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

Phase 3

Active, not recruiting

• Conditions: Relapsing Remitting Multiple Sclerosis; Secondary Progressive Multiple Sclerosis; Primary Progressive Multiple Sclerosis
• Interventions: Drug: Rituximab; Drug: Ocrelizumab; Drug: Fexofenadine; Drug: Paracetamol; Drug: Methylprednisolone

• Registration Number: NCT04688788
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2020-12-22
• Study First Submitted QC: 2020-12-26
• Study First Posted: 2020-12-30
• Study Start: 2021-04-28
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-13
• Last Update Posted: 2024-05-16
• Primary Completion: 2026-05-05
• Study Completion: 2028-05-05

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 600

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rituximab	Paracetamol	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).
Ocrelizumab	Fexofenadine	Intravenous ocrelizumab (Ocrevus®) 600 mg every 6th month (first 2 infusions 300 mg/300 mg given 2 weeks apart).
Rituximab	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).
Ocrelizumab	Paracetamol	Intravenous ocrelizumab (Ocrevus®) 600 mg every 6th month (first 2 infusions 300 mg/300 mg given 2 weeks apart).
Rituximab	Fexofenadine	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).
Ocrelizumab	Ocrelizumab	Intravenous ocrelizumab (Ocrevus®) 600 mg every 6th month (first 2 infusions 300 mg/300 mg given 2 weeks apart).
Ocrelizumab	Methylprednisolone	Intravenous ocrelizumab (Ocrevus®) 600 mg every 6th month (first 2 infusions 300 mg/300 mg given 2 weeks apart).
Rituximab	Methylprednisolone	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).

Primary Outcome Measures

Name	Time	Method
Percentage of patients without new or enlarging T2 white matter lesions on brain MRI scans	Month 6 to month 24	MRI outcome

Secondary Outcome Measures

Name	Time	Method
Percentage of patients with 6-month confirmed disability progression (CDP) in Expanded Disability Status Scale (EDSS)	Baseline to month 24	Clinical outcome
Annualised relapse rate based on cumulative number of confirmed relapses from baseline to months 24	Baseline to month 24	Clinical outcome
Percentage of patients with 6-months CDP in Timed 25 Foot Walk (T25FW)	Baseline to month 24	Clinical outcome
Percentage of patients with 6-months CDP in 9-Hole-Peg Test (9HPT)	Baseline to month 24	Clinical outcome
Percentage of patients with 6-months CDP in Symbol Digit Modalities Test (SDMT)	Baseline to month 24	Clinical outcome
Change in Multiple Sclerosis Impact Scale (MSIS-29)	Baseline to month 24	Patient related outcome measure (PROM). A 29 item questionnaire with values ranging from 29 (good) to 145 (worse).
Change in Fatigue Scale for Motor and Cognitive Functions (FSMC)	Baseline to month 24	PROM. A 20 item questionnaire with values ranging from 20 (no fatigue at all) and 100 (severest grade of fatigue.
EuroQol- 5 Dimension (EQ-5D)	Baseline to month 24	PROM. A 5 item questionnaire with values ranging from 5 (good) to 15 (worse).
Change in T2 white matter lesion volume	From month 6 to month 24	MRI outcome
Change in serum neurofilament light chain level	From baseline to month 24	Blood biomarker
Percentage of patients without gadolinium-enhancing lesions (GdEL)	Month 6 and month 24 MRI scans	MRI outcome
Change in T1 white matter lesion volume	From month 6 to month 24	MRI outcome
Percentage brain volume change (PBVC) from month 6 to month 24	From month 6 to month 24	MRI outcome
Blood levels of cluster of differentiation antigen 19 (CD19)+ B cells	At month 6 and month 24	Blood biomarker

Trial Locations

Locations (11)

Department of Neurology, Herlev Hospital; 🇩🇰 Herlev, 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, Nordsjællands Hospital i Hillerød; 🇩🇰 Hillerød, Denmark

Department of Neurology, Kolding Hospital; 🇩🇰 Kolding, Denmark

Department of Neurology, Hospital of Southern Jutland, Sønderborg; 🇩🇰 Sønderborg, Denmark

Department of neurology, Regionshospitalet Viborg; 🇩🇰 Viborg, Denmark

Danish Multiple Sclerosis Center, Rigshospitalet; 🇩🇰 Glostrup, Copenhagen, Denmark

Department of Neurology, Odense University Hospital; 🇩🇰 Odense, Denmark

Department of Neurology, Regionshospitalet Holstebro; 🇩🇰 Holstebro, Denmark