Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial.

Background: Enhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS. Methods: In this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed. Findings: Forty participants were randomly assigned to real (n = 21) or placebo stimulation (n = 19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean ± Standard deviation; Real: 1.02 ± 0.62, Sham: 1.02 ± 0.57, p-value = 1.00) and treatment period (Real: 0.90 ± 0.55, Sham: 0.94 ± 0.55, p-value = 0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio = 0.27 95% Confidence interval 0.09-0.80, p-value = 0.019). Interpretation: tSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies. Funding: The "Fondazione 'Nicola Irti' per le opere di carità e di cultura", Rome, Italy, supported present study.