Early Exercise Efforts in Multiple Sclerosis

Exercise as a Supplemental Treatment Strategy Early in the Disease Course of Multiple Sclerosis

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Combination product: Systematic exercise training; Behavioral: Educational program

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Section for Sport Science, Department of Public Health, University of Aarhus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Systematic exercise training; Two weekly supervised aerobic exercise trainings for 48 weeks. The training will be planned by exercise physiologists, and performed in a progressive manner.	Combination product: Systematic exercise training; Combination of standard medical treatment and systematic early exercise training in persons with MS.
Active Comparator: Educational program; Educational program on physical activity and health, consisting of four educational sessions in the intervention period.	Behavioral: Educational program; Informations regarding health benefits of physical activity and exercise.
No Intervention: Standard treatment alone; Data from The Danish MS Registry will serve as control-data for standard treatment alone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Annual Relapse Rate (ARR)	Number of relapses, registered and validated by neurologist, on annual basis	ARR, 1 year intervention; 1 year follow up.
Percentage brain volume change	Brain atrophy will be measured from MRI-scans	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multiple Sclerosis Functional Composite (MSFC)	Composite score from Timed 25-Feet Walk Test (T25FWT), 9-Hole Peg Test (9HPT), Paced Auditory Serial Addition Test (PASAT)	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Expanded Disability Status Scale (EDSS) score	Disability status score assessed and registered by neurologist. The scale ranges from 0-10 in 0.5 unit increments representing higher levels of disability.	Baseline, after 1 year intervention, and again at 1 year follow up.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional capacity, Six-minute walk test (6MWT)	Distance covered during a six-minute maximal walking test	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Functional capacity, Six-spot-step-test (SSST)	SSSt is a measure of walking ability, balance and coordination. Measured as the time to complete the six-spot course.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Functional capacity, Accelerometry	Measurement of level of physical activity by wearing a accelerometer for 7 days at each timepoint. Measured in counts/min.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Aerobic capacity	Maximal oxygen uptake test on bike ergometer, measured by indirect calorimetry.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Cognition, Symbol Digit Modality Test (SDMT)	Assessment of cognitive function (processing speed), with a higher number of correct answers in the test representing better cognitive function.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Cognition, Paced Auditory Serial Addition Test (PASAT)	Assessment of cognitive function (processing speed and memory), with a higher number of correct answers in the test representing better cognitive function.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Cognition, Selective Reminding Test (SRT)	Assessment of cognitive function (memory), with a higher number of correct answers in the test representing better cognitive function.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Short Form Health Survey 36 (SF-36)	Questionnaire assessing health status. The SF-36 consists of eight subscales, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Multiple Sclerosis Impact Scale 29 (MSIS-29)	Questionnaire assessing the impact of the disease. 20 questions measure the physical impact, and 9 questions measure the psychological impact. Each question is scored from 1-5. A greater score is equal to a larger impact.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Multiple Sclerosis Walking Scale 12 (MSWS-12)	Questionnaire assessing the impact of the disease on walking. Each question is scored from 1-5 and then summed and transformed to a 0-100 scale. Higher scores indicate a greater impact on walking.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Modified Fatigue Impact Scale (MFIS)	Questionnaire assessing the effects of fatigue on physical, cognitive and psychosocial functioning. The score of the MFIS is the sum of the scores for the 21 items. A higher score represents a higher impact of fatigue, in general or in relation to one of the above mentioned areas.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Number of lesions	Number of lesions, measured by MRI-scanning.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Lesion load	Volume of lesions, measured by MRI-scanning.	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Kurtosis	MRI-measure of microstructural changes in the brain	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.
Inflammation	Blood samples will be analyzed for key inflammatory cytokines	Baseline, 24 weeks, after 1 year intervention, and again at 1 year follow up.

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: University of Southern Denmark; Region of Southern Denmark
• Investigators: Principal Investigator: Morten Riemenschneider, MSc, Section for Sport Science, Department of Public Health, Aarhus University

Publications and helpful links

General Publications

• Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17. doi: 10.1016/S0140-6736(08)61620-7.
• Dalgas U, Stenager E, Ingemann-Hansen T. Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training. Mult Scler. 2008 Jan;14(1):35-53. doi: 10.1177/1352458507079445. Epub 2007 Sep 19.
• Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014 Feb;89(2):225-40. doi: 10.1016/j.mayocp.2013.11.002.
• Ziemssen T, De Stefano N, Sormani MP, Van Wijmeersch B, Wiendl H, Kieseier BC. Optimizing therapy early in multiple sclerosis: An evidence-based view. Mult Scler Relat Disord. 2015 Sep;4(5):460-469. doi: 10.1016/j.msard.2015.07.007. Epub 2015 Jul 17.
• Patwardhan MB, Matchar DB, Samsa GP, McCrory DC, Williams RG, Li TT. Cost of multiple sclerosis by level of disability: a review of literature. Mult Scler. 2005 Apr;11(2):232-9. doi: 10.1191/1352458505ms1137oa.
• Elovaara I. Early treatment in multiple sclerosis. J Neurol Sci. 2011 Dec;311 Suppl 1:S24-8. doi: 10.1016/S0022-510X(11)70005-3.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2018
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: October 16, 2017
• First Submitted That Met QC Criteria: October 23, 2017
• First Posted (Actual): October 26, 2017

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Exercise; Multiple sclerosis; Early treatment; Disease-modifying treatment
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: Morten_Riemenschneider_PhD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data will be stored in The Danish National Archives after completion of the project, and data can be accessed through request to The Danish National Archives.
• IPD Sharing Time Frame: The data will become available after completion of the project, expectedly January 2021. The Danish National Archives stores data without a time frame (forever).
• IPD Sharing Access Criteria: Sharing of data can happen upon request to The Danish National Archives.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No