Muscle Strain in Multiple Sclerosis Patients Measured by Ultrasound Speckle Tracking Technique

Study Overview
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Brief Summary
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The primary study, as outlined in the original trial registration, aiming to use ultrasound speckle tracking (STU) to monitor muscle contractility in multiple sclerosis (MS) patients receiving vs. not receiving fampridine, as well as to relate these results to performance-based measures and biomarkers to explore disease progression and muscle activity, has been cancelled. Instead four exploratory studies that originate from the initial trial registration but with revised aims, outcome measures and time points, have been prepared - see the DEVIATIONS TO TRIAL PROTOCOL included in the Statistical Analysis Plan filed under Document section. Summary of original trial registration: Despite effective treatments, the majority of patients with multiple sclerosis experience walking impairments to a degree where walking aids or a wheelchair is required. Since 2009, medical treatment of walking impairments has been possible with fampridine, which has proven effective in approximately 40% of the patients. At present, the treatment is offered on the basis of a measurable improved walking function evaluated by simple performance-based walking tests. The treatment is offered on the basis of a measurable improved walking distance. This is shown today using simple performance-based walking tests that are difficult to complete for those MS patients who are without gait function but could still benefit from fampridine treatment. Ultrasound speckle tracking is a non-invasive ultrasound technique, with the potential to measure muscle function, including muscle contractility (through strain). Ultrasound speckle tracking is designed for dynamic cardiac muscular examination, but can in a modified version be used for assessment of the skeletal muscles. The purpose of this project is to use ultrasound speckle tracking to monitor muscle contractility in MS patients receiving vs. not receiving fampridine treatment. Furthermore, to relate these results to biomarkers in blood and urine to examine disease progression and muscle activity.

Detailed Description
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The primary study, as outlined in the original trial registration, aiming to use ultrasound speckle tracking (STU) to monitor muscle contractility in multiple sclerosis (MS) patients receiving vs. not receiving fampridine, as well as to relate these results to performance-based measures and biomarkers to explore disease progression and muscle activity, has been cancelled. Instead four exploratory studies that originate from the initial trial registration but with revised aims, outcome measures and time points, have been prepared - see the DEVIATIONS TO TRIAL PROTOCOL included in the Statistical Analysis Plan filed under Document section The detailed description that was included in the original trial registration: Despite effective treatments, the majority of multiple sclerosis (MS) patients experience difficulty in walking and the need of a walker or wheelchair. Since 2009, medical treatment of walking impairments has been possible with fampridine, which has proven effective at approximately 40% of patients. At present, the treatment is offered on the basis of a measurable improved walking function evaluated by simple performance-based walking tests. Multiple sclerosis patients, who do not have the sufficient gait function to complete these tests, may still benefit from fampridine treatment in other activities of daily life. However, these patients are currently not eligible for fampridine treatment due to current requirements of a measurable improved effect. Ultrasound speckle tracking (UST) is a non-invasive ultrasound technique, with the potential to directly analyze the muscle strain in the muscles. UST is designed for dynamic cardiac muscular examination, but can be used in a modified version for skeletal muscle examination. The technique has already been tested in a minor pilot study with MS patients. The objective of the present study is to use UST to monitor muscle strain in the weight-bearing and transfer-related muscles in MS patients who receive fampridine vs. patients who do not receive this treatment. Strain is evaluated over time during different isometric contractions. Furthermore, the relation between these results and the performance based measures of clinical function and biomarkers in blood and urine will be examined to explore disease progression and muscle activity. MS patients will be recruited from sclerosis clinics at Odense University Hospital (OUH), Esbjerg, Kolding and Sønderborg. All participants will undergo the existing standard practice for patients receiving fampridine treatment, including functional and neurological examination. In addition to the regular practice, participants will be offered UST, answer relevant questionnaires as well as the collection of blood- and urine samples (8 ml of blood and 10 ml of urine will be centrifuged and kept in 0.5 ml aliquots and stored in the already established biobank at the Department of Neurology, OUH. Participants will be tested at baseline (just before start of fampridine treatment), after 14 days of treatment and again one year after baseline. All three test sessions will include the above mentioned testing protocol. The primary end-point will be at one-year follow-up. A sub-group of 30 randomly selected participants will supplementary perform a 3-dimensional gait analysis in the motion laboratory. A list generated from 30 randomly found numbers from 1 to 60 will be used. In the motion laboratory, the outcomes: Kinematics, kinetics, gait summary measures and temporo spatial outcome measures will be generated. Participants, who respond to the fampridine after 14 days of treatment, will continue in the project as cases, whereas non-responders persist in the trial as an untreated control group. The study is approved by the Regional Committees on Health Research Ethics for Southern Denmark, project Identification: S-20170203. Sample size is based on previously published studies regarding effect of fampridine treatment as well as already detected differences in pilot data obtained from 2 MS patients and 4 healthy controls on m supraspinatus at 40% of maximal load. With an alpha value of p<0.05 and a power of 0.80, sample size is 60. The study will be conducted in accordance to the Good Clinical Practice and the Declaration of Helsinki and has been approved by the National Committee on Health Research Ethics and the Danish Data Protection Agency. To our knowledge, this is the first study to evaluate muscle function in MS patients through muscle strain measured using UST as well as examine its correlation to biomarkers for disease progression and muscle activity. Consequently, the result of the present study could expand clinical guidelines for fampridine treatment in MS patients. Furthermore, UST could be implemented for clinical use in assessing muscle strength and treatment response and can ultimately be used to monitor disease progression in MS patients independent of fampridine treatment. The included analysis of blood and urine opens new opportunities for diagnostic and prognostic biomarkers. In addition to provide new knowledge of disease mechanisms, it may also serve as potential new targets for future treatments.

Official Title
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Muscle Strain in Multiple Sclerosis Patients Measured by Ultrasound Speckle Tracking

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Fampridine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fills the criteria for fampridine treatment Fills the diagnostic McDonald criteria for MS Age between 18 and 100 years EDSS between 4 and 7 Exclusion Criteria: Diagnosed epilepsy MS attack or an acute decrease of functional capacity within the last 60 days Change in immunomodulatory treatment within the last 60 days Cancer within the last 5 years Clinically significant systemic disease Concurrent treatment with cimetidine, carvediol, propanolol and metformine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective cohort Study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>The participants receive Fampridine treatment (10 mg x 2 daily) for 14 days. They are testet prior to treatment and following the 14 days of treatment. | Drug: Fampridine<br>* sustained-release tablet 10 mg morning and evening.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gait Profile Score (GPS) - (subgroup of 30 allocated to 3D gait analysis) | Change in GPS. GPS is a summary measure of kinematic data. The GPS evaluates the overall quality of gait by comparing nine kinematic variables, described as Gait Variable Scores (GVS), relative to normative data. GPS is the root mean square (RMS) difference between the data of relevant kinematic variables of an individual patient and the averaged data from a reference group comprised of people without gait impairments. Originally we had registred that we would use the Gait Deviation Index (GDI). GDI is a unitless value from 0 to 100. It is based upon kinematic data and is an overall quantitative index that summarises the overall gait pathology into a single score for each patient by comparison with non-pathological gait. The GDI and GPS is highly correlated. We chose to use the GPS due to the inclusion of the GVS. | Baseline, 14 days (Change from baseline to 14 days follow-up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gait Variable Scores (GVS) - (subgroup of 30 allocated to 3D gait analysis) | Change in GVS. GVS refers to the Root Mean Square difference between the data of the following kinematic variables of an individual patient and the averaged data from a reference group comprised of people without gait impairments: Pelvic tilt, obliquity and rotation; hip flexion-extension, adduction-abduction, and rotation; knee flexion-extension; ankle dorsiflexion; and foot progression. | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Functional test - 6 Spot Step Test (SSST) | Change in time it takes the participant to walk through a rectangular area of 1x 5 meters while 5 cylinder blocks must be kicked out of 5 circles marked on the floor. | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Functional test - Timed 25 Footwalk (T25-FW) | Change in time it takes the participant to walk as safe and as quickly as possible through a straight clearly marked lane of 7.62 meters (25 feet). | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Functional test - 2-minute Walk Test (2MWT) | Change in distance that the participant is able to walk in 2 minutes. | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Walking speed - (subgroup of 30 allocated to 3D gait analysis) | Change in walking speed (m/s) | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Step length - (subgroup of 30 allocated to 3D gait analysis) | Change in step length (m) | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Step width - (subgroup of 30 allocated to 3D gait analysis) | Change in step width (m) | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Stride length - (subgroup of 30 allocated to 3D gait analysis) | Change in stride length (m) | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Cadence - (subgroup of 30 allocated to 3D gait analysis) | Change in cadence (steps/min.) | Baseline, 14 days (Change from baseline to 14 days follow-up) | 
| Questionnaire - 12-Item Multiple Sclerosis Walking Scale (MSWS-12), Danish version | Change in MSWS-12. Data is converted to a scale from 0 to 100, where 0 represents the best and 100 the worst. A change score of at least -4 represents a clinically meaningful improvement in the gait function. | Baseline, 14 days (Change from baseline to 14 days follow-up) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Speckle tracking ultrasonography, Muscle strain, Fampridine, Multiple Sclerosis, Neurological diseases, Biomarkers, muscle contractility