Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06569550
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-08-12
Brief Title:
Fatigue Alleviation Through Neuromodulating Therapy in Multiple Sclerosis
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Neuromodulation of the Left Premotor Cortex With Transcranial Magnetic Stimulation to Alleviate Fatigue in Multiple Sclerosis - a Randomised Controlled Clinical Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FANTiMS
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
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
Detailed Description:
BACKGROUND
Multiple sclerosis MS is an immune mediated disease targeting the central nervous system Globally the prevalence and incidence are increasing It is a chronic condition with no known definitive cure Fatigue is among the most disabling MS symptoms and is highly prevalent afflicting up to 78-95 of patients Fatigue in persons with MS PwMS is consistently associated with lower quality of life and severity of fatigue is generally associated with employment status and may worsen over time
PATHOPHYSIOLOGY
The pathophysiological basis for fatigue in MS is poorly understood with several possible contributors However trait fatigue in everyday life associates with task-related hyperactivation of the premotor cortex during a non-fatiguing grip force task Patients who are able to increase premotor activity after performing a fatiguing motor task are less affected by fatigue during everyday life Taken together these findings support the hypothesis that patients suffering from trait fatigue allocate their premotor neural resources less efficiently than patients without fatigue This implies a mismatch in the physiological neuronal inhibitionexcitation balance and is evident as hyperactivity of the premotor cortex during normal motor activities which in turn impedes an efficient upscaling of premotor activity
CURRENT TREATMENTS
Currently the pharmacological treatment options for MS-related fatigue are limited and unsatisfactory Neither of the 2 commonly used pharmaceutical agents Amantadine nor Modafinil show both a significant and a clinically relevant reduction in fatigue Physical exercise has an overall positive and clinically relevant effect on MS-related fatigue but physical therapy is not a feasible intervention for all PwMS Evidence from TMS studies of the motor-cortex in fatigued PwMS suggests that this effect may be mediated by changes in motor network excitability
RTMS
Repetitive Transcranial Magnetic Stimulation rTMS is a non-invasive method for inducing plastic focal changes in the brain It has been investigated for multitudes of ailments and is considered a generally safe intervention rTMS has been repeatedly shown to have a direct and lasting neuromodulating effect on the motor cortex after stimulation of the premotor network It is suggested that inhibitory rTMS targeting the dorsal premotor cortex can improve motor performance
PREVIOUS TRIALS
While rTMS is extensively investigated in other contexts there exists few studies on MS-related fatigue A single small study n33 focused on safety targeting either motor cortex or prefrontal cortex with an H-coil failed to show a significant effect of the intervention Several studies have shown an effect on fatigue as a secondary outcome However the heterogeneity in interventional protocol and target prevents further analysis As far as the investigators are aware no studies have investigated alleviating fatigue by neuromodulation of the premotor network
OBJECTIVES
The investigators will conduct a double-blinded randomized controlled trial investigating the effect of rTMS in fatigue in PwMS The investigators will conduct clinical measurements for their primary outcome Clinical outcomes will be supported by ultra-high field MRI and neurophysiological measurements as well as supplementary clinical outcomes in order to acquire a broad dataset for further illumination of mechanisms For outcomes see relevant section
STUDY DESIGN
The trial consists of a baseline period an intervention period and a follow-up period
At the baseline visit D0 all participants will undergo clinical testing structural 7T MRI 7T MR Spectroscopy MRS to acquire baseline neurometabolite concentrations functional connectivity rs-fMRI and structural connectivity DWI Between D0 and the first intervention day participants will wear a wrist-borne accelerometer and fill out a fatigue diary
The intervention period consists of 5 sequential weekdays Monday through Friday On the first day of treatment D1 neurophysiological measures of motor excitationinhibition will be acquired before and immediately after the intervention using single- and paired-pulse TMS with electromyography EMG as a readout On the fifth and last intervention day D5 participants will undergo immediate follow-up 7T MRI with metabolic functional- and structural connectivity measures
The main follow-up is 6 days after the last rTMS session day 11 counting from first intervention Here they will undergo follow-up clinical testing follow-up 7T MRI with metabolic functional- and structural connectivity measures Between D5 and the Follow-up participants will again wear a wrist-borne accelerometer and fill out a fatigue diary At first day after end of intervention and at 4 weeks after end of intervention participants will be invited to fill out electronic questionnaires of relevant patient-reported outcomes
CRITERIA FOR DISCONTINUATION
Patients are discontinued in the study in case of inability to perform a baseline MRI scan occurrence of MS relapse new occurrence of any condition that is a contraindication for rTMS excessive lack of compliance to the experimental protocol as assessed by the experimenters Additionally all subjects reserve the right to at any time withdraw from the study for any reason
QUALITY ASSURANCE
This is a one-site study and will be monitored by an internal monitoring process akin to Good Clinical Practice guidelines All procedures will be done according to a pre-defined protocol ensuring a standard operating procedure for acquisition of all data
Additionally The MR- and EMG-data quality is inspected during and right after data acquisition as is normal practice in the clinical routine and research
Logbooks are kept for all sessions and all deviations from protocol will be noted Data quality is further assessed through the subsequent offline data processing stage through standardized processing pipelines
All staff who perform MR and TMS have received comprehensive training in the respective methods as well as safety training All staff involved in the project will be familiar with the procedure and methods and trained the experimental procedure before conducting measurements
DATA ANALYSIS PLAN
Primary outcome All patients who attend at least one rTMS session and have follow-up data available will be included in the intention-to-treat analysis for the primary outcome regardless of amount of rTMS sessions completed
EMG and MRI data will be preprocessed by a blinded researcher according to standardized pipelines For EMG data all trials will be manually checked by a blinded researcher for muscle artefacts preceding the TMS pulse and offending trials removed
Multiple sclerosis MS is an immune mediated disease targeting the central nervous system Globally the prevalence and incidence are increasing It is a chronic condition with no known definitive cure Fatigue is among the most disabling MS symptoms and is highly prevalent afflicting up to 78-95 of patients Fatigue in persons with MS PwMS is consistently associated with lower quality of life and severity of fatigue is generally associated with employment status and may worsen over time
PATHOPHYSIOLOGY
The pathophysiological basis for fatigue in MS is poorly understood with several possible contributors However trait fatigue in everyday life associates with task-related hyperactivation of the premotor cortex during a non-fatiguing grip force task Patients who are able to increase premotor activity after performing a fatiguing motor task are less affected by fatigue during everyday life Taken together these findings support the hypothesis that patients suffering from trait fatigue allocate their premotor neural resources less efficiently than patients without fatigue This implies a mismatch in the physiological neuronal inhibitionexcitation balance and is evident as hyperactivity of the premotor cortex during normal motor activities which in turn impedes an efficient upscaling of premotor activity
CURRENT TREATMENTS
Currently the pharmacological treatment options for MS-related fatigue are limited and unsatisfactory Neither of the 2 commonly used pharmaceutical agents Amantadine nor Modafinil show both a significant and a clinically relevant reduction in fatigue Physical exercise has an overall positive and clinically relevant effect on MS-related fatigue but physical therapy is not a feasible intervention for all PwMS Evidence from TMS studies of the motor-cortex in fatigued PwMS suggests that this effect may be mediated by changes in motor network excitability
RTMS
Repetitive Transcranial Magnetic Stimulation rTMS is a non-invasive method for inducing plastic focal changes in the brain It has been investigated for multitudes of ailments and is considered a generally safe intervention rTMS has been repeatedly shown to have a direct and lasting neuromodulating effect on the motor cortex after stimulation of the premotor network It is suggested that inhibitory rTMS targeting the dorsal premotor cortex can improve motor performance
PREVIOUS TRIALS
While rTMS is extensively investigated in other contexts there exists few studies on MS-related fatigue A single small study n33 focused on safety targeting either motor cortex or prefrontal cortex with an H-coil failed to show a significant effect of the intervention Several studies have shown an effect on fatigue as a secondary outcome However the heterogeneity in interventional protocol and target prevents further analysis As far as the investigators are aware no studies have investigated alleviating fatigue by neuromodulation of the premotor network
OBJECTIVES
The investigators will conduct a double-blinded randomized controlled trial investigating the effect of rTMS in fatigue in PwMS The investigators will conduct clinical measurements for their primary outcome Clinical outcomes will be supported by ultra-high field MRI and neurophysiological measurements as well as supplementary clinical outcomes in order to acquire a broad dataset for further illumination of mechanisms For outcomes see relevant section
STUDY DESIGN
The trial consists of a baseline period an intervention period and a follow-up period
At the baseline visit D0 all participants will undergo clinical testing structural 7T MRI 7T MR Spectroscopy MRS to acquire baseline neurometabolite concentrations functional connectivity rs-fMRI and structural connectivity DWI Between D0 and the first intervention day participants will wear a wrist-borne accelerometer and fill out a fatigue diary
The intervention period consists of 5 sequential weekdays Monday through Friday On the first day of treatment D1 neurophysiological measures of motor excitationinhibition will be acquired before and immediately after the intervention using single- and paired-pulse TMS with electromyography EMG as a readout On the fifth and last intervention day D5 participants will undergo immediate follow-up 7T MRI with metabolic functional- and structural connectivity measures
The main follow-up is 6 days after the last rTMS session day 11 counting from first intervention Here they will undergo follow-up clinical testing follow-up 7T MRI with metabolic functional- and structural connectivity measures Between D5 and the Follow-up participants will again wear a wrist-borne accelerometer and fill out a fatigue diary At first day after end of intervention and at 4 weeks after end of intervention participants will be invited to fill out electronic questionnaires of relevant patient-reported outcomes
CRITERIA FOR DISCONTINUATION
Patients are discontinued in the study in case of inability to perform a baseline MRI scan occurrence of MS relapse new occurrence of any condition that is a contraindication for rTMS excessive lack of compliance to the experimental protocol as assessed by the experimenters Additionally all subjects reserve the right to at any time withdraw from the study for any reason
QUALITY ASSURANCE
This is a one-site study and will be monitored by an internal monitoring process akin to Good Clinical Practice guidelines All procedures will be done according to a pre-defined protocol ensuring a standard operating procedure for acquisition of all data
Additionally The MR- and EMG-data quality is inspected during and right after data acquisition as is normal practice in the clinical routine and research
Logbooks are kept for all sessions and all deviations from protocol will be noted Data quality is further assessed through the subsequent offline data processing stage through standardized processing pipelines
All staff who perform MR and TMS have received comprehensive training in the respective methods as well as safety training All staff involved in the project will be familiar with the procedure and methods and trained the experimental procedure before conducting measurements
DATA ANALYSIS PLAN
Primary outcome All patients who attend at least one rTMS session and have follow-up data available will be included in the intention-to-treat analysis for the primary outcome regardless of amount of rTMS sessions completed
EMG and MRI data will be preprocessed by a blinded researcher according to standardized pipelines For EMG data all trials will be manually checked by a blinded researcher for muscle artefacts preceding the TMS pulse and offending trials removed
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None