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

Sponsor

Robert Zivadinov, MD, PhD (Other)

Overall Status

Recruiting

CT.gov ID

NCT04925557

Collaborator

(none)

Enrollment

Location

Arms

43.1

Anticipated Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Secondary-progressive Multiple Sclerosis	Drug: Mayzent Drug: Ocrevus	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 27, 2021

Anticipated Primary Completion Date :

Apr 30, 2025

Anticipated Study Completion Date :

Apr 30, 2025

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Change from baseline in PET Activation at 12 Months [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;

Secondary Outcome Measures

Change from baseline in PET activation at 6,12,24 and 36 months between Mayzent and active comparator [6, 12, 24 and 36 months]
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
Number of new ultrasmall superparamagnetic iron oxide particles [6, 12, 24 and 36 months]
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.

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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