Repetitive TMS for ALS

(QuARTS-ALS Trial)

Overseen by Sean Nestor, Dr.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

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

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing a high dose magnetic pulse therapy on ALS patients. The therapy uses magnetic fields to stimulate brain areas, which may help improve symptoms like muscle strength and function. Magnetic pulse therapy has been studied for its potential to improve motor function and muscle strength in various neurological conditions, including 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 data supports the effectiveness of the treatment Repetitive Transcranial Magnetic Stimulation (rTMS) for ALS?

Repetitive Transcranial Magnetic Stimulation (rTMS) has been suggested to potentially modify the rate of disease progression in ALS, although the treatment of ALS remains challenging. Additionally, rTMS is known to affect motor pathways and cortical excitability, which are relevant in ALS. ^{1 2 3 4 5}

Is repetitive transcranial magnetic stimulation (rTMS) safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) has been studied for safety since the 1990s, with guidelines developed to minimize risks. While generally considered safe, it can cause seizures in rare cases and may have other side effects like cognitive changes. Safety guidelines have been updated over the years to ensure its safe use in both healthy individuals and those with neuropsychiatric conditions. ^{6 7 8 9 10}

How is repetitive transcranial magnetic stimulation (rTMS) different from other treatments for ALS?

Repetitive transcranial magnetic stimulation (rTMS) is unique because it uses magnetic fields to noninvasively stimulate the brain's motor cortex, potentially modulating neurotransmission and altering disease progression in ALS. Unlike traditional drug treatments, rTMS directly targets brain activity and may help improve motor performance and quality of life. ^{3 4 11 12 13}

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

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Repetitive Transcranial Magnetic Stimulation (Procedure)

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.

Participant Groups

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 Canada for the following indications:

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+

Dr. Rajin Mehta

Sunnybrook Health Sciences Centre

Chief Medical Officer

MD from University of Toronto

Dr. Andrew J. Smith

Sunnybrook Health Sciences Centre

President and CEO since 2017

MD, MSc from University of Toronto; Surgical Oncology Fellowship at Memorial Sloan-Kettering Cancer Center

Findings from Research

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) 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]

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]

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) 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]

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]

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]

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]

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) 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Cortical muscle representation in amyotrophic lateral sclerosis patients: changes with disease evolution. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Further evidence for corticomotor hyperexcitability in amyotrophic lateral sclerosis. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation of motor pathways directed to muscles supplied by cranial nerves in amyotrophic lateral sclerosis. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis. [2008]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Assessing the upper motor neuron in amyotrophic lateral sclerosis using the triple stimulation technique: A multicenter prospective study. [2021]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

7. Ireland 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. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Side effects of repetitive transcranial magnetic stimulation. [2005]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Assessment of safety of self-controlled repetitive trans-vertebral magnetic stimulation. [2021]

10. United States 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. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Motor cortex stimulation for amyotrophic lateral sclerosis. Time for a therapeutic trial? [2008]

12. United States pubmed.ncbi.nlm.nih.gov

Single-pulse transcranial magnetic stimulation in amyotrophic lateral sclerosis. [2020]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Utility of transcranial magnetic stimulation in delineating amyotrophic lateral sclerosis pathophysiology. [2018]