Muscle Strain in Multiple Sclerosis Patients Measured by Ultrasound Speckle Tracking Technique
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Fampridine
Intervention type(s): Drug
Intervention description(s): sustained-release tablet 10 mg morning and evening.
Intervention MeSH terms: 4-Aminopyridine
Intervention model: Single Group Assignment
Intervention model description: Prospective cohort Study
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Speckle tracking ultrasonography; Muscle strain; Fampridine; Multiple Sclerosis; Neurological diseases; Biomarkers; muscle contractility