Fatigue Alleviation Through Neuromodulating Therapy in Multiple Sclerosis

NCT06569550 | Recruiting DMC

• 1 other identifier: FANTiMS
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Fatigue; Multiple Sclerosis, Relapsing-Remitting

Keywords

Transcranial Magnetic Stimulation, Repetitive; Magnetic Resonance Imaging; Magnetic Resonance Imaging, Spectroscopy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Change from baseline in regional brain tissue concentration of glutamate/glutamine in the stimulated premotor cortex, measured by single-voxel Magnetic Resonance Spectroscopy

  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

  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)

  Follow-up at 1 and 28 days post intervention. Compared to baseline.

• Change from baseline in objective fatiguability, measured by the Fatiguability Index (FI)

  Follow-up at 6 days post intervention. Compared to baseline.

• Change from baseline in patient-reported fatiguability, measured by the Pittsburgh Fatiguability Score (PFS)

  Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.

Other Outcomes (26)

• Change from baseline in patient reported physical fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC), physical subscore

  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

  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)

  Time-series, 5 intervention days.

Study Arms (2)

Active Repetitive Transcranial Magnetic Stimulation (rTMS)

ACTIVE COMPARATOR

Active Repetitive Transcranial Magnetic Stimulation (rTMS)

Device: Real Repetitive Transcranial Magnetic Stimulation

Sham Repetitive Transcranial Magnetic Stimulation

SHAM COMPARATOR

Sham Repetitive Transcranial Magnetic Stimulation

Device: Sham Repetitive Transcranial Magnetic Stimulation

Interventions

Sham Repetitive Transcranial Magnetic Stimulation DEVICE

Five sessions of real paired-pulse rTMS at 0.72Hz (inter-pulse interval of 30ms and inter-pair interval of 1381ms), for a total of 1300 pulse-pairs (30 minutes), across 5 sequential days, Monday to Friday. The stimulation is applied with a MagPro XP Orange stimulator (MagVenture A/S, Farum, Denmark), through a B65-Cool-A/P-CO coil (Magventure A/S) with an active and placebo (sham) side. The sham side does not deliver a magnetic pulse to the participant. The target is the left PMd, at MNI coordinates (34, -2, 66), transformed into patient space. Optimal coil placement, with respects to induced e-field at the target coordinates, is simulated with SimNIBS, based on the participants own MR images. The coil positioning is guided and monitored continuously with a neuronavigation system (Localite, Bonn, Germany) and the aid of robotic arm (Axilum Robotics, Schiltigheim, France ).

Sham Repetitive Transcranial Magnetic Stimulation

Real Repetitive Transcranial Magnetic Stimulation DEVICE

Five sessions of real paired-pulse rTMS at 0.72Hz (inter-pulse interval of 30ms and inter-pair interval of 1381ms), for a total of 1300 pulse-pairs (30 minutes), across 5 sequential days, Monday to Friday. The stimulation is applied with a MagPro XP Orange stimulator (MagVenture A/S, Farum, Denmark), through a B65-Cool-A/P-CO coil (Magventure A/S) with an active and placebo (sham) side. The active side is an actively cooled figure-of-eight coil with an outer diameter of 65mm. Intensity is 80% of resting motor threshold. It is kept the same across all 5 sessions. The target is the left PMd, at MNI coordinates (34, -2, 66), transformed into patient space. Optimal coil placement, with respects to induced e-field at the target coordinates, is simulated with SimNIBS, based on the participants own MR images. The coil positioning is guided and monitored continuously with a neuronavigation system (Localite, Bonn, Germany) and the aid of robotic arm (Axilum Robotics, Schiltigheim, France ).

Active Repetitive Transcranial Magnetic Stimulation (rTMS)

Eligibility Criteria

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

You may qualify if:

• A confirmed diagnosis of relapse-remitting or secondary progressive multiple sclerosis, according to most recent McDonald's criteria (Thompson et al., 2018). This diagnosis must not be more recent than 3 months
• Must have fatigue as a complaint, and an FSMC score corresponding to at least moderate fatigue (\>53)
• Stable MS medication for at least 3 months

You may not qualify if:

• Pregnancy, any subject with the potential to become pregnant must ensure against this (e.g. by taking oral contraceptives, or other high efficacy method)
• History of neurologic disease or other significant medical conditions, aside from MS
• EDSS \> 6.5
• Major psychiatric disorder, including current clinical depression.
• Intake of medication that primarily acts on CNS or neurotransmission, except SSRI or SNRI
• Pacemaker or other implanted electronic devices
• Any intracranial metal
• Any metallic implant incompatible with MR scanning
• Claustrophobia
• Either patient or their close relatives suffering from epilepsy
• Current Drug or alcohol abuse

Sponsors & Collaborators

• Danish Multiple Sclerosis Center: collaborator
• Scleroseforeningen: collaborator
• Independent Research Fund Denmark: collaborator
• Danish Research Centre for Magnetic Resonance: lead

Study Sites (1)

Danish Research Centre for Magnetic Resonance

Hvidovre, Capital Region, 2650, Denmark

RECRUITING

Related Publications (1)

• Nygaard S, Madsen MAJ, Wiggermann V, Cabras C, Christiansen L, Svatkova A, Lundell H, Hojsgaard Chow H, Romme Christensen J, Blinkenberg M, Sellebjerg F, Siebner H. Repetitive transcranial magnetic stimulation to alleviate fatigue in multiple sclerosis-study protocol for a randomized sham-controlled double-blinded clinical trial. Front Neurol. 2026 Feb 26;17:1759679. doi: 10.3389/fneur.2026.1759679. eCollection 2026.

  PMID: 41835064 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Fatigue

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Hartwig R Siebner, MD, DMSc

  Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre & University of Copenhagen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hartwig R Siebner, MD, DMSc

CONTACT

3862 6541; hartwig@drcmr.dk

Sofus AD Nygaard, MD

CONTACT

sofusadn@drcmr.dk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The TMS stimulation machine (MagPro XP orange edition, MagVenture A/S, Farum, Denmark), in combination with an A/P-coil with a separate active and placebo (sham) side. The sham side is designed to deliver \<5% of the magnetic field of the active side, with similar tactile and auditory input. The coil is designed to be reversible, with no markings as to which side is which. There is an internal sensor that allows the device to determine which side is up. Masking is ensured by a pre-programmed code, unique to each participant, which is input in the device whereafter the device will indicate if the "wrong" side is being used for stimulation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized (1:1) parallel group study to either active treatment or sham

Study Record Dates

• First Submitted: August 12, 2024
• First Posted: August 26, 2024
• Study Start: August 14, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: January 28, 2026

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)