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

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

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.

Study Overview

• Status: Completed
• Conditions: Secondary-progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Ocrevus; Drug: Mayzent

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Robert Zivadinov, MD, PhD; Phone Number: 716-859-7040; Email: rzivadinov@bnac.net
• Study Contact Backup: Name: Cheryl Kennedy, LMSW, MPH; Phone Number: 716-888-4847; Email: ckennedy@bnac.net

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14203
      • University at Buffalo, Buffalo General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI Measures between Mayzent and control-treated groups (PBVC)	Percent brain volume change (PBVC) between baseline and 12, 24, and 36 months	12, 24 and 36 months
MRI Measures between Mayzent and control-treated groups (PCVC)	Percent cortical volume change (PCVC), between baseline and 12, 24, and 36 months	12, 24 and 36 months
MRI Measures between Mayzent and control-treated groups(PTVC)	Percent thalamus volume change (PTVC) between baseline and 12, 24, and 36 months	12, 24 and 36 months
MRI Measures between Mayzent and control-treated groups (QSM)	Quantitative susceptibility mapp (QSM) change between baseline and 12, 24, and 36 months	12, 24 and 36 months
Cumulative number of new gadolinium CE lesions	The cumulative number of new gadolinium CE lesions on T1-weighted images at months 6, 12, 24 and 36 months	6, 12, 24 and 36 months
Cumulative number of new or newly enlarging T2 lesions	The cumulative number of new or newly enlarging hyperintense T2 lesions measured at months 6, 12, 24 and 36 months	6, 12, 24 and 36 months
Absolute change in Hyperintense T2 Lesions volume	The absolute change in hyperintense T2-lesion volume (LV) measured at months 6, 12, 24 and 36 months	6, 12, 24 and 36 months
Absolute change in Hypo-intense T1 Lesions volume	The absolute change in hypo-intense T1-lesion volume (LV) measured at months 6, 12, 24 and 36 months	6, 12, 24 and 36 months
Absolute change in serum neurofilament and glial protein	The absolute change in serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) at 6, 12, 24 and 36 months	6, 12, 24 and 36 months
Association between imaging and clinical and cognitive outcomes	The association between imaging and clinical and cognitive outcomes, incl. the composite EDSS+SDMT, over 24 and 36 months of the study	24 and 36 months
Number of participants with Treatment related adverse events	Safety of Mayzent and active control group over 12, 24, and 36 months of the study	12, 24, and 36 months

Collaborators and Investigators

• Sponsor: State University of New York at Buffalo

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2021
• Primary Completion (Actual): June 1, 2023
• Study Completion (Actual): August 5, 2023

Study Registration Dates

• First Submitted: May 24, 2021
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Disease Attributes; Neoplastic Processes; Chronic Disease; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Ocrelizumab; Siponimod
• Other Study ID Numbers: 00003884

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No