Fatigue Alleviation Through Neuromodulating Therapy in Multiple Sclerosis
NCT Number: NCT06569550
Acronym: FANTiMS
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Multiple Sclerosis, Relapsing-Remitting|Fatigue
Interventions: DEVICE: Real Repetitive Transcranial Magnetic Stimulation|DEVICE: Sham Repetitive Transcranial Magnetic Stimulation
Sponsor: Danish Research Centre for Magnetic Resonance
Collaborators: Danish Multiple Sclerosis Center|Scleroseforeningen|Independent Research Fund Denmark
Sex: ALL
Age: ADULT
Enrollment: 60
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT
Start Date: 2024-08-14
Completion Date: 2026-02-01

Summary:
The goal of this clinical trial is to learn if repetitive Transcranial Magnetic Stimulation (rTMS) of the left premotor cortex can lessen fatigue in patients with Multiple Sclerosis, and if this is a feasible intervention. It will also give further information on fatigue in Multiple Sclerosis. The main questions it aims to answer is:

* Does premotor rTMS decrease fatigue symptoms in patients with Multiple Sclerosis?
* Is the change in fatigue reflected in an altered balance between brain excitation and inhibition in the targeted premotor cortex?

Researchers will compare real rTMS with sham rTMS (which does not stimulate with a magnetic field), to see if real rTMS works to alleviate fatigue.

Participants will:

* Receive real or sham rTMS for 30 minutes, 5 days in a row
* Visit the clinic before and 6 days after for baseline and follow-up
* Fill out on-line questionnaires 1 day and 4 weeks after the end of intervention
* Undergo a total of 3 brain scans (Magnetic Resonance Imaging at ultra-high field), at baseline, end of intervention, and follow-up
* Undergo lab neurophysiological measurements before and after the first intervention session
* Keep a fatigue diary and wear an activity tracker in the period before and after the intervention

Primary Outcome Measures: Change from baseline in patient reported fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC) from baseline to +6 days, Difference in change in score in Fatigue Scale for Motor and Cognitive functions, between baseline and clinical follow-up, between real and sham group.

It is a validated 20 item score, designed for fatigue in MS. It has motor and cognitive subscales. Range 20-100. Cut-off for mild, moderate and severe fatigue is 43, 53 and 63 respectively., Follow-up at 6 days post intervention. Compared to baseline
Secondary Outcome Measures: Change from baseline in regional brain tissue concentration of glutamate/glutamine in the stimulated premotor cortex, measured by single-voxel Magnetic Resonance Spectroscopy, Difference in change in concentration in metabolites, measured using Ultra High Field MR Spectroscopy, between baseline and day 5 of the intervention and clinical follow-up. Between real and sham group.

Glutamate and Glutamine are some of the major excitatory neurotransmitters. It is measured as an outcome to assess the inhibitory load in the premotor/motor system.

At lower fields, they are often combined (to Glx) due to difficulties in separating them. At 7T this is typically not necessary., Day 5 of intervention and 6 days post end of intervention, compared to baseline|Change from baseline in Brain tissue concentration of GABA in the stimulated premotor cortex, measured by single-voxel Magnetic Resonance Spectroscopy, Difference in change in concentration in metabolites, measured using Ultra High Field MR Spectroscopy, between baseline and day 5 of the intervention and clinical follow-up. Between real and sham group.

GABA is one of the major inhibitory neurotransmitters. It is measured as an outcome to assess the inhibitory load in the premotor/motor system., Day 5 of intervention and 6 days post end of intervention, compared to baseline|Change from baseline in patient reported fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC), Difference in change in score in Fatigue Scale for Motor and Cognitive functions, between baseline and questionnaire follow-up, between real and sham group. Changes in fatigue score at other time points, than main follow-up, will be treated as a secondary outcome.

It is a validated 20 item score, designed for fatigue in MS. It has motor and cognitive subscales. Range 20-100. Cut-off for mild, moderate and severe fatigue is 43, 53 and 63 respectively., Follow-up at 1 and 28 days post intervention. Compared to baseline.|Change from baseline in objective fatiguability, measured by the Fatiguability Index (FI), Difference in change in fatiguability (state fatigue) measured as fatiguability index (FI). FI is calculated based on a sustained 30s maximum voluntary contraction, where FI is defined as the ratio between the actual area under the curve over the theoretical max if 100% had been sustained for the entire contraction. Range 0-1., Follow-up at 6 days post intervention. Compared to baseline.|Change from baseline in patient-reported fatiguability, measured by the Pittsburgh Fatiguability Score (PFS), Pittsburgh Fatiguability Score (PFS) is a self-reported rating scale of fatiguability. It contains 10 activities, each scored from 0-5 (5 being worst) for both induced cognitive and physical fatigue.

The investigators have no specific hypothesis for the score at 1 day post intervention due to the retrospective aspect of this score., Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.
Other Outcome Measures: Change from baseline in patient reported physical fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC), physical subscore, Difference in change in score in Fatigue Scale for Motor and Cognitive functions, for the 2 physical and cognitive subscores, between baseline and questionnaire follow-up, between real and sham group. Changes in fatigue score subscores will be treated as secondary outcomes.

It is a validated 20 item score, designed for fatigue in MS. It has 10 items each for motor and cognitive subscales. Range 10-50., Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.|Change from baseline in patient reported cognitive fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC), cognitive subscore, Difference in change in score in Fatigue Scale for Motor and Cognitive functions, for the 2 physical and cognitive subscores, between baseline and questionnaire follow-up, between real and sham group. Changes in fatigue score subscores will be treated as secondary outcomes.

It is a validated 20 item score, designed for fatigue in MS. It has 10 items each for motor and cognitive subscales. Range 10-50., Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.|Per-session changes in patient reported fatigue using the Visual-Analogue Fatigue Scale (VAFS), Difference in change in fatigue, by VAFS scale, before/after each intervention, across the 5 intervention sessions. Participants will self-assess fatigue by a VAS scale before and after each intervention.

Asking before and after at each sessions allows differentiation between acute effects due to the intervention, and effects that consolidate between sessions., Time-series, 5 intervention days.|Change from baseline in patient-reported depression symptoms, measured with the Major Depression Inventory (MDI), MDI depression score is a commonly used rating scale for depressive symptoms. Range 0-50. Cut-offs for mild-, moderate- and severe depression are 21, 26 and 31 respectively., Follow-up at 6 days post intervention. Compared to baseline.|Change from baseline in motor-network functional connectivity, measured by resting state functional MRI, Resting state (rs-) Blood-oxygen level dependent (BOLD-) functional (f-) Magnetic Resonance Imaging (MRI) is a method for quantifying functional connectivity. The investigators will analyze the functional connectivity within the premotor-motor network, and how this connectivity changes as a result of the intervention.

An exploratory framework to illuminate mechanisms of fatigue will be employed., Day 5 of intervention and 6 days post end of intervention, compared to baseline|Change from baseline in motor network structural connectivity, measured by Diffusion Weighted Imaging, Diffusion Weighted Imaging (DWI) is a special MR technique to describe brain microstructure, most commonly white matter fiber direction and integrity. The investigators will analyze the structural connectivity within the premotor-motor network, and how this connectivity changes as a result of the intervention.

An exploratory framework to illuminate mechanisms of fatigue will be employed., Day 5 of intervention and 6 days post end of intervention, compared to baseline.|Change from baseline in patient reported sleep quality, measured by the Epworth Sleepiness Scale (ESS), Difference in change in Epworth Sleepiness Scale. The ESS is a well-validated and often used score of sleepiness, used across many different fields. The range is from 0-24 and a score above 10 usually indicated a dysfunction of sleep., Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.|Change from baseline in patient-reported symptom severity, measured by the Multiple Sclerosis Impact Scale (MSIS-29), Multiple Sclerosis Impact Scale (MSIS-29) is a self-reported rating scale for the impact of MS on daily quality of life. It contains 29 items, scored from 1-5 (5 being worst)., Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.|Per-session patient reported side-effects, with the TMS Adverse Events and Associated Sensations Questionnaire (TMS-SENS-Q), The TMS Adverse Events And Associated Sensations Questionnaire (TMS-SENS-Q) will be used to ask participants to self-report side-effects of rTMS after each rTMS intervention. It asks participants to self-report severity, onset and duration of 20 potential symptoms of TMS, including "other"., Time-series, 5 intervention days.|Change from baseline in bimanual dexterity, measured with the 9-hole peg test (9HPT), Cohort description, exploratory. Difference in change in scores in 9-hole peg test. The 9HPT is well-validated and often used test of fine motor function. The score consists of the average completion time across 2 trials per hand. There exists normative material, stratified by age., Follow-up at 6 days post intervention. Compared to baseline.|Change from baseline in processing speed, measured with the Symbol Digit Modalities Test (SDMT), Cohort description, exploratory. Difference in change in scores in Symbol Digit Modalities Test. The SDMT is a well-validated and often used cognitive test, generally considered to assess processing speed. The score is the total number of symbols correctly assigned a number via a pre-determined key, in 90 seconds. There exists normative material, stratified by age., Follow-up at 6 days post intervention. Compared to baseline.|Change from baseline in ambulation speed, measured with the Timed 25ft walk test (T25FW), Cohort description, exploratory. Difference in change in scores in 25ft walk test. The T25FW is a well-validated and often used test to assess walking ability. The score is the average time taken to walk 25ft across 2 trials. There exists normative material, stratified by age., Follow-up at 6 days post intervention. Compared to baseline.|Change from baseline in visual memory, measured with the Brief Visual Memory Test, revised edition (BVMT-R), Cohort description, exploratory. Difference in change in scores in BVMT-R. The BVMT-R is a well-validated and often used test to assess short term visual memory, in MS. The score is the sum of remembered visual cues across 3 trials, in accordance with BICAMS guidelines. There exists normative material, stratified by age., Follow-up at 6 days post intervention. Compared to baseline.|Change from baseline in verbal memory, measured with the California Verbal Learning Test (CVLT), Cohort description, exploratory. Difference in change in scores in CVLT. The CVLT is a well-validated and often used test to assess short term verbal memory, in MS. The outcome is the sum og words recalled across the 5 initial trials, in accordance with BICAMS guidelines. There exists normative material, stratified by age., Follow-up at 6 days post intervention. Compared to baseline.|Multiple Sclerosis related disability, measured by the Extended Disability Status Scale (EDSS) at baseline, Used for proper cohort description when reporting. The EDSS is a clinical rating scale ranging from 0 (no symptoms or objective signs of disability related to Multiple Sclerosis) to 10 (death caused by Multiple Sclerosis)., One-time measurement at baseline.|Change across 1 intervention session in measured Intracortical Inhibition (SICI), Difference in change between real and sham group, in intracortical inhibition (SICI) measured with paired-pulse TMS-EMG.

The SICI is the ratio between the amplitude of a motor-evoked potential from 2 TMS pulses delivered at 80% and 120% of the resting motor threshold at an interval of 2.5ms, and a control potential evoked by a single pulse at 120% of resting motor threshold., Day 1, measurements done immediately (within 1 hour) before and after the intervention|Change across 1 intervention session in measured Intracortical Facilitation (ICF), Difference in change between real and sham group, in intracortical facilitation (ICF) measured with paired-pulse TMS-EMG.

The ICF is the ratio between the amplitude of a motor-evoked potential from 2 TMS pulses delivered at 80% and 120% of the resting motor threshold at an interval of 10ms, and a control potential evoked by a single pulse at 120% of resting motor threshold., Day 1, measurements done immediately (within 1 hour) before and after the intervention|Change across 1 intervention session in TMS-evoked recruitment curve at rest, Difference in change between real and sham group, in characteristics of at-rest recruitment curve, measured with single-pulse TMS-EMG.

A recruitment curve is the characteristic input/output relationship between stimulation-intensity of the TMS-pulse and the amplitude of the motor-evoked potential., Day 1, measurements done immediately (within 1 hour) before and after the intervention|Change across 1 intervention session in TMS-evoked recruitment curve at slight tonic contraction, Difference in change between real and sham group, in characteristics of recruitment curve at slight tonic contraction, measured with single-pulse TMS-EMG.

A recruitment curve is the characteristic input/output relationship between stimulation-intensity of the TMS-pulse and the amplitude of the motor-evoked potential., Day 1, measurements done immediately (within 1 hour) before and after the intervention|Change across 1 intervention session in TMS-induced cortical silent period, Difference in change between real and sham group, in the duration of the TMS-induced cortical silent period of the EMG-trace, measured in the hand contralateral to the stimulation site., Day 1, measurements done immediately (within 1 hour) before and after the intervention|Change across 1 intervention session in TMS-induced ipsilateral silent period, Difference in change between real and sham group, in the duration of the TMS-induced ipsilateral silent period of the EMG-trace. Ipsilateral meaning the reduction in EMG-activity in the measured muscle on the same side of the participant as the stimulation site., Day 1, measurements done immediately (within 1 hour) before and after the intervention|Change from baseline in participant-reported fatigue severity, measured by a fatigue diary, Difference in change in day-to-day fatigue measured using a diary of fatigue scores, filled out by each subject at home in the week before/after the intervention week.

The diary consists of a VAS-fatigue scale, as well as a rating for distribution between physical and cognitive fatigue. It is adapted from other sources., Week after intervention, compared to week before intervention|Change from baseline in participant-reported sleep quality, measured by a fatigue diary, Difference in change in sleep quality according to fatigue diary. As part of the fatigue diary, each patient will be asked each morning for the approximate hours of sleep and the quality of their sleep., Week after intervention, compared to week before intervention|Change from baseline in daily activity levels, measured by a wrist-borne accelerometer, Difference in change in stepcount based on data from wearable accelerometer, worn by each subject at home in the week before/after the intervention week., Week after intervention, compared to week before intervention|Change from baseline in Sleep quality, measured by a wrist-borne accelerometer, Difference in change in sleep efficiency, as assessed based on data from wearable accelerometer, worn by each subject at home in the week before/after the intervention week., Week after intervention, compared to week before intervention|Effective dose at target brain region, calculated through E-field simulation, Exploratory. Simulated effective electric field dose at the targeted brain region (PMd), based on the individual pulse stimulation locations and an individual head-model based on subject-specific MR images. Simulated using SimNIBS.

Exploratory analysis of whether actual stimulation intensity drives a potential positive treatment effect., Intervention Days 1-5