Study to Assess the Efficacy of Mayzent on Microglia in Secondary Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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To assess the efficacy of Mayzent on microglia pathology in patients with active SPMS, as compared to the active control group of MS patients treated with the Ocrevus, as measured by changes in microglial activation in the lesional and non-lesional NAWM and NAGM and in the peri-plaque area of chronic lesions in the brain.

Detailed Description
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Multiple sclerosis (MS) is primarily a demyelinating disease of the central nervous system (CNS), but many patients also undergo progressive atrophy, especially in the gray matter (GM). GM atrophy plays a particularly prominent role in development of cognitive and physical disability in MS. Evidence is mounting that there is a profound infiltration of activated microglia and blood-borne macrophages throughout the lesions, whereas in slowly expanding (smoldering) or chronic active expanding lesions, the microglia and macrophages are concentrated as a dense rim around the lesions. Microglia is also activated, in a more diffuse way, in the white matter (WM) and GM with concomitant axonal degeneration and meningeal inflammation. Thus, chronic activation of microglia has been linked to neurodegeneration in the progressive phase of the disease and development of brain atrophy. No longitudinal studies in MS examined the association between development of microglia-related pathology in patients treated with siponimod (Mayzent®). This will be the first study to examine the treatment effect of Mayzent on microglia in MS.

Official Title
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Open-label, Single-blind, Observational, Comparative, Prospective, 36-month, Longitudinal, Controlled Study to Assess Efficacy of Siponimod (Mayzent®) on Microglia in Patients With Active Secondary Progressive Forms of Multiple Sclerosis

Conditions
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Secondary-progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: Mayzent
* Drug: Ocrevus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with active SPMS according to the Lublin 2014 criteria. Activity is determined by MRI activity (contrast-enhancing lesions; new and unequivocally enlarging T2 lesions) and/or clinical relapses in the 24 months prior to the study baseline. If the clinical MRI is not available to determine the activity (contrast-enhancing lesions; new and unequivocally enlarging T2 lesions), then a screening MRI will be offered to the subjects to determine inclusion/exclusion criteria eligibility. Age between 18 and 60 years Have EDSS scores between 3.0 and 6.5 Treatment naïve to both Mayzent and to Ocrevus Not being on S1P modulators or B-cell therapies for the last 9 months Subjects starting treatment as part of their clinical routine Be willing and able to comply with the study procedures for the duration of the trial Have given written informed consent and signed Health Insurance Portability and Accountability Act (HIPAA) authorization before any study-related activities are carried out Normal kidney functioning (creatinine clearance >59) No known hypersensitivity reactions to contrast agents None of the exclusion criteria Exclusion Criteria: Have received treatment within 30 days prior to enrollment with steroids or any other concomitant immunomodulatory therapies Have received an investigational drug or experimental procedure within the past 30 days Low affinity (LAB) for the DNA single nucleotide polymorphism (SNP) of the TSPO gene on chromosome 22q13.2, using a TaqMan assay A CYP2C9*3/*3 genotype Have experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure in the last 6 months Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker Patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests Conditions that may be associated with iron overload (e.g. hemochromatosis, thalassemia and recent blood transfusions) Patients with known hypersensitivity to Feraheme® or any of its components or a history of allergic reaction to any intravenous iron product Women who are pregnant, lactating or of childbearing age who do not consent to approved contraceptive use during the study Subjects who are scheduled for a routine diagnostic MRI exam in the next 4 weeks Other warnings and precautions to Mayzent or Ocrevus treatment according to Prescribing Information (PI) will be examined on an individual basis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ocrevus<br>Patients diagnosed with secondary-progressive multiple sclerosis who have been prescribed Ocrevus by their neurologist. | Drug: Ocrevus<br>* PET imaging to evaluate the effects of Ocrevus on the microglia of the brain.<br>|
| Active Comparator: Mayzent<br>Patients diagnosed with secondary-progressive multiple sclerosis who have been prescribed Mayzent by their neurologist. | Drug: Mayzent<br>* PET imaging to evaluate the effects of Mayzent on the microglia of the brain.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in PET Activation at 12 Months | Change from baseline in PET activation of PBR06 in lesional and non-lesional NAWM and NAGM in the brain of the patients under treatment with Mayzent when 100% of patients reach 12 months; | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in PET activation at 6,12,24 and 36 months between Mayzent and active comparator | Change from baseline in PET activation of PBR06 in lesional and non-lesional NAWM and NAGM in the brain of the patients treated with Mayzent and active control group at 6, 12, 24 and 36 months from baseline | 6, 12, 24 and 36 months | 
| Number of new ultrasmall superparamagnetic iron oxide particles | The cumulative number of new ultrasmall superparamagnetic iron oxide (USPIO) particles contrast enhancing (CE) active lesions on T1-weighted images between Mayzent and active control group, as measured at 6, 12, 24 and 36 months from baseline. | 6, 12, 24 and 36 months |