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

• ClinicalTrials.gov Identifier: NCT04688788
• Recruitment Status: Recruiting
• First Posted: December 30, 2020
• Last Update Posted: May 4, 2022
• Sponsor: Rigshospitalet, Denmark
• Collaborators: Odense University Hospital; Aarhus University Hospital; Aalborg University Hospital; Herlev Hospital; Hillerod Hospital, Denmark; Zealand University Hospital; Kolding Sygehus; Regional Hospital Holstebro; 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
• Information provided by (Responsible Party): Jeppe Romme Christensen, Rigshospitalet, Denmark

Study Description

Brief Summary:

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.

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, 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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 594 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: April 28, 2025
• Estimated Study Completion Date: April 28, 2028

Arms and Interventions

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 Name: 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: 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.

Outcome Measures

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)

Eligibility Criteria

• 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)

       • 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 75 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 tuberculosis
• 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 lymphopenia grade 2 can be accepted if lymphocytes are rising markedly compared to on treatment levels)
• 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

Contacts and Locations

Contacts

Contact: Jeppe Romme Christensen, MD, PhD; 0045 38633379; jeppe.romme.christensen@regionh.dk

Contact: Finn Sellebjerg, Prof., MD, PhD; 0045 38633236; finn.thorup.sellebjerg@regionh.dk

Locations

Denmark

Danish Multiple Sclerosis Center, Rigshospitalet; Recruiting

Glostrup, Copenhagen, Denmark, 2600

Contact: Jeppe Romme Christensen, MD, PhD 0045 38633379 jeppe.romme.christensen@rh.regionh.dk

Department of Neurology, Aalborg University Hospital; Recruiting

Aalborg, Denmark, 9000

Contact: Inga Urbonaviciute, MD

Department of Neurology, Aarhus University Hospital; Recruiting

Aarhus, Denmark, 8200

Contact: Morten Stilund, MD, PhD

Department of Neurology, Hospital of South West Jutland, Esbjerg; Recruiting

Esbjerg, Denmark, 6700

Contact: Tobias Sejbæk, MD, PhD

Department of Neurology, Herlev Hospital; Not yet recruiting

Herlev, Denmark, 2730

Contact: Arkadiusz Weglewski, MD, PhD

Department of Neurology, Nordsjællands Hospital i Hillerød; Not yet recruiting

Hillerød, Denmark, 3400

Contact: Mai B Poulsen, MD, PhD

Department of Neurology, Regionshospitalet Holstebro; Recruiting

Holstebro, Denmark, 7500

Contact: Morten Stilund, MD, PhD

Department of Neurology, Kolding Hospital; Recruiting

Kolding, Denmark, 6000

Contact: Henrik Boye Jensen, MD, PhD

Department of Neurology, Odense University Hospital; Recruiting

Odense, Denmark, 5000

Contact: Zsolt Illes, Prof., MD

Department of Neurology, Sjællands Universitetshospital, Roskilde; Not yet recruiting

Roskilde, Denmark, 4000

Contact: Lena Roug, MD

Department of Neurology, Hospital of Southern Jutland, Sønderborg; Recruiting

Sønderborg, Denmark, 6400

Contact: Matthias Kant, MD, PhD

Department of neurology, Regionshospitalet Viborg; Recruiting

Viborg, Denmark, 8800

Contact: Sivagini Prakash, MD

Sponsors and Collaborators

Rigshospitalet, Denmark

Odense University Hospital

Aarhus University Hospital

Aalborg University Hospital

Herlev Hospital

Hillerod Hospital, Denmark

Zealand University Hospital

Kolding Sygehus

Regional Hospital Holstebro

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

Investigators

• Principal Investigator: Jeppe Romme Christensen, MD, PhD; Danish Multiple Sclerosis Center Rigshospitalet

More Information

• Responsible Party: Jeppe Romme Christensen, National coordinating principal investigator, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT04688788
• Other Study ID Numbers: DanNORMS_version 2.3
• First Posted: December 30, 2020
• Last Update Posted: May 4, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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