Di Lazzaro Vincenzo, Ranieri Federico, Doretti Alberto, Boscarino Marilisa, Maderna Luca, Colombo Eleonora, Soranna Davide, Zambon Antonella, Ticozzi Nicola, Musumeci Gabriella, Capone Fioravante, Silani Vincenzo
Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, Roma 00128, Italy.
Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo 21, Roma 00128, Italy.
Lancet Reg Health Eur. 2024 Jul 30;45:101019. doi: 10.1016/j.lanepe.2024.101019. eCollection 2024 Oct.
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.
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.
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).
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.
The "Fondazione 'Nicola Irti' per le opere di carità e di cultura", Rome, Italy, supported present study.
谷氨酸能传递增强导致运动神经元死亡被认为是肌萎缩侧索硬化症（ALS）的主要病理生理机制。经颅静态磁刺激（tSMS）可抑制运动皮层兴奋性，因此tSMS可作为ALS的一种潜在治疗方法进行评估。本研究的目的是调查tSMS治疗ALS的疗效和安全性。
在这项2期试验中，我们将ALS患者随机分配，在6个月的时间里每天接受tSMS或安慰剂刺激。对于每位参与者，我们计算平均疾病每月进展率（MPR），即治疗开始前（至少三个月期间）和六个月治疗期间ALS功能评定量表修订版（ALSRFS-R）总分的变化。主要疗效指标是治疗开始前后MPR的差异。次要指标包括安全性和耐受性、依从性以及皮质脊髓输出的变化。对所有完成6个月治疗的患者进行了18个月的长期随访，考虑复合终点事件（气管切开术或死亡）。该试验已在ClinicalTrials.gov注册，编号：NCT04393467，状态：已结束。
40名参与者被随机分配到实际刺激组（n = 21）或安慰剂刺激组（n = 19）。32名参与者（18名实际刺激组和14名安慰剂组）完成了6个月的治疗。两组在治疗前（平均值±标准差；实际刺激组：1.02±0.62，假刺激组：1.02±0.57，p值 = 1.00）和治疗期间（实际刺激组：0.90±0.55，假刺激组：0.94±0.55，p值 = 0.83）的MPR差异均无统计学意义。次要临床终点结果表明该治疗可行且安全，tSMS的依从性较高。两组之间皮质脊髓输出的变化无显著差异。在18个月的长期随访结束时，实际刺激组患者的无气管切开术生存率与安慰剂组相比具有统计学意义的显著提高（风险比 = 0.27，95%置信区间0.09 - 0.80，p值 = 0.019）。
tSMS在6个月的治疗期间并未改变疾病进展。然而，长期随访显示，接受实际刺激治疗的患者无气管切开术生存率大幅提高，这支持在更大规模、更长时间的研究中对tSMS进行评估。
意大利罗马的“Fondazione 'Nicola Irti' per le opere di carità e di cultura”资助了本研究。
