Testing Pulse Stimulation to Improve Motor Function in People With ALS: A Pilot Study (TPS4ALS)

Modulation of the Motor Pathway by Transcranial Pulse Stimulation in People With ALS: a Pilot Randomized Trial

The goal of this clinical trial is to assess the efficacy of TPS of the motor cortex on biomarkers and clinical endpoints in patients with ALS. The main questions it aims to answer are:

• Stage 1: Is there a change in the short intracortical inhibition (SICI) of the motor cortex from baseline to week 8?
• Stage 2: Is there a change from baseline to month 6 in the ALS functional rating scale-revised (ALSFRS-R) total score?

In stage 2, researchers will compare the group receiving the stimulation vs the group receiving a sham stimulation to see if there is a difference in motor cortex activity and in the ALSFRS-R score

Participants will receive either:

• the TPS treatment
• a sham TPS treatment

Study Overview

• Status: Recruiting
• Conditions: Amyotrophic Lateral Sclerosis (ALS)
• Intervention / Treatment: Device: Transcranial Pulse Stimulation

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alba Leon, MD; Phone Number: +34932 48 30 00; Email: aleonjorba@psmar.cat

Study Locations

• Spain
  • Catalonia
    • Barcelona, Catalonia, Spain, 08003
      • Recruiting
      • Hospital Del Mar
      • Contact: Sergio Vidal, MD; Phone Number: +34932 48 30 00; Email: sergio.vidal.notari@psmar.cat
      • Principal Investigator: Alba Leon, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with diagnosis of sporadic ALS (definite or clinically probable) as defined by the World Federation of Neurology revised El Escorial criteria
• SVC of 50% or greater of estimated measure and presence of measurable motor evoked potential
• 21 to 80 years old and male or female

Exclusion Criteria:

• patients with fALS (based on medical history) that are unable to tolerate TMS and MRI studies or have a contraindication as described below

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TPS; The stimulation will be 20 min duration as indicated in the CE mark approval. Each session involves 6,000 pulses in the hand region of the motor cortex with 3,000 on each side of the brain. The system uses a low energy flux density maximum of 0.25 mJ/mm2 accordingly with EMA and FDA guidelines (high energy is defined as > 0.5 mJ/mm2). The standard therapy involves 6 sessions in 2 weeks as indicated in the CE mark.	Device: Transcranial Pulse Stimulation; low intensity shock-waves stimulation of the motor cortex, bilateral
Sham Comparator: sham; The transcranial pulse stimulation with the same device and the same protocol uses a membrane on the device that blocks the sound waves. Participants' motor cortex is not stimulated.	Device: Transcranial Pulse Stimulation; low intensity shock-waves stimulation of the motor cortex, bilateral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the short intracortical inhibition (SICI) of the motor cortex from baseline to week 8.		baseline to week 8
Change from baseline to month 6 in the ALS functional rating scale-revised (ALSFRS-R) total score	The ALS Functional Rating Scale-Revised Each function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Higher scores mean a better outcome.	baseline to week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change plasma neurofilament light chain (NfL) levels		baseline to week 4 and 8
Changes in muscle strength, assessed by the Medical Research Council (MRC) sum score		baseline to week 4 and 8
Changes in hand-held dynamometry		baseline to week 8
Differences (treated vs sham) and change in the slow vital capacity (SVC)		from baseline to month 6
Differences (treated vs sham) and change in plasma NfL levels	Candidate biomarkers are: SOD1, Ataxin 2, C90rf72, UNC13A, TDP43, stathmin 2, NfL and NfH levels	baseline to month 6
Change in Motor Evoked Potential (MEP) Amplitudes	ppTMS will be used to assess changes in motor cortex excitability via MEP amplitude (measured in millivolts)	baseline to week 4 and 8
Change in Resting Motor Threshold	RMT will be recorded to assess baseline motor cortex excitability (measured as a percentage of maximum stimulator output)	baseline to week 4 and 8
Change in Intra-Cortical Facilitation	ICF will be measured to assess synaptic excitability	baseline to week 4 and 8

Other Outcome Measures

Outcome Measure	Time Frame
Change in biomarker SOD1 Levels in nEVs from Plasma	baseline to week 4 and 8
Change in biomarker Ataxin 2 Levels in nEVs from Plasma	baseline to week 4 and 8
Change in biomarker C9orf72 Levels in nEVs from Plasma	baseline to week 4 and 8
Change in biomarker UNC13A Levels in nEVs from Plasma	baseline to week 4 and 8
Change in biomarker TDP43 Levels in nEVs from Plasma	baseline to week 4 and 8
Change in biomarker Stathmin 2 Levels in nEVs from Plasma	baseline to week 4 and 8
Change in NfH Levels in nEVs from Plasma	baseline to week 4 and 8

Collaborators and Investigators

• Sponsor: Parc de Salut Mar

Publications and helpful links

General Publications

• Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G. Amyotrophic lateral sclerosis. Lancet. 2022 Oct 15;400(10360):1363-1380. doi: 10.1016/S0140-6736(22)01272-7. Epub 2022 Sep 15.
• Voroslakos M, Takeuchi Y, Brinyiczki K, Zombori T, Oliva A, Fernandez-Ruiz A, Kozak G, Kincses ZT, Ivanyi B, Buzsaki G, Berenyi A. Direct effects of transcranial electric stimulation on brain circuits in rats and humans. Nat Commun. 2018 Feb 2;9(1):483. doi: 10.1038/s41467-018-02928-3.
• Kim HC, Lee W, Kunes J, Yoon K, Lee JE, Foley L, Kowsari K, Yoo SS. Transcranial focused ultrasound modulates cortical and thalamic motor activity in awake sheep. Sci Rep. 2021 Sep 29;11(1):19274. doi: 10.1038/s41598-021-98920-x.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2024
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: November 6, 2024
• First Submitted That Met QC Criteria: November 7, 2024
• First Posted (Estimated): November 8, 2024

Study Record Updates

• Last Update Posted (Estimated): November 8, 2024
• Last Update Submitted That Met QC Criteria: November 7, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis (ALS); Transcranial Pulse Stimulation (TPS)
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: NEU-TPS-ALS-01; FUSF-RAP-S-23-00096 (Other Grant/Funding Number: Focused Ultrasound Foundation and ALS Foundation. USA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: we will provide access to protocol, SAP and ICF
• IPD Sharing Access Criteria: protocol will be published as supplementary material. SAP and ICF will be provided upon reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No