Clinical trial NCT04688788: Non-inferiority Study of Ocrelizumab and Rituximab in Active Multiple Sclerosis
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Relapsing Remitting Multiple Sclerosis
Secondary Progressive Multiple Sclerosis
Primary Progressive Multiple Sclerosis
Keywords: Magnetic resonance imaging
Rituximab
Ocrelizumab
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Aarhus University Hospital
name: Aalborg University Hospital
name: Herlev Hospital
name: Hillerod Hospital, Denmark
name: Kolding Sygehus
name: Gødstrup Hospital
name: Hvidovre University Hospital
name: Hospital of South West Jutland, Esbjerg, Denmark
name: GCP unit, Copenhagen University Hospital
name: GCP-unit at Aarhus University Hospital, Aarhus, Denmark
name: Hospital of Southern Jutland, Sønderborg, Denmark
name: Hospital of Central Denmark Region, Viborg, Denmark
name: Danske Regioner
name: Hospital of Southern Jutland, Aabenraa, Denmark
name: Sanquin Research & Blood Bank Divisions
First posted: 2020-12-30
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A prospective, 2:1 randomized, open-label, multi-centre, phase 3 non-inferiority clinical trial with blinded primary endpoint.
Primary purpose: TREATMENT

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.

Eligibility 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)

       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

Primary outcomes:
measure: Percentage of patients without new or enlarging T2 white matter lesions on brain MRI scans
timeFrame: Month 6 to month 24
Secondary outcomes:
measure: Percentage of patients with 6-month confirmed disability progression (CDP) in Expanded Disability Status Scale (EDSS)
timeFrame: Baseline to month 24
measure: Annualised relapse rate based on cumulative number of confirmed relapses from baseline to months 24
timeFrame: Baseline to month 24
measure: Percentage of patients with 6-months CDP in Timed 25 Foot Walk (T25FW)
timeFrame: Baseline to month 24
measure: Percentage of patients with 6-months CDP in 9-Hole-Peg Test (9HPT)
timeFrame: Baseline to month 24
measure: Percentage of patients with 6-months CDP in Symbol Digit Modalities Test (SDMT)
timeFrame: Baseline to month 24
measure: Change in Multiple Sclerosis Impact Scale (MSIS-29)
timeFrame: Baseline to month 24
measure: Change in Fatigue Scale for Motor and Cognitive Functions (FSMC)
timeFrame: Baseline to month 24
measure: EuroQol- 5 Dimension (EQ-5D)
timeFrame: Baseline to month 24
measure: Percentage of patients without gadolinium-enhancing lesions (GdEL)
timeFrame: Month 6 and month 24 MRI scans
measure: Change in T2 white matter lesion volume
timeFrame: From month 6 to month 24
measure: Change in T1 white matter lesion volume
timeFrame: From month 6 to month 24
measure: Percentage brain volume change (PBVC) from month 6 to month 24
timeFrame: From month 6 to month 24
measure: Change in serum neurofilament light chain level
timeFrame: From baseline to month 24
measure: Blood levels of cluster of differentiation antigen 19 (CD19)+ B cells
timeFrame: At month 6 and month 24
Other outcomes:
measure: Antidrug antibody frequency
timeFrame: Baseline, month 6 and month 24
measure: Drug concentration
timeFrame: Month 6 and month 24
measure: 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)
timeFrame: Baseline
Locations:
city: Glostrup
country: Denmark
facility: Danish Multiple Sclerosis Center, Rigshospitalet
state: Copenhagen
city: Aalborg
country: Denmark
facility: Department of Neurology, Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Department of Neurology, Aarhus University Hospital
city: Esbjerg
country: Denmark
facility: Department of Neurology, Hospital of South West Jutland, Esbjerg
city: Herlev
country: Denmark
facility: Department of Neurology, Herlev Hospital
city: Hillerød
country: Denmark
facility: Department of Neurology, Nordsjællands Hospital i Hillerød
city: Holstebro
country: Denmark
facility: Department of Neurology, Regionshospitalet Holstebro
city: Kolding
country: Denmark
facility: Department of Neurology, Kolding Hospital
city: Odense
country: Denmark
facility: Department of Neurology, Odense University Hospital
city: Sønderborg
country: Denmark
facility: Department of Neurology, Hospital of Southern Jutland, Sønderborg
city: Viborg
country: Denmark
facility: Department of neurology, Regionshospitalet Viborg
Study officials:
affiliation: Danish Multiple Sclerosis Center Rigshospitalet
name: Jeppe Romme Christensen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: