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

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.

Study Overview

• Status: Recruiting
• Conditions: Relapsing Remitting Multiple Sclerosis; Primary Progressive Multiple Sclerosis; Secondary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Rituximab; Drug: Fexofenadine; Drug: Paracetamol; Drug: Methylprednisolone; Drug: Ocrelizumab

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, 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.

• Study Type: Interventional
• Enrollment (Estimated): 594
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jeppe Romme Christensen, MD, PhD; Phone Number: 0045 38633379; Email: jeppe.romme.christensen@regionh.dk
• Study Contact Backup: Name: Finn Sellebjerg, Prof., MD, PhD; Phone Number: 0045 38633236; Email: finn.thorup.sellebjerg@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Recruiting
    • Department of Neurology, Aalborg University Hospital
    • Contact: Inga Urbonaviciute, MD
  • Aarhus, Denmark, 8200
    • Recruiting
    • Department of Neurology, Aarhus University Hospital
    • Contact: Morten Stilund, MD, PhD
  • Esbjerg, Denmark, 6700
    • Recruiting
    • Department of Neurology, Hospital of South West Jutland, Esbjerg
    • Contact: Tobias Sejbæk, MD, PhD
  • Herlev, Denmark, 2730
    • Recruiting
    • Department of Neurology, Herlev Hospital
    • Contact: Arkadiusz Weglewski, MD, PhD
  • Hillerød, Denmark, 3400
    • Recruiting
    • Department of Neurology, Nordsjællands Hospital i Hillerød
    • Contact: Mai B Poulsen, MD, PhD
  • Holstebro, Denmark, 7500
    • Recruiting
    • Department of Neurology, Regionshospitalet Holstebro
    • Contact: Morten Stilund, MD, PhD
  • Kolding, Denmark, 6000
    • Recruiting
    • Department of Neurology, Kolding Hospital
    • Contact: Henrik Boye Jensen, MD, PhD
  • Odense, Denmark, 5000
    • Recruiting
    • Department of Neurology, Odense University Hospital
    • Contact: Zsolt Illes, Prof., MD
  • Sønderborg, Denmark, 6400
    • Recruiting
    • Department of Neurology, Hospital of Southern Jutland, Sønderborg
    • Contact: Matthias Kant, MD, PhD
  • Viborg, Denmark, 8800
    • Recruiting
    • Department of neurology, Regionshospitalet Viborg
    • Contact: Sivagini Prakash, MD
  • Copenhagen
    • Glostrup, Copenhagen, Denmark, 2600
      • Recruiting
      • Danish Multiple Sclerosis Center, Rigshospitalet
      • Contact: Jeppe Romme Christensen, MD, PhD; Phone Number: 0045 38633379; Email: jeppe.romme.christensen@rh.regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab; Intravenous biosimilar rituximab (Ruxience®) 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 Names: Ruxience; 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: 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.; Drug: Ocrelizumab; Ocrelizumab is a recombinant humanised monoclonal IgG1 antibody which depletes CD20-positive cells. Ocrelizumab is approved for multiple sclerosis.; Other Names: Ocrevus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients without new or enlarging T2 white matter lesions on brain MRI scans	MRI outcome	Month 6 to month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with 6-month confirmed disability progression (CDP) in Expanded Disability Status Scale (EDSS)	Clinical outcome	Baseline to month 24
Annualised relapse rate based on cumulative number of confirmed relapses from baseline to months 24	Clinical outcome	Baseline to month 24
Percentage of patients with 6-months CDP in Timed 25 Foot Walk (T25FW)	Clinical outcome	Baseline to month 24
Percentage of patients with 6-months CDP in 9-Hole-Peg Test (9HPT)	Clinical outcome	Baseline to month 24
Percentage of patients with 6-months CDP in Symbol Digit Modalities Test (SDMT)	Clinical outcome	Baseline to month 24
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).	Baseline to month 24
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.	Baseline to month 24
EuroQol- 5 Dimension (EQ-5D)	PROM. A 5 item questionnaire with values ranging from 5 (good) to 15 (worse).	Baseline to month 24
Percentage of patients without gadolinium-enhancing lesions (GdEL)	MRI outcome	Month 6 and month 24 MRI scans
Change in T2 white matter lesion volume	MRI outcome	From month 6 to month 24
Change in T1 white matter lesion volume	MRI outcome	From month 6 to month 24
Percentage brain volume change (PBVC) from month 6 to month 24	MRI outcome	From month 6 to month 24
Change in serum neurofilament light chain level	Blood biomarker	From baseline to month 24
Blood levels of cluster of differentiation antigen 19 (CD19)+ B cells	Blood biomarker	At month 6 and month 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antidrug antibody frequency	Anti drug antibodies against rituximab or ocrelizumab	Baseline, month 6 and month 24
Drug concentration	Rituximab or ocrelizumab 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)	Genotypes associated with rituximab efficacy and safety (FCRGIIA 131, FCGRIIIA 158, C1QA 276) and relapse frequency (LRP2)	Baseline

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Odense University Hospital; Aarhus University Hospital; Hvidovre University Hospital; Herlev Hospital; Hillerod Hospital, Denmark; Aalborg University Hospital; Gødstrup Hospital; Kolding Sygehus; GCP-unit at Aarhus University Hospital, Aarhus, Denmark; Hospital of South West Jutland, Esbjerg, Denmark; GCP unit, Copenhagen University Hospital; Hospital of Southern Jutland, Sønderborg, Denmark; Hospital of Central Denmark Region, Viborg, Denmark; Danske Regioner; Hospital of Southern Jutland, Aabenraa, Denmark
• Investigators: Principal Investigator: Jeppe Romme Christensen, MD, PhD, Danish Multiple Sclerosis Center Rigshospitalet

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2021
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: December 22, 2020
• First Submitted That Met QC Criteria: December 26, 2020
• First Posted (Actual): December 30, 2020

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 2, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Magnetic resonance imaging; Rituximab; Ocrelizumab
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Disease Attributes; Chronic Disease; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Immunological; Anti-Allergic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Histamine H1 Antagonists, Non-Sedating; Methylprednisolone; Rituximab; Ocrelizumab; Fexofenadine
• Other Study ID Numbers: DanNORMS_version 3.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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