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

Relapsing Remitting Multiple Sclerosis Clinical Trial

— DanNORMS  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04688788
• Other study ID #: DanNORMS_version 3.2
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 28, 2021
• Est. completion date: May 5, 2028

Study information

• Verified date: May 2024
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 600
• Est. completion date: May 5, 2028
• Est. primary completion date: May 5, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Multiple Sclerosis, Relapsing-Remitting
• Primary Progressive Multiple Sclerosis
• Relapsing Remitting Multiple Sclerosis
• Sclerosis
• Secondary Progressive Multiple Sclerosis

Intervention

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.
• Ocrelizumab
Ocrelizumab is a recombinant humanised monoclonal IgG1 antibody which depletes CD20-positive cells. Ocrelizumab is approved for multiple sclerosis.
• Fexofenadine
Premedication with oral fexofenadine 360 mg is given before every infusion to reduce frequency and intensity of infusion related reactions.
• Paracetamol
Premedication with oral. paracetamol 1000 mg is given before every infusion to reduce frequency and intensity of infusion related reactions.
• Methylprednisolone
Premedication with oral methylprednisolone 100 mg is given before every infusion to reduce frequency and intensity of infusion related reactions.

Locations

Country	Name	City	State
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	Danish Multiple Sclerosis Center, Rigshospitalet	Glostrup	Copenhagen
Denmark	Department of Neurology, Herlev Hospital	Herlev
Denmark	Department of Neurology, Nordsjællands Hospital i Hillerød	Hillerød
Denmark	Department of Neurology, Regionshospitalet Holstebro	Holstebro
Denmark	Department of Neurology, Kolding Hospital	Kolding
Denmark	Department of Neurology, Odense University Hospital	Odense
Denmark	Department of Neurology, Hospital of Southern Jutland, Sønderborg	Sønderborg
Denmark	Department of neurology, Regionshospitalet Viborg	Viborg

Sponsors (17)

Lead Sponsor

Collaborator

Rigshospitalet, Denmark

Aalborg University Hospital, Aarhus University Hospital, Danske Regioner, GCP unit, Copenhagen University Hospital, GCP-unit at Aarhus University Hospital, Aarhus, Denmark, Gødstrup Hospital, Herlev Hospital, Hillerod Hospital, Denmark, Hospital of Central Denmark Region, Viborg, Denmark, Hospital of South West Jutland, Esbjerg, Denmark, Hospital of Southern Jutland, Aabenraa, Denmark, Hospital of Southern Jutland, Sønderborg, Denmark, Hvidovre University Hospital, Kolding Sygehus, Odense University Hospital, Sanquin Research & Blood Bank Divisions

Country where clinical trial is conducted

Denmark, 

Outcome

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