Clinical trial NCT05983211: Quantitative and Repetitive TMS in ALS - Recruiting for Stage 2
Official title: A Biomarker-Directed Neuromodulation Trial Using Quantitative and Repetitive Transcranial Magnetic Stimulation in Amyotrophic Lateral Sclerosis (The QuARTS-ALS Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS
Repetitive transcranial magnetic stimulation
Corticospinal Excitability
Motor Neuron Disease
MR Spectroscopy
Cortical Hyperexcitability
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
First posted: 2023-08-09
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Stage 1 \[Enrolment closed\]:

A prospective, single-arm, open-label pilot trial evaluating the safety, feasibility and changes in neuronal excitability biomarkers of accelerated rTMS using cTBS inhibitory paradigms over M1 in patients with ALS

Stage 2 \[CURRENTLY ENROLING\]:

A prospective, single-arm, open-label pilot trial evaluating the safety, target engagement via biomarkers, and dose discovery of multi-targeted, accelerated continuous theta burst stimulation (cTBS) regimen of repetitive transcranial magnetic stimulation (rTMS) over multiple primary motor cortex (M1) regions bilaterally with repeated maintenance cTBS sessions for 24 weeks in patients with ALS.
Primary purpose: TREATMENT

Brief summary: Stage 1 \[Enrolment closed\]:

The goal of this open-label pilot clinical trial is to evaluate the safety and feasibility of accelerated, repetitive transcranial magnetic stimulation (rTMS) using continuous theta-burst stimulation (cTBS) in patients with ALS.

Stage 2 \[CURRENTLY ENROLLING\]:

The goal of this open-label pilot clinical trial is to evaluate the safety, tolerability and target engagement of accelerated, high dose cTBS using TMS in patients with ALS.

Detailed description: Stage 1 \[Enrolment closed\]:

The purpose of this stage is to evaluate the safety, feasibility, and changes in neuronal excitability biomarkers of accelerated repetitive transcranial magnetic stimulation (rTMS) using continuous theta-burst stimulation (cTBS) inhibitory paradigms over M1 in patients with ALS.

Stage 2 \[CURRENTLY ENROLLING\]:

The purpose of this study is to:

1. Assess the safety and feasibility of accelerated cTBS treatment with maintenance cTBS treatments in individuals with ALS over a 24-week period.
2. Assess changes in MR spectroscopy measures of glutamate and GABA, ATP and metabolites markers, and neuronal structure markers, changes in serum neurofilament light chain, and changes in corticohyperexcitability biomarkers measured by single and paired pulse quantitative TMS.
3. Assess the changes in ALSFRS-R and muscle strength dynamometry.

Eligibility criteria: 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;
* Patients are allowed to start or continue the standard of care treatments for ALS. Presently these include oral riluzole, and oral or intravenous edaravone;
* Able to lie supine without BiPAP or breathing discomfort for at least 1 hour;
* No 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 medications or medical conditions that, at the discretion of the Principal Investigator, could potentially increase the risk of seizures or interfere with stage outcomes;
* 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, but are not limited to: 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;

Exclusion Criteria:

* Known diagnosis of dementia;
* Definitely or possibly pregnant (if applicable);
* History of allergy to Ag-AgCl electrode gel (standard neurophysiology electrodes);
* Unable to tolerate TMS procedures;
* Lack of MRI brain performed prior to the stage, inability to perform an MRI at baseline due to orthopnea, or:
* 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 stage.

Primary outcomes:
measure: Safety and Feasibility of cTBS rTMS in patients with ALS
timeFrame: Up to 30 days before compared to during the initial 5 days of cTBS treatment and up to 24 weeks after
Secondary outcomes:
measure: Neurofilament light chain (NfL) levels
timeFrame: Up to 30 days before compared to the last treatment day, 12 weeks, and 24 weeks after cTBS treatment
measure: ALSFRS-R scores
timeFrame: Up to 30 days before compared to 12 and 24 weeks after cTBS treatment
measure: Corticospinal Excitability change measured by quantitative TMS
timeFrame: Up to 30 days before compared to 12 and 24 weeks after cTBS treatment
measure: Magnetic Resonance Spectroscopy parameters as measured by MRS
timeFrame: Up to 30 days before compared to the end of treatment week, 5 weeks, 12 weeks, and 24 weeks after cTBS treatment
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre; University of Toronto
name: Agessandro Abrahao, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Centre; University of Toronto
name: Lorne Zinman, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Research Institute; University of Toronto
name: Sean Nestor, Dr.
role: PRINCIPAL_INVESTIGATOR
References: