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

Sponsor

Rigshospitalet, Denmark (Other)

Overall Status

Recruiting

CT.gov ID

NCT04688788

Collaborator

Odense University Hospital (Other), Aarhus University Hospital (Other), Aalborg University Hospital (Other), Herlev Hospital (Other), Hillerod Hospital, Denmark (Other), Zealand University Hospital (Other), Kolding Sygehus (Other), Regional Hospital Holstebro (Other), Hvidovre University Hospital (Other), Hospital of South West Jutland, Esbjerg, Denmark (Other), GCP unit, Copenhagen University Hospital (Other), GCP-unit at Aarhus University Hospital, Aarhus, Denmark (Other), Hospital of Southern Jutland, Sønderborg, Denmark (Other), Hospital of Central Denmark Region, Viborg, Denmark (Other), Danske Regioner (Other)

594

Enrollment

Locations

Arms

Anticipated Duration (Months)

49.5

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

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

Anticipated 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.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 :

Apr 28, 2021

Anticipated Primary Completion Date :

Apr 28, 2025

Anticipated Study Completion Date :

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

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: Ocrelizumab

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

Other Names:

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

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

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).
Percentage of patients without gadolinium-enhancing lesions (GdEL) [Month 6 and month 24 MRI scans]
MRI outcome
Change in T2 white matter lesion volume [From month 6 to month 24]
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
Change in serum neurofilament light chain level [From baseline to month 24]
Blood biomarker
Blood levels of cluster of differentiation antigen 19 (CD19)+ B cells [At month 6 and month 24]
Blood biomarker

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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):

▪≥2 relapse previous 12 months OR
1 relapse previous 12 months with severe residual symptoms and EDSS ≥ 3.0 OR
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 relapse previous 12 months OR
≥1 contrast-enhancing lesion or ≥2 new/enlarging T2 lesions on brain and/or spinal cord MRI previous 12 months

Progressive MS patients:

≥1 relapse previous 12 months OR
≥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
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

(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

Locations

	Site	City	State	Country	Postal Code
1	Danish Multiple Sclerosis Center, Rigshospitalet	Glostrup	Copenhagen	Denmark	2600
2	Department of Neurology, Aalborg University Hospital	Aalborg		Denmark	9000
3	Department of Neurology, Aarhus University Hospital	Aarhus		Denmark	8200
4	Department of Neurology, Hospital of South West Jutland, Esbjerg	Esbjerg		Denmark	6700
5	Department of Neurology, Herlev Hospital	Herlev		Denmark	2730
6	Department of Neurology, Nordsjællands Hospital i Hillerød	Hillerød		Denmark	3400
7	Department of Neurology, Regionshospitalet Holstebro	Holstebro		Denmark	7500
8	Department of Neurology, Kolding Hospital	Kolding		Denmark	6000
9	Department of Neurology, Odense University Hospital	Odense		Denmark	5000
10	Department of Neurology, Sjællands Universitetshospital, Roskilde	Roskilde		Denmark	4000
11	Department of Neurology, Hospital of Southern Jutland, Sønderborg	Sønderborg		Denmark	6400
12	Department of neurology, Regionshospitalet Viborg	Viborg		Denmark	8800