cumulative number of confirmed relapses from baseline to months 24 [ Time Frame: Baseline to month 24 ]
    Clinical outcome

  3. Percentage of patients with 6-months CDP in Timed 25 Foot Walk (T25FW) [ Time Frame: Baseline to month 24 ]
    Clinical outcome

  4. Percentage of patients with 6-months CDP in 9-Hole-Peg Test (9HPT) [ Time Frame: Baseline to month 24 ]
    Clinical outcome

  5. Percentage of patients with 6-months CDP in Symbol Digit Modalities Test (SDMT) [ Time Frame: Baseline to month 24 ]
    Clinical outcome

  6. Change in Multiple Sclerosis Impact Scale (MSIS-29) [ Time Frame: Baseline to month 24 ]
    Patient related outcome measure (PROM). A 29 item questionnaire with values ranging from 29 (good) to 145 (worse).

  7. Change in Fatigue Scale for Motor and Cognitive Functions (FSMC) [ Time Frame: Baseline to month 24 ]
    PROM. A 20 item questionnaire with values ranging from 20 (no fatigue at all) and 100 (severest grade of fatigue.

  8. EuroQol- 5 Dimension (EQ-5D) [ Time Frame: Baseline to month 24 ]
    PROM. A 5 item questionnaire with values ranging from 5 (good) to 15 (worse).

  9. Percentage of patients without gadolinium-enhancing lesions (GdEL) [ Time Frame: Month 6 and month 24 MRI scans ]
    MRI outcome

  10. Change in T2 white matter lesion volume [ Time Frame: From month 6 to month 24 ]
    MRI outcome

  11. Change in T1 white matter lesion volume [ Time Frame: From month 6 to month 24 ]
    MRI outcome

  12. Percentage brain volume change (PBVC) from month 6 to month 24 [ Time Frame: From month 6 to month 24 ]
    MRI outcome

  13. Change in serum neurofilament light chain level [ Time Frame: From baseline to month 24 ]
    Blood biomarker

  14. Blood levels of cluster of differentiation antigen 19 (CD19)+ B cells [ Time Frame: At month 6 and month 24 ]
    Blood biomarker


Other Outcome Measures:
  1. Antidrug antibody frequency [ Time Frame: Baseline, month 6 and month 24 ]
    Anti drug antibodies against rituximab or ocrelizumab

  2. Drug concentration [ Time Frame: Month 6 and month 24 ]
    Rituximab or ocrelizumab drug concentration

  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) [ Time Frame: Baseline ]
    Genotypes associated with rituximab efficacy and safety (FCRGIIA 131, FCGRIIIA 158, C1QA 276) and relapse frequency (LRP2)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04688788


Locations
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Denmark
Danish Multiple Sclerosis Center, Rigshospitalet
Glostrup, Copenhagen, Denmark, 2600
Department of Neurology, Aalborg University Hospital
Aalborg, Denmark, 9000
Department of Neurology, Aarhus University Hospital
Aarhus, Denmark, 8200
Department of Neurology, Hospital of South West Jutland, Esbjerg
Esbjerg, Denmark, 6700
Department of Neurology, Herlev Hospital
Herlev, Denmark, 2730
Department of Neurology, Nordsjællands Hospital i Hillerød
Hillerød, Denmark, 3400
Department of Neurology, Regionshospitalet Holstebro
Holstebro, Denmark, 7500
Department of Neurology, Kolding Hospital
Kolding, Denmark, 6000
Department of Neurology, Odense University Hospital
Odense, Denmark, 5000
Department of Neurology, Hospital of Southern Jutland, Sønderborg
Sønderborg, Denmark, 6400
Department of neurology, Regionshospitalet Viborg
Viborg, Denmark, 8800
Sponsors and Collaborators
Rigshospitalet, Denmark
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
Sanquin Research & Blood Bank Divisions
Investigators
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Principal Investigator: Jeppe Romme Christensen, MD, PhD Danish Multiple Sclerosis Center Rigshospitalet
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Responsible Party: Jeppe Romme Christensen, National coordinating principal investigator, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT04688788    
Other Study ID Numbers: DanNORMS_version 3.2
First Posted: December 30, 2020    Key Record Dates
Last Update Posted: May 16, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Jeppe Romme Christensen, Rigshospitalet, Denmark:
Magnetic resonance imaging
Rituximab
Ocrelizumab
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Multiple Sclerosis, Chronic Progressive
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Chronic Disease
Disease Attributes
Fexofenadine
Methylprednisolone
Rituximab
Ocrelizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists