Effects of Transcranial Static Magnetic Field Stimulation (tSMS) in Progressive Multiple Sclerosis

NCT05811013 | Recruiting

• 1 other identifier: tSMS-MS
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

In multiple sclerosis (MS) brains, inflammation induces specific abnormalities of synaptic transmission, collectively called inflammatory synaptopathy. Such synaptopathy consists in unbalanced glutamatergic and GABAergic transmission and in remarkable changes in synaptic plasticity, causing excitotoxic neurodegeneration and impairing the clinical compensation of the ongoing brain damage, thereby exacerbating the clinical manifestation of the disease. In progressive MS (PMS), synaptopathy is characterized by pathological potentatiation of glutamate-mediated synaptic up-scaling (Centonze et al., 2008; Rossi et al., 2013) and loss of long-term synaptic potentiation \[LTP (Weiss et al., 2014)\], both caused by proinflammatory molecules (released by microglia, astroglia, and infiltrating T and B lymphocytes) (Malenka et al., 2004; Di Filippo et al., 2017; Stampanoni Bassi et al., 2019). The combination of increased up-scaling and decreased LTP has a significant impact on the clinical manifestations of PMS, often presenting with signs and symptoms indicating length-dependent degeneration of neurons of the corticospinal tract. Altered LTP expression impairs brain ability to compensate ongoing neuronal loss (Stampanoni Bassi et al., 2020), and pathological TNF-mediated up-scaling may directly promote excitotoxic damage and neurodegeneration (Rossi et al., 2014). In addition, up-scaling and LTP are mutually exclusive at a given synapse through a mechanism of synaptic occlusion (i.e., pre-existing up-scaling saturates and prevents subsequent LTP expression), further promoting neurodegeneration by preventing the pro-survival effect of LTP, the induction of which activates intracellular anti-apoptotic pathways (Bartlett \& Wang, 2013). It follows that a neuromodulation approach that can chronically (over several months) dampen up-scaling expression in the primary motor cortex (M1) of PMS patients could be beneficial by preventing excitotoxic neurodegenerative damage triggered by up-scaling itself (Centonze et al. 2008, Rossi et al. 2014), and also by promoting LTP induction and LTP-dependent functional compensation of deficits, thereby reducing the speed of the neurodegeneration process through increased LTP-dependent neuronal survival and preservation of dendritic spines (Ksiazek-Winiarek et al., 2015). Our study aims to test whether transcranial static magnetic field stimulation (tSMS) could represent such a therapeutic approach, as recently proposed in patients with amyotrophic lateral sclerosis (ALS) (Di Lazzaro et al, 2021). Forty (40) ambulatory patients with PMS, presenting with the ascending myelopathy phenotype of the disease, will be recruited at the MS Center of the Unit of Neurology of the IRCCS Neuromed in Pozzilli (IS). In this randomized, sham-controlled, double-blind, within-subjects, cross-over study (allocation ratio 1:1), we will test the ability of repeated sessions of tSMS applied bilaterally over the M1 to safely reduce disability progression in patients with PMS. Patients will be randomly assigned to either real or sham tSMS. Each patient will participate in two experimental phases (real or sham stimulation). Each patient will self-administer tSMS over right and left M1, two session per day, 60 minutes each. The order will be randomly established and counterbalanced across participants. Both investigators and participants will be blinded to stimulation parameters. In the "real stimulation" phase, tSMS will be applied for 120 minutes each day, at home, for 12 consecutive months. In the "sham stimulation" phase, sham tSMS will be delivered with non-magnetic metal cylinders, with the same size, weight and appearance of the magnets. Clinical evaluations, including the Multiple Sclerosis Functional Composite measure (MSFC) will be performed before, during and after each experimental phase ("real" and "sham"). In addition, blood levels of neurofilaments, excitability and plasticity of M1, and MRI measures of cortical thickness will be measured before, during and after each stimulation phase.

Conditions

Progressive Multiple Sclerosis

Keywords

Progressive Multiple Sclerosis; transcranial Static Magnetic Field Stimulation; disability progression; cortical hyperexcitability; cortical plasticity

Outcome Measures

Primary Outcomes (1)

• Functional assessment, that "change" is being assessed.

  The primary aim the project is to evaluate the effect of tSMS in ambulatory patients with PMS with ascending myelopathy phenotype (from now on, simply called PMS) on clinical severity, assessed through the three components of the Multiple Sclerosis Functional Composite (MSFC).

  BASELINE EVALUATION 1-30 DAYS BEFORE REAL OR SHAM tSMS T0; 6 MONTHS OF STIMULATION (SESSION 1, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 1, T12); 6 MONTHS OF STIMULATION (SESSION 2, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 2, T12)

Secondary Outcomes (18)

• Neurological Assessment, that "change" is being assessed.

  BASELINE EVALUATION 1-30 DAYS BEFORE REAL OR SHAM tSMS T0; 6 MONTHS OF STIMULATION (SESSION 1, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 1, T12); 6 MONTHS OF STIMULATION (SESSION 2, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 2, T12)

• Neuropsychological and psychometric evaluation

  BASELINE EVALUATION 1-30 DAYS BEFORE REAL OR SHAM tSMS T0; 6 MONTHS OF STIMULATION (SESSION 1, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 1, T12); 6 MONTHS OF STIMULATION (SESSION 2, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 2, T12)

• Neuropsychological and psychometric evaluation

  BASELINE EVALUATION 1-30 DAYS BEFORE REAL OR SHAM tSMS T0; 6 MONTHS OF STIMULATION (SESSION 1, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 1, T12); 6 MONTHS OF STIMULATION (SESSION 2, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 2, T12)

• Neuropsychological and psychometric evaluation

  BASELINE EVALUATION 1-30 DAYS BEFORE REAL OR SHAM tSMS T0; 6 MONTHS OF STIMULATION (SESSION 1, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 1, T12); 6 MONTHS OF STIMULATION (SESSION 2, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 2, T12)

• Neuropsychological and psychometric evaluation

  BASELINE EVALUATION 1-30 DAYS BEFORE REAL OR SHAM tSMS T0; 6 MONTHS OF STIMULATION (SESSION 1, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 1, T12); 6 MONTHS OF STIMULATION (SESSION 2, T6); 1-30 DAYS AFTER THE END OF STIMULATION (SESSION 2, T12)

Study Arms (2)

Transcranial static magnetic field stimulation (tSMS)

EXPERIMENTAL

Transcranial static magnetic field stimulation (tSMS) will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months.

Device: Transcranial static magnetic field stimulation (tSMS)

Sham tSMS

SHAM COMPARATOR

Sham Transcranial static magnetic field stimulation (tSMS) Sham tSMS will be delivered with non-magnetic metal cylinders, with the same size, weight and appearance of the magnets (MAG45s; Neurek SL, Toledo, Spain). Real and sham magnets will be held with an ergonomic helmet (MAGmv1.0; Neurek SL, Toledo, Spain).

Device: Sham Transcranial static magnetic field stimulation (tSMS)

Interventions

Transcranial static magnetic field stimulation (tSMS) DEVICE

Patients will be randomly assigned to either real or sham tSMS. Real or sham tSMS will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months. Patients will choose whether to undergo stimulation at home or in the hospital on an outpatient setting. Real tSMS will be delivered with two cylindrical neodymium magnets (grade N45) of 45 mm diameter and 30 mm of thickness, with a weight of 360 g (MAG45r; Neurek SL, Toledo, Spain), applied with south polarity, each pointing toward the motor cortex. To discharge the weight of the helmet from the head during the sessions, patients will be instructed to rest the back of head and helmet on an inclined surface in a comfortable position. They will be also instructed to rest, minimizing movement, and not to watch audiovisuals during the stimulation sessions.

Transcranial static magnetic field stimulation (tSMS)

Sham Transcranial static magnetic field stimulation (tSMS) DEVICE

Real or sham tSMS will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months. Sham tSMS will be delivered with non-magnetic metal cylinders, with the same size, weight and appearance of the magnets (MAG45s; Neurek SL, Toledo, Spain).

Sham tSMS

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to give written informed consent to the study
• Age range 18-65 years
• Diagnosis of primary of secondary progressive MS according to 2017 revised Macdonald's criteria (Thompson et al., 2017), presenting with signs of symptoms of progressive dysfunction of the corticospinal tract
• EDSS ≤ 6,5
• Ability to participate to the study protocol
• No or stable (at least six months) DMT or rehabilitative treatments before study entry, and willingness not to change these therapies (including cannabinoids, SSRI, baclofen) during the study.

You may not qualify if:

• Relapsing-remitting MS or progressive MS presenting with signs of symptoms other than those typical of the ascending myelopathy phenotype (i.e. progressive cerebellar or cognitive involvement)
• Female with positive pregnancy test at baseline or having active pregnancy plans
• Comorbidities for which synaptic plasticity may be altered (i.e., Parkinson's disease, Alzheimer's disease, stroke)
• Contraindications to TMS
• History or presence of any unstable medical condition such as malignancy or infection
• Use of medications with increased risk of seizures (i.e. Fampridine, 4-Aminopyridine)
• Concomitant use of drugs that may alter synaptic transmission and plasticity (L-dopa, antiepileptics)

Sponsors & Collaborators

• Neuromed IRCCS: lead

Study Sites (1)

IRCCS Neuromed

Pozzilli, Isernia, 86077, Italy

RECRUITING

Related Publications (25)

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MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Diego Centonze, MD, PhD

CONTACT

+39 0865 929170; centonze@uniroma2.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: All patients, caregivers, and investigators assessing outcomes will be blind to the intervention assignment.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Neurology Unit

Model Details: We will conduct a randomized, sham-controlled, double-blind, within-subjects, cross-over study (allocation ratio 1:1) to test the ability of repeated sessions of tSMS to safely reduce disability progression in patients with PMS.

Study Record Dates

• First Submitted: March 16, 2023
• First Posted: April 13, 2023
• Study Start: May 27, 2023
• Primary Completion: May 27, 2025
• Study Completion (Estimated): May 27, 2026
• Last Updated: October 16, 2024

Record last verified: 2024-10

Locations

IT (1)