Clinical trial NCT03847545: Muscle Strain in Multiple Sclerosis Patients Measured by Ultrasound Speckle Tracking Technique
Official title: Muscle Strain in Multiple Sclerosis Patients Measured by Ultrasound Speckle Tracking
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Multiple Sclerosis
Keywords: Speckle tracking ultrasonography
Muscle strain
Fampridine
Multiple Sclerosis
Neurological diseases
Biomarkers
muscle contractility
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Sygehus Lillebaelt
name: Region of Southern Denmark
name: The Augustinus Foundation, Denmark.
name: Lounkær Fonden
name: Fonden for scleroseramte på Fyn
name: The Danish Multiple Sclerosis Society
name: TH MAIGAARDS EFTF. FRU LILY BENTHINE LUNDS FOND AF 1. JUNI 1978
name: Fonden til Lægevidenskabens Fremme
name: Overlægeråds forskningsfond
First posted: 2019-02-20
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective cohort Study
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Gait Profile Score (GPS) - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
Secondary outcomes:
measure: Gait Variable Scores (GVS) - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Functional test - 6 Spot Step Test (SSST)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Functional test - Timed 25 Footwalk (T25-FW)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Functional test - 2-minute Walk Test (2MWT)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Walking speed - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Step length - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Step width - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Stride length - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Cadence - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Questionnaire - 12-Item Multiple Sclerosis Walking Scale (MSWS-12), Danish version
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
Other outcomes:
measure: Neurological examination - Expanded Disability Status Scale (EDSS)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Neurological examination - Multiple Sclerosis Impairment Scale (MSIS)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Functional test - Nine Hole Peg Test (9HPT)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Peak range of motion (kinematic) - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (follow-up from baseline), 52 weeks (follow-up from "baseline" and "14 days")
measure: Peak and mean joint moments (kinetic) - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Single support - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Single Limp Index - (subgroup of 30 allocated to 3D gait analysis)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Questionnaire - Oxford Shoulder Score (OSS), Danish version
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Questionnaire - UCLA Activity Scale, Danish version
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Neurofilament light
timeFrame: Baseline, 14 days (follow-up from baseline), 52 weeks (follow-up from "baseline" and "14 days")
measure: TNF
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: TNFR1
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: TNFR2
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: IL-1alpha
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: IL-1beta
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: IL-1Ra
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Creatinin phosphokinase
timeFrame: Baseline, 14 days (follow-up from baseline), 52 weeks (follow-up from "baseline" and "14 days")
measure: Lactate dehydrogenase
timeFrame: Baseline, 14 days (follow-up from baseline), 52 weeks (follow-up from "baseline" and "14 days")
measure: Myoglobin
timeFrame: Baseline, 14 days (follow-up from baseline), 52 weeks (follow-up from "baseline" and "14 days")
measure: Skeletal troponin
timeFrame: Baseline, 14 days (follow-up from baseline), 52 weeks (follow-up from "baseline" and "14 days")
measure: eGFR
timeFrame: Baseline, 14 days (follow-up from baseline), 52 weeks (follow-up from "baseline" and "14 days")
measure: Test for urinary tract infection (UTI)
timeFrame: Baseline, 14 days follow-up, 52 weeks follow-up
measure: Muscle strain of the supraspinatus muscle
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Muscle strain of the biceps brachii muscle
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Muscle strain of the soleus muscle
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: IL-2
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: IL-4
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: IL-8
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: IL-17
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: INF-gamma
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
measure: Glial fibrillary acidic protein (GFAP)
timeFrame: Baseline, 14 days (Change from baseline to 14 days follow-up)
Locations:
city: Odense C
country: Denmark
facility: University of Southern Denmark - Odense Univarsity Hospital
Study officials:
affiliation: Department of Neurology, Odense University Hospital, Odense, Denmark
name: Helle H. Nielsen, MD, PhD
role: STUDY_DIRECTOR
affiliation: Department of Neurology, Odense University Hospital, Odense, Denmark
name: Maria Thorning, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gottberg K, Einarsson U, Ytterberg C, de Pedro Cuesta J, Fredrikson S, von Koch L, Widen Holmqvist L. Health-related quality of life in a population-based sample of people with multiple sclerosis in Stockholm County. Mult Scler. 2006 Oct;12(5):605-12. doi: 10.1177/1352458505070660.
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citation: Frich, L.H., et al., Direct isometric muscle strain analyses using speckle tracking technology. A validation study, in European Muscle Conference 2017. 2017, Journal of Muscle Research and Cell Motility: Potsdam