Intermittent Theta-Burst Stimulation for Lower-Limb Spasticity and Pain in Multiple Sclerosis

NCT07786506 | Not Yet Recruiting

• 1 other identifier: TMS-SPASMS-01
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Spasticity and neuropathic pain are frequent and disabling symptoms of multiple sclerosis. Intermittent theta-burst stimulation (iTBS) is a non-invasive neuromodulation technique that may modulate cortical and corticospinal excitability and thereby improve motor symptoms and pain. This randomized, parallel-group, sham-controlled, assessor-blinded study will evaluate the clinical efficacy of active iTBS compared with sham stimulation in adults with multiple sclerosis and clinically significant lower-limb spasticity and pain. Participants will receive five stimulation sessions over one week. Spasticity, pain, patient-reported outcomes, and the electrophysiological H/M ratio will be assessed at baseline and at Weeks 2 and 4 after the intervention.

Conditions

Multiple Sclerosis; Muscle Spasticity; Neuropathic Pain

Keywords

multiple sclerosis; lower-limb spasticity; neuropathic pain; intermittent theta-burst stimulation; iTBS; repetitive transcranial magnetic stimulation; rTMS; motor cortex; H-reflex; H/M ratio

Outcome Measures

Primary Outcomes (2)

• The Modified Tardieu Scale Quality of Muscle Reaction Score

  The entire more affected lower limb will be examined using the Modified Tardieu Scale. At baseline, the muscle group corresponding to the dominant spastic pattern will be predefined as the individual target muscle group and the same muscle group will be reassessed at all subsequent visits. The quality of muscle reaction at fast stretch velocity V3 is scored from 0 to 5, where 0 indicates no resistance and higher scores indicate a more pronounced catch or clonus; a lower score indicates less spasticity.

  Baseline, Week 2, and Week 4 after the final stimulation session

• Worst Lower-Limb Pain Intensity on the Numeric Rating Scale

  Participants will rate the worst pain intensity experienced in the affected lower limb during the preceding 14 days on an 11-point Numeric Rating Scale from 0 (no pain) to 10 (worst imaginable pain). Lower scores indicate less pain.

  Baseline, Week 2, and Week 4 after the final stimulation session

Secondary Outcomes (12)

• Neuropathic Pain Features Measured by the Douleur Neuropathique 4 Questionnaire

  Baseline, Week 2, and Week 4 after the final stimulation session

• Multiple Sclerosis Impact Scale - Physical Impact Score

  Baseline, Week 2, and Week 4 after the final stimulation session

• Multiple Sclerosis Impact Scale - Psychological Impact Score

  Baseline, Week 2, and Week 4 after the final stimulation session

• Multiple Sclerosis Quality of Life-54 - Physical Health Composite Score

  Baseline, Week 2, and Week 4 after the final stimulation session

• Multiple Sclerosis Quality of Life-54 - Mental Health Composite Score

  Baseline, Week 2, and Week 4 after the final stimulation session

Study Arms (2)

active iTBS

EXPERIMENTAL

Participants will receive active intermittent theta-burst stimulation over the primary motor cortex contralateral to the more affected lower limb.

Device: Active Intermittent Theta-Burst Stimulation (iTBS)

sham iTBS

SHAM COMPARATOR

Participants will receive sham stimulation over the same cortical target and according to the same visit schedule as the active group.

Device: Sham Intermittent Theta-Burst Stimulation

Interventions

Active Intermittent Theta-Burst Stimulation (iTBS) DEVICE

Active iTBS will be delivered using a Neuro-MS/D Advanced Therapeutic magnetic stimulator (Neurosoft) with a figure-of-eight coil. The stimulation target will be the representation of the muscle group corresponding to the dominant spastic pattern of the more affected lower limb in the contralateral primary motor cortex. The target will be identified using motor-evoked potentials and neuronavigation based on the participant's individual MRI. Active motor threshold will be determined from the tibialis anterior muscle. Stimulation intensity will be set at 80% of the active motor threshold. Each burst will consist of 3 pulses at 50 Hz, repeated at 5 Hz. Each 600-pulse block will use a 2-second on/8-second off pattern and last approximately 3 minutes 9 seconds. Two 600-pulse blocks will be delivered per day, separated by a 15-minute interval, for a total of 1,200 pulses per day. Treatment will be administered on five consecutive weekdays, giving 10 stimulation blocks in total.

active iTBS

Sham Intermittent Theta-Burst Stimulation DEVICE

In both groups, the TMS coil will be positioned over the primary motor cortex representation of the more affected lower limb and sham electrodes will be attached to the forehead. During sham stimulation, surface electrodes placed on the forehead will deliver low-intensity electrical stimulation at 2 mA to reproduce the somatosensory experience of TMS. The TMS device will simultaneously produce the characteristic clicking sound of coil discharge. The software will conceal the assigned mode from the participant and stimulation operator. The visit schedule, positioning, and total procedural duration will match the active condition.

sham iTBS

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of multiple sclerosis according to the 2024 McDonald criteria.
• Expanded Disability Status Scale (EDSS) score from 2.5 to 6.0.
• Clinically significant spasticity in at least one muscle group of the more affected lower limb, defined as a Modified Tardieu Scale quality of muscle reaction score of at least 2 at velocity V3.
• Lower-limb pain intensity of at least 4/10 on a 0-10 Visual Analogue Scale at screening.
• Stable pharmacological treatment, including disease-modifying therapy, for at least 3 months before enrolment.
• Ability to understand the study procedures and provide written informed consent.

You may not qualify if:

• Epilepsy or another condition associated with an increased risk of seizure.
• Metallic implants, implanted electronic devices, or other conditions contraindicating transcranial magnetic stimulation.
• Clinical relapse of multiple sclerosis within 30 days before enrolment.
• Pregnancy or breastfeeding.

Sponsors & Collaborators

• Comenius University: lead

Study Sites (1)

2nd Department of Neurology, Faculty of Medicine, Comenius University Bratislava and University Hospital Bratislava

Bratislava, 83305, Slovakia

Location

MeSH Terms

Conditions

Multiple Sclerosis; Muscle Spasticity; Neuralgia

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Peripheral Nervous System Diseases; Neuromuscular Diseases; Pain

Study Officials

• Peter Valkovič, prof. MD PhD.

  Faculty of Medicine, Comenius University Bratislava

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Karolína Lisá, MD

CONTACT

+421 2 5954 2297; karolina.lisa@gmail.com

Jaroslav Meluš, MD, PhD.

CONTACT

+421 2 5954 2297; jaroslavmelus@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Treatment allocation will be implemented automatically by the stimulation software and concealed from the participant, the stimulation operator, and the outcome assessor. The software interface will not display whether active or sham stimulation is being delivered. The Principal Investigator will not routinely access treatment allocation and may perform emergency unblinding only when medically necessary. The reason and circumstances of each emergency unblinding will be documented.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Forty participants will be assigned in a 1:1 ratio to active iTBS (n=20) or sham iTBS (n=20).

Study Record Dates

• First Submitted: August 17, 2026
• First Posted: August 26, 2026
• Study Start: August 10, 2026
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 31, 2026
• Last Updated: August 26, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

SL (1)