Clinical trial NCT03322761: Early Exercise Efforts in Multiple Sclerosis
Official title: Exercise as a Supplemental Treatment Strategy Early in the Disease Course of Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Multiple Sclerosis
Keywords: Multiple sclerosis
Exercise
Disease-modifying treatment
Early treatment
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: University of Southern Denmark
name: Region of Southern Denmark
First posted: 2017-10-26
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study seeks to investigate whether early exercise efforts can expand the use of exercise in Multiple sclerosis (MS), from symptom treatment only, to early supplementary disease-modifying treatment.

The study will be conducted in a randomized and controlled manner, with single blinding. Participants will be allocated to either a systematic aerobic exercise intervention or an educational programme on exercise and physical activity. Both interventions will last 1 year, and involve a 1 year follow-up period.

It is hypothesized that early exercise efforts can modify the disease activity and disability progression.

Detailed description: Multiple Sclerosis (MS) is an autoimmune and neurodegenerative disease in the central nervous system (CNS), characterized by a complex pathogenesis and heterogeneous symptoms. The histopathological hallmark of the disease is sclerotic lesions. These inflammatory lesions manifests as disabling relapses, and the number of relapses in the first few years after disease onset is associated with progression of disability, with a higher number of relapses leading to a more rapid progression. In addition, diffuse neurodegeneration seems to occur early in the disease, and even though it is not always clinically evident it is associated with disease progression. A reduction in relapse rate and neurodegeneration early in the MS disease course may slow the progression of disabilities and can possibly reduce overall disease burden. For the individual person with MS (pwMS) a reduction in overall disease burden will often improve quality of life, and since MS is a lifelong disease this is of great interest. Preventing disability in pwMS is also highly relevant in a societal perspective, as it lowers the large costs associated with increased disability. As a consequence, the importance of early treatment have been emphasized.

Treatment of MS have seen great advances in the recent years, resulting in an increasing number of available disease-modifying treatments (DMT). Despite the fact that the current DMTs favourable alter a number of clinical outcomes and the course of the disease, it is still a serious and deteriorating condition with significant disease activity, impaired neurological functions and thus progression of disabilities. New and supplemental treatment strategies are therefore still warranted, and exercise have gained attention as a safe and tolerable rehabilitation strategy. Recently, exercise furthermore have gained substantial attention, as the first indications of neuroprotective and disease-modifying effects of exercise has been published. However, despite the focus on early treatment in medical DMTs no studies have investigated the effects of exercise as a supplemental treatment strategy early in the disease course of MS.

Consequently, the purpose of this study is to investigate the effects of early exercise efforts on disease activity and disability progression. In a sub-group the effects will furthermore be investigated on brain volume, specific brain regions, and inflammation.

It is hypothesized that early exercise efforts can modify the disease activity and disability progression, by reducing the relapse rate, the progression of Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) scores. The rate of brain atrophy and the lesion load, obtained by MRI scans, is also hypothesized to be reduced. This is expected to be due to an exercise-induced reduction in inflammation.

The study will be a randomised and controlled study with randomisation to either an systematic aerobic exercise intervention or an educational programme on exercise and physical activity. Both interventions are in addition to standard treatment, and will last 1 year. The exercise intervention will consist of 2 supervised exercise sessions per week in the complete duration of the study, while the standard treatment plus exercise education program will consist of 4 educational sessions on the health benefits associated with exercise and physical activity held every third month throughout the intervention period. The training in the exercise group will be aerobic exercise (running, cycling, rowing or on a cross-trainer) planned by exercise physiologists and performed in a progressive manner. To allow handling of a large number of participants, who is also geographically spread, the exercise intervention will be locally anchored, but at the same time supervised by student employees from Section for Sports Science and controlled by internet- and telephonic communication. In addition to the two intervention groups, data from The Danish MS registry will serve as population based standard treatment control data. All groups will be followed up 1 year after cessation of the interventions.

To set the estimated number of participants a two-sample two-sided power calculation has been conducted. The basis for this calculation is an report from Tallner et al. who have shown a difference in relapse rate during a two-year period (equal to our 1 year intervention, and 1 year follow-up) of 0.65 relapses between physically active and physically inactive MS patients (active: 0.95 +/- 0.97 relapses in 2 years ; inactive: 1.60 +/- 1.64 relapses in 2 years). 83 patients with MS should be enrolled in each intervention group (a 20% drop-out rate has been included). Newly published data on the brain atrophy in percentage of total brain volume after 24 weeks of resistance training have been the basis for a similar calculation of the number of participants in the sub-group, from whom MRI-scans and blood samples will be obtained. 41 participants from each intervention group should form this sub-group.

MS is a complex disease with heterogenous symptoms, and by combining the disciplines of exercise physiology, neurology and radiology this study can be the first long-term and large-scale exercise study to investigate the possible neuroprotective and disease-modifying effects of exercise when initiated early in the disease course of MS. Consequently, this project has the potential to change present clinical practice and generate further attention to exercise, not only as symptom treatment, but also as an supplemental disease-modifying treatment strategy early in the course of MS.

Eligibility criteria: Inclusion Criteria:

* Signed consent
* Definite diagnosis with Relapsing remitting multiple sclerosis (RRMS)
* No more than 2 years since diagnosis
* Expectedly able to carry out high intensity aerobic training
* Able to transport themselves to and from training sessions

Exclusion Criteria:

* Pregnancy
* Dementia, alcohol abuse, or pacemaker
* Metallic implants, hindering MRI-scans
* Comorbidities hindering participation in high intensity aerobic training

Primary outcomes:
measure: Change in Annual Relapse Rate (ARR)
timeFrame: ARR, 1 year intervention; 1 year follow up.
measure: Percentage brain volume change
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Secondary outcomes:
measure: Multiple Sclerosis Functional Composite (MSFC)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Expanded Disability Status Scale (EDSS) score
timeFrame: Baseline, after 1 year intervention, and again at 1 year follow up.
Other outcomes:
measure: Functional capacity, Six-minute walk test (6MWT)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Functional capacity, Six-spot-step-test (SSST)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Functional capacity, Accelerometry
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Aerobic capacity
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Cognition, Symbol Digit Modality Test (SDMT)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Cognition, Paced Auditory Serial Addition Test (PASAT)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Cognition, Selective Reminding Test (SRT)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Short Form Health Survey 36 (SF-36)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Multiple Sclerosis Impact Scale 29 (MSIS-29)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Multiple Sclerosis Walking Scale 12 (MSWS-12)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Modified Fatigue Impact Scale (MFIS)
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Number of lesions
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Lesion load
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Kurtosis
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
measure: Inflammation
timeFrame: Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Locations:
city: Aarhus
country: Denmark
facility: Section for Sport Science, Department of Public Health, University of Aarhus
Study officials:
affiliation: Section for Sport Science, Department of Public Health, Aarhus University
name: Morten Riemenschneider, MSc
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Kjolhede T, Siemonsen S, Wenzel D, Stellmann JP, Ringgaard S, Pedersen BG, Stenager E, Petersen T, Vissing K, Heesen C, Dalgas U. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult Scler. 2018 Sep;24(10):1356-1365. doi: 10.1177/1352458517722645. Epub 2017 Jul 28.
citation: Riemenschneider M, Hvid LG, Ringgaard S, Nygaard MKE, Eskildsen SF, Petersen T, Stenager E, Dalgas U. Study protocol: randomised controlled trial evaluating exercise therapy as a supplemental treatment strategy in early multiple sclerosis: the Early Multiple Sclerosis Exercise Study (EMSES). BMJ Open. 2021 Jan 12;11(1):e043699. doi: 10.1136/bmjopen-2020-043699.