An interventional study of Active Intermittent Theta-Burst Stimulation (iTBS) and Sham Intermittent Theta-Burst Stimulation in Multiple Sclerosis, Muscle Spasticity and Neuropathic Pain, sponsored by Comenius University. Not yet recruiting at 1 site in Slovakia. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-08-26.
Sponsored by Comenius University · Not applicable, Interventional, and Treatment
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.
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. Lower-limb spasticity and neuropathic pain can substantially impair mobility, daily functioning, and quality of life. Current symptomatic treatments include oral antispastic medication and targeted botulinum toxin type A injections, but their effects may be incomplete or time-limited. Intermittent theta-burst stimulation is a repetitive transcranial magnetic stimulation protocol with the potential to modulate cortical and corticospinal excitability.
The study will determine whether active iTBS applied over the primary motor cortex produces a greater reduction in lower-limb spasticity and neuropathic pain than sham iTBS in patients with MS.
This is a randomized, two-arm, parallel-group, sham-controlled, assessor-blinded clinical study conducted at the Multiple Sclerosis Centre of the 2nd Department of Neurology, Faculty of Medicine, Comenius University Bratislava and University Hospital Bratislava. Eligible participants will be randomized to active iTBS or sham iTBS. Stimulation will target the primary motor cortex contralateral to the more affected lower limb and the cortical representation of the muscle group corresponding to the dominant spastic pattern, identified using motor-evoked potentials and neuronavigation. Participants will undergo five sessions on consecutive weekdays. The active protocol comprises 1,200 pulses per day, delivered as two 600-pulse blocks separated by a 15-minute inter-block interval.
Clinical and neurophysiological assessments will be performed at baseline and at Weeks 2 and 4 after the intervention by an assessor blinded to treatment allocation. Assessments include the Tardieu Scale, pain measures, MS-specific quality-of-life and symptom questionnaires, and the H/M ratio measured by electromyography. Participants with a persistent clinical indication after completion of the four-week follow-up may receive botulinum toxin type A as standard-of-care rescue treatment.
3,264 studies on the registry are indexed under Multiple Sclerosis; 659 are open to participants now.
This study's planned enrollment of 40 is below the median of 50 across 2,201 interventional studies indexed under Multiple Sclerosis.
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Exclusion Criteria:
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Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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)
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
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.
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.
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.
Time frame: 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.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Neuropathic Pain Features Measured by the Douleur Neuropathique 4 Questionnaire
The Douleur Neuropathique 4 (DN4) questionnaire will be scored from 0 to 10. Higher scores indicate more neuropathic pain features; a score of 4 or more supports the presence of neuropathic pain.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Multiple Sclerosis Impact Scale - Physical Impact Score
The physical-impact subscale of the Multiple Sclerosis Impact Scale version 2 will be transformed to a 0-100 score. Higher scores indicate a greater physical impact of MS.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Multiple Sclerosis Impact Scale - Psychological Impact Score
The psychological-impact subscale of the Multiple Sclerosis Impact Scale version 2 will be transformed to a 0-100 score. Higher scores indicate a greater psychological impact of MS.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Multiple Sclerosis Quality of Life-54 - Physical Health Composite Score
The Physical Health Composite of the Multiple Sclerosis Quality of Life-54 will be scored from 0 to 100. Higher scores indicate better health-related quality of life.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Multiple Sclerosis Quality of Life-54 - Mental Health Composite Score
The Mental Health Composite of the MSQOL-54 will be scored from 0 to 100. Higher scores indicate better health-related quality of life.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Fatigue Scale for Motor and Cognitive Functions Total Score
The Fatigue Scale for Motor and Cognitive Functions total score ranges from 20 to 100. Higher scores indicate more severe fatigue.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Hospital Anxiety and Depression Scale - Anxiety Subscale Score
The Hospital Anxiety and Depression Scale Anxiety subscale ranges from 0 to 21. Higher scores indicate more severe anxiety symptoms.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Hospital Anxiety and Depression Scale - Depression Subscale Score
The Hospital Anxiety and Depression Scale Depression subscale ranges from 0 to 21. Higher scores indicate more severe depressive symptoms.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Multiple Sclerosis Neuropsychological Screening Questionnaire Score
The patient-report Multiple Sclerosis Neuropsychological Screening Questionnaire total score ranges from 0 to 60. Higher scores indicate greater perceived neuropsychological impairment.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Patient-Determined Disease Steps Score
The Patient-Determined Disease Steps score ranges from 0 (normal) to 8 (bedridden). Higher scores indicate greater walking disability.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
H/M Ratio as a Neurophysiological Marker of Spinal Excitability
The H-reflex will be elicited by stimulation of the tibial nerve and recorded from the soleus muscle. The maximal H-reflex amplitude will be divided by the maximal M-wave amplitude and expressed as Hmax/Mmax × 100%. The same limb, electrode placement, and acquisition protocol will be used at all visits.
Time frame: Baseline, Week 2, and Week 4 after the final stimulation session
Treatment-Emergent Adverse Events
Number and proportion of participants experiencing any treatment-emergent adverse event during the stimulation week and follow-up. Events will be recorded by type, severity, seriousness, and relationship to the stimulation procedure.
Time frame: From the first stimulation session through Week 4 after the final stimulation session
Plan to share: No
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