Quantitative and Repetitive TMS in ALS

Study Overview
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Brief Summary
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The goal of this open-label pilot clinical trial is to evaluate the safety, tolerability and target engagement of accelerated, high dose continuous theta-burst stimulation (cTBS) using transcranial magnetic stimulation (TMS) in patients with ALS.

Detailed Description
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The purpose of this study is to: Evaluate the safety and feasibility of cTBS neuromodulation with bilateral repetitive TMS treatment using an accelerated schedule in patients with ALS. Assess the changes in corticospinal excitability using quantitative single- and paired-pulse TMS measures. Assess the changes in MR spectroscopy of glutamate and GABA spectra after cTBS neuromodulation.

Official Title
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A Biomarker-Directed Neuromodulation Trial Using Quantitative and Repetitive Transcranial Magnetic Stimulation in Amyotrophic Lateral Sclerosis (The QuARTS-ALS Trial)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Device: Repetitive Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis with ALS as per the 2020 Gold Coast Criteria; Age ≥ 18 years; Able to provide informed consent to study procedures and treatments; If taking Riluzole, must be on a stable dose for at least 12 weeks prior to Baseline; If undergoing Edaravone treatment, must be on a stable dose of at least one completed cycle (IV or Oral Edaravone) prior to Baseline; If taking AMX005, must be on stable dose for at least 4 weeks prior to Baseline; Manual muscle testing with MRC score ≥4- AND nerve conduction study CMAP amplitude ≥1.0mV in the first dorsi interosseous (FDI) on at least one side; Able to tolerate TMS procedures; Obtainable corticospinal excitability parameters at Baseline; Able to lie supine without BiPAP or breathing discomfort for at least 1 hour; Exclusion Criteria: Known diagnosis of dementia; Definitely or possibly pregnant (if applicable); History of allergy to Ag-AgCl electrode gel (standard neurophysiology electrodes); Any contraindications to TMS as follow: Metal implants in the head or neck (such as aneurysm clips, vessel stents), implanted medication pump, implanted brain stimulators, pacemaker, cochlear implants, or history of epilepsy. Dental fillings are permitted; Current use of an antipsychotic or antiarrhythmic medication; On medications that affect TMS measures in a PRN regimen (as needed). Continuous use of these medications on a fixed dose of 30 days prior to first Baseline Visit or after a wash-out period of 2 weeks is accepted. These medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants, selective and non-selective serotonin reuptake inhibitors, hypnotics (including anti-histamine drugs) and anticholinergics drugs; History of seizure, convulsion, or epilepsy; Any contraindications to MRI such as: Large body habitus and not fitting comfortably into the scanner; Difficulty laying still for up to 1 hour in the MRI unit or significant claustrophobia; Metallic implants; Any contraindications for receiving rTMS treatment as follow: have received rTMS for any previous indication due to the potential compromise of subject blinding; have increased intracranial pressure, a space occupying brain lesion, any history of seizure except those therapeutically induced by ECT or a febrile seizure of infancy, significant head trauma with clear radiological evidence of cerebrovascular injury on imaging; have an intracranial implant or any other metal object within or near the head, excluding the mouth, that cannot be safely removed; have clinically significant laboratory abnormality, in the opinion of the one of the principal investigators or study physicians; are currently taking more than lorazepam 2 mg daily (or equivalent) or any dose of an anticonvulsant due to the potential to limit rTMS efficacy; Any other clinical condition that, in the opinion of the Site Investigator, would place the subject at increased risk or preclude the subject's full compliance with completion of the study.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: A prospective, single-arm, open-label pilot trial evaluating the safety, feasibility and changes in corticospinal excitability biomarkers after accelerated repetitive transcranial magnetic stimulation (rTMS) using continuous theta burst stimulation (cTBS) inhibitory paradigms over the bilateral primary motor cortex (M1) in patients with ALS.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Accelerated cTBS Neuromodulation<br>ALS patients receiving an accelerated schedule of continuous theta burst rTMS bilaterally at a regimen of 40 seconds per treatment, for up to 8 treatment sessions per day, delivered one per hour, over 5 days. | Device: Repetitive Transcranial Magnetic Stimulation<br>* Accelerated rTMS using continuous theta burst stimulation inhibitory paradigms over bilateral M1 hand region outputted at 90% of resting motor threshold, using bursts of 3 pulses at 50 Hz. Bursts are repeated at 5 Hz for a total of 600 pulses over 40 seconds. ALS patients will receive rTMS bilaterally at a regimen of cTBS for 40 seconds per treatment, for up to 8 treatment sessions per day, delivered one per hour, over 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Feasibility of cTBS rTMS in patients with ALS | Incidence of AEs and SAEs after accelerated continuous theta burst stimulation inhibitory intervention in individuals with ALS through the incidence of repetitive TMS treatment related adverse events, serious adverse events, discontinuations due to adverse events/serious adverse events, or accelerated ALS disease progression as defined by ≥6-point decline in the ALSFRS-R scores. | One Week before, and One and Three Weeks after cTBS treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Corticospinal Excitability change measured by TMS Resting Motor Threshold | Change from baseline in Resting Motor Threshold (RMT) | One and Three Weeks after cTBS treatment | 
| Corticospinal Excitability change measured by TMS Short Intracortical Inhibition | Change from baseline in Short Intracortical Inhibition (SICI) | One and Three Weeks after cTBS treatment | 
| Corticospinal Excitability change measured by TMS Short Intracortical Facilitation | Change from baseline in Short Intracortical Facilitation (SICF) | One and Three Weeks after cTBS treatment | 
| Corticospinal Excitability change measured by TMS Cortical Silent Period | Change from baseline in Cortical Silent Period (CSP) | One and Three Weeks after cTBS treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Corticospinal Excitability, Repetitive transcranial magnetic stimulation, Motor Neuron Disease, MR Spectroscopy, Cortical Hyperexcitability, ALS