Repetitive TMS for ALS

(QuARTS-ALS Trial)

Overseen By Sean Nestor, Dr

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Sunnybrook Health Sciences Centre

Must be taking: Riluzole, Edaravone

Must not be taking: Anticonvulsants, High-dose lorazepam

Disqualifiers: Dementia, Pregnancy, Seizure history, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for people with ALS, a progressive disease affecting nerve cells in the brain and spinal cord, using a technique called repetitive transcranial magnetic stimulation (rTMS). Researchers aim to determine if this treatment is safe and well-tolerated, while also assessing its effectiveness in targeting brain areas affected by ALS. The trial is currently enrolling participants diagnosed with ALS who can lie comfortably for an hour without breathing discomfort. As an unphased trial, this study offers participants the chance to contribute to pioneering research that could lead to new treatment options for ALS.

Will I have to stop taking my current medications?

You can continue taking standard ALS treatments like riluzole and edaravone. If you're on medications that affect TMS, you need to be on a stable dose for 30 days before starting or have a 2-week break from them. Check with the trial team about any other medications you are taking.

What prior data suggests that this technique is safe for ALS patients?

Research shows that repetitive transcranial magnetic stimulation (rTMS) is generally safe for people with ALS. Various studies have tested rTMS for safety and potential side effects. Most participants did not experience serious issues. The most common side effects included mild headaches or slight discomfort at the treatment site, which typically resolved on their own.

One study found that participants who underwent rTMS reported only mild, temporary side effects. This finding suggests that rTMS is safe for most people and does not cause major harm. While further research is necessary, current evidence indicates that rTMS is a promising and safe treatment option for ALS. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Repetitive Transcranial Magnetic Stimulation (rTMS) for ALS is unique because it uses magnetic fields to stimulate nerve cells in the brain, potentially slowing the progression of this neurodegenerative disease. Unlike standard treatments, which primarily focus on managing symptoms through medications like riluzole and edaravone, rTMS offers a non-invasive approach that directly targets the brain's motor areas. Researchers are excited about this technique because it provides a novel way to potentially enhance neural plasticity and improve motor function, offering hope for more effective management of ALS.

What evidence suggests that repetitive TMS might be an effective treatment for ALS?

Research shows that repetitive transcranial magnetic stimulation (rTMS) might benefit people with ALS, a disease affecting nerves and muscles. Some studies suggest that rTMS can improve symptoms and enhance quality of life. For example, one study found that rTMS might help with cognitive issues in ALS patients, easing the workload for their caregivers. While rTMS is not a cure, early research indicates it could be a promising way to manage ALS symptoms. In this trial, participants will receive an accelerated schedule of continuous theta burst rTMS, which uses magnetic fields to stimulate brain cells and might help slow some effects of the disease. ^{3 5 6 7 8}

Who Is on the Research Team?

Agessandro Abrahao, Dr

Principal Investigator

Sunnybrook Health Sciences Centre; University of Toronto

Lorne Zinman, Dr

Principal Investigator

Sunnybrook Health Sciences Centre; University of Toronto

Sean Nestor, Dr.

Principal Investigator

Sunnybrook Research Institute; University of Toronto

Are You a Good Fit for This Trial?

This trial is for adults with ALS who can lie down comfortably for an hour, give informed consent, and have been on stable doses of certain ALS medications. They must be able to tolerate TMS procedures and meet specific muscle strength and nerve conduction criteria. People with metal implants in the head/neck, pacemakers, severe claustrophobia, or those on certain medications that affect TMS cannot participate.

Inclusion Criteria

Able to provide informed consent to study procedures and treatments

I have been diagnosed with ALS according to the 2020 criteria.

I can lie on my back without needing breathing support for at least an hour.

Exclusion Criteria

I have been diagnosed with dementia.

I have a history of seizures or epilepsy.

I am currently taking medication for psychosis or heart rhythm problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Up to 4 weeks

Treatment

Participants receive accelerated cTBS treatment with maintenance cTBS treatments over a 24-week period

24 weeks

8 treatment sessions per day for 5 days, followed by maintenance treatments every 2 weeks for 12 weeks, then every 4 weeks for 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Extension

Participants may continue to receive maintenance treatments as part of an open-label extension

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Repetitive Transcranial Magnetic Stimulation

Trial Overview The study tests the safety and effectiveness of a high dose continuous theta-burst stimulation (cTBS) using transcranial magnetic stimulation (TMS) in ALS patients. It's an open-label pilot trial where all participants receive the same treatment without any placebo control.

How Is the Trial Designed?

Group I: Accelerated cTBS Neuromodulation Experimental Treatment 1 Intervention

Stage 2 \[CURRENTLY ENROLLING\]: ALS patients receiving an accelerated schedule of continuous theta burst rTMS bilaterally at multiple M1 regions at a regimen of 40 seconds, 1 minute 20 seconds, 2 minutes, or 4 minutes per treatment for up to 8 treatment sessions per day, delivered one per hour, over 5 days. Additional single-day maintenance treatments will follow these 5 days at a frequency of every 2 weeks for 12 weeks, then every 4 weeks for 12 weeks.

Repetitive Transcranial Magnetic Stimulation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Migraines

Approved in European Union as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Anxiety disorders

Approved in Canada as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Published Research Related to This Trial

Repetitive transcranial magnetic stimulation (rTMS) has not been thoroughly studied for side effects, with the main known risk being the acute production of seizures.

While tissue damage from rTMS is unlikely, there are concerns about potential cognitive effects and the possibility of long-term changes in brain function that have not yet been fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of repetitive transcranial magnetic stimulation. Wassermann, EM.[2005]

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

Self-controlled repetitive trans-vertebral magnetic stimulation (rTVMS) was found to be safe, with no serious adverse events reported in a study involving 30 healthy volunteers and 12 patients with spinal cord disorders across 1690 trials.

While minor discomfort was reported in about 10% of trials, rTVMS did not significantly affect blood pressure in patients and even increased peripheral oxygen saturation in healthy volunteers, suggesting its potential for safe use in both research and treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of safety of self-controlled repetitive trans-vertebral magnetic stimulation. Sasada, S., Kadowaki, S., Tazoe, T., et al.[2021]

In a study involving 18 subjects with major depression, repetitive transcranial magnetic stimulation (rTMS) for up to 4 weeks was found to be generally safe, with no significant mean deficits in neuropsychologic function or auditory thresholds.

However, two patients experienced mild high-frequency hearing loss, indicating that while rTMS is safe for most, individual responses may vary and warrant further investigation into long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. Loo, C., Sachdev, P., Elsayed, H., et al.[2019]

In a preliminary study involving 20 transgenic rats and 4 ALS patients, low-frequency rTMS (1 Hz) was well tolerated and showed a slight slowing of disease progression in patients, while high-frequency rTMS (20 Hz) did not yield beneficial effects.

Despite no observable effects in the rat model, the findings in ALS patients suggest that low-frequency rTMS may offer a new therapeutic avenue for further exploration in managing ALS, warranting larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motor cortex stimulation for amyotrophic lateral sclerosis. Time for a therapeutic trial? Di Lazzaro, V., Oliviero, A., Saturno, E., et al.[2008]

Transcranial magnetic stimulation (TMS) using the triple stimulation technique (TST) was found to be more sensitive than conventional TMS in detecting upper motor neuron (UMN) dysfunction in 98 ALS patients, with 62% showing decreased TST amplitude ratios compared to 25% for conventional TMS.

The TST amplitude ratio correlated well with clinical measures of disease severity, such as the ALS Functional Rating Scale (ALSFRS-R), indicating that TST can be a valuable tool in routine clinical practice for assessing UMN dysfunction in ALS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing the upper motor neuron in amyotrophic lateral sclerosis using the triple stimulation technique: A multicenter prospective study. Grapperon, AM., Verschueren, A., Jouve, E., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool that can effectively treat clinical depression and potentially other brain disorders, but it carries risks, including the potential to induce seizures, as evidenced by 7 known cases by 1996.

A workshop established safety guidelines for rTMS, emphasizing the importance of monitoring, ethical considerations, and the expertise required for its administration to minimize risks and enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Wassermann, EM.[2022]

In a study of 11 patients with amyotrophic lateral sclerosis (ALS) over 11.6 months, transcranial magnetic stimulation (TMS) mapping revealed a significant decrease in map area by 25% and normalized volume by 47%, indicating progressive cortical neuronal loss.

The study found that changes in TMS map parameters were more sensitive indicators of cortical cell loss compared to other TMS measures, suggesting that TMS mapping could be a valuable tool for monitoring disease progression in ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cortical muscle representation in amyotrophic lateral sclerosis patients: changes with disease evolution. de Carvalho, M., Miranda, PC., Luís, ML., et al.[2019]

In a study involving 10 healthy subjects and 10 patients with amyotrophic lateral sclerosis (ALS), it was found that ALS patients exhibited significantly greater repetitive firing of motoneurons in response to transcranial magnetic stimulation (TMS), indicating a heightened excitability of the motor pathways.

The results suggest that ALS may lead to increased corticomotor hyperexcitability, either at the level of the spinal motoneurons or in the motor cortex, which could have implications for understanding the disease's impact on motor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Further evidence for corticomotor hyperexcitability in amyotrophic lateral sclerosis. Naka, D., Mills, KR.[2019]

Transcranial magnetic stimulation (TMS) has been shown to reveal early cortical dysfunction in ALS, indicating that hyperexcitability in the motor cortex may precede clinical symptoms, suggesting a central origin of the disease.

TMS techniques can effectively differentiate ALS from other similar disorders, highlighting their potential as a diagnostic tool in identifying ALS despite the presence of peripheral symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utility of transcranial magnetic stimulation in delineating amyotrophic lateral sclerosis pathophysiology. Vucic, S., Kiernan, MC.[2018]

In a pilot study involving 10 ALS patients, 5-Hz repetitive transcranial magnetic stimulation (rTMS) showed temporary improvements in motor function and quality of life compared to sham treatment after two weeks of daily sessions.

The observed benefits, including increased muscle strength and quality of life, were not sustained two weeks after the treatment ended, highlighting the need for further research through a double-blind therapeutic trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis. Zanette, G., Forgione, A., Manganotti, P., et al.[2008]

In a study of 55 patients with amyotrophic lateral sclerosis (ALS) monitored over 24 months, transcranial magnetic stimulation (TMS) effectively identified changes in the corticospinal tract, particularly through increased central motor conduction time (CMCT), which indicated upper motor neuron involvement.

TMS demonstrated that as ALS progressed, markers like resting motor threshold and CMCT increased linearly with disease duration, suggesting that TMS could be a valuable tool for early detection of upper motor neuron issues in ALS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-pulse transcranial magnetic stimulation in amyotrophic lateral sclerosis. Civardi, C., Collini, A., Mazzini, L., et al.[2020]

Transcranial magnetic stimulation (TMS) effectively detects abnormalities in central motor circuits in ALS patients, with 96% showing significant central or peripheral motor pathway involvement.

The study found a strong correlation between TMS results and clinical severity, suggesting that TMS can provide valuable early diagnostic information about ALS by assessing cranial muscle function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation of motor pathways directed to muscles supplied by cranial nerves in amyotrophic lateral sclerosis. Desiato, MT., Bernardi, G., Hagi H, A., et al.[2019]

Citations

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Trial: Repetitive Transcranial Magnetic Stimulation as Th... The purpose of this study is to compare the effectiveness of rTMS in improving the depression in patients with ALS with placebo stimulation.

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The effect of repetitive transcranial magnetic stimulation on ... The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis.