Comparative Study of High-Efficacy Disease Modifying Treatment of Relapsing Multiple Sclerosis (CoSHEDRMS)

The goal of this prospective, multi-center, non-blinded, non-randomized, non-intervention clinical trial is to compare immunologic, virologic and epigenetic factors in patients with active multiple sclerosis in standard 2.line treatment with ocrelizumab, rituximab, ofatumumab or natalizumab in Region Midt, Denmark. It aims to answer how the immunologic, virologic and epigenetic response in these patients are compared to healthy controls, and analyze their treatment effect in relation to this response. Participants will get an extra blood sample, when they have their routine blood samples taken.

Study Overview

• Status: Recruiting
• Conditions: Relapsing Remitting Multiple Sclerosis
• Intervention / Treatment: Other: Blood samples

Detailed Description

The CoSHED RMS study will include patients with active multiple sclerosis aged 18-65 years fulfilling the criteria for 2. line treatment and starting treatment with one of the four high-efficacy disease modifying treatments ocrelizumab, rituximab, ofatumumab or natalizumab. Researchers will compare immunologic, virologic and epigenetic parameters in the four treatment groups to a age and gender matched healthy control group. The study duration is 12 months, and patients can continue in an extension phase for additional 12 month. The primary endpoint is changes in B cell populations between the four treatments within 12 months. The study will evaluate a number of efficacy and safety endpoints using clinical, MRI, routine blood samples and research biomarkers.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Camilla Mærsk-Møller, MD; Phone Number: +4521392792; Email: cammae@rm.dk
• Study Contact Backup: Name: Morten Stilund, MD; Phone Number: +4578430926; Email: mortstil@rm.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Recruiting
    • Aarhus University
    • Contact: Helene Nørrelund; Phone Number: +4593508486; Email: hwn@au.dk
    • Contact: Camilla Mærsk-Møller, MD; Phone Number: +4521392792; Email: cammae@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Multiple sclerosis diagnosis and definition of disease course according to the 2017 McDonald criteria
• Expanded disability status scale (EDSS) ≤6.5
• Signed written informed consent

• 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

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, rituximab, ofatumumab or natalizumab

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Ocrelizumab; Patients with active multiple sclerosis starting standard treatment with ocrelizumab	Other: Blood samples; Extra blood samples
Other: Rituximab; Patients with active multiple sclerosis starting standard treatment with rituximab	Other: Blood samples; Extra blood samples
Other: Ofatumumab; Patients with active multiple sclerosis starting standard treatment with ofatumumab	Other: Blood samples; Extra blood samples
Other: Natalizumab; Patients with active multiple sclerosis starting standard treatment with natalizumab	Other: Blood samples; Extra blood samples
Other: Healthy controls; An age and gender matched healthy control group	Other: Blood samples; Extra blood samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in B cell populations	Changes in B cell populations in the four treatment groups	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapses	Number of patients with relapse or relapses from start of treatment from baseline to 12 months	1 year
Annualized Relapse Rate	Annualized Relapse Rate based on the total amount of relapses per year from baseline to 12 months	1 year
T-cells, B-cell subsets and monocyte-subsets	Changes in frequency of T-cells, B-cell-subsets and monocyte-subsets from baseline, 6 months and to 12 months	1 year
EBV	Changes in Epstein Barr-Virus DNA load from baseline, 6 months and to 12 months	1 year
HERVs	Changes in Human Endogenous Retrovirus expression from baseline, 6 months and to 12 months	1 year
Complement	Changes in complement system activity from baseline, 6 months and to 12 months	1 year
MRI lesions	Changes in number of lesions on MRI scans of the brain from baseline, 6 months and to 12 months	1 year

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; Regionshospitalet Viborg, Skive; Gødstrup Hospital; Sorbonne University
• Investigators: Study Director: Morten Stilund, MD, University of Aarhus

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2023
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: November 28, 2023
• First Submitted That Met QC Criteria: November 28, 2023
• First Posted (Estimated): December 7, 2023

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Other Study ID Numbers: CoSHED

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: After finishing the study, available for 1 year
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• 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