Effects of exercise training among adults with multiple sclerosis Protocol for a systematic review that informs an updated prescriptive guideline

Effects of exercise training among adults with multiple sclerosis Protocol for a systematic review that informs an updated prescriptive guideline | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of exercise training among adults with multiple sclerosis Protocol for a systematic review that informs an updated prescriptive guideline Louise Declerck, Kathleen Martin Ginis, Amy Latimer Cheung, Brenda Jeng, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6148397/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Feb, 2026 Read the published version in Systematic Reviews → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Research demonstrates that exercise training is both safe and beneficial for individuals with multiple sclerosis (MS). There is a timely opportunity for updating the guidelines for exercise training in MS, as the number of RCTs examining the effects of exercise training on a range of functional and biomedical outcomes among adults with MS has increased substantially in the past decade. The evidence for updating the guidelines should be gathered through rigorous methodology, thereby ensuring a comprehensive analysis. This systematic review of the literature will evaluate the type and dose of exercise training necessary to improve fitness, biomarkers of health and disease, physical and cognitive functions, symptoms of MS, quality of life, and/or participation in activities of daily life among adults with MS presenting with mild, moderate, or severe disability. Methods: This protocol for a systematic review follows the PRISMA-P guidelines and was registered on Prospero. We will undertake a systematic and comprehensive search will be conducted across 8 electronic bibliographic databases. Retrieved references will be screened by two authors based on pre-established inclusion and exclusion criteria. Relevant data will be extracted into piloted tables and synthesized qualitatively. Methodological quality of the included studies will be determined using the Tool for the Assessment of Study quality and Reporting in Exercise (TESTEX). Risk of bias will be assessed through the revised Cochrane risk-of-bias tool for RCTs (RoB 2). Finally, the certainty of evidence provided for the outcomes of interest will be evaluated through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. Discussion: The evidence gathered and analyzed through this review will be crucial for our next step of updating the exercise guidelines for MS. These updated guidelines will provide people with MS, their families and/or their caregivers, as well as health care professionals and MS services organization or advocates, with clear information to promote exercise training among patients with MS. This will subsequently facilitate implementation of exercise training programs into MS-care. Registration details: PROSPERO registration number CRD42025628825 exercise multiple sclerosis guidelines evidence-based recommendations neurological rehabilitation Introduction Multiple sclerosis (MS) is a chronic, immune-mediated and neurodegenerative disease of the central nervous system (CNS) with an estimated prevalence of 1 million adults in the United States and 2.9 million adults worldwide ( 1 , 2 ). The extent and location of damage within the CNS result in outcomes including declines in physiological conditioning as well as physical and cognitive functions, and worsening of symptoms such as fatigue, depression, and anxiety ( 3 ). Those outcomes, in turn, can have significant negative impact on health, well-being, quality of life and participation in daily activities in MS ( 4 ). The disease itself is managed through medications that target immune system components including signaling proteins and cells, and reduce rates of relapses, lesions, and disease progression ( 5 ). Nevertheless, people with MS still demonstrate the aforementioned outcomes based on (a) residual CNS damage and/or smoldering disease and (b) alterations in health behaviors resulting in prevalent and influential comorbidity. This underscores the importance of adjuvant therapeutic approaches for the management of MS and its life-altering outcomes that can be administered alongside medications. Exercise training, defined as planned, structured, and repetitive physical activity undertaken for improving or maintaining fitness ( 6 ), represents a key approach for rehabilitation and symptom management in MS ( 7 ). There is broad consensus that exercise training is beneficial for individuals with MS across a range of outcomes from cells through quality of life and societal participation ( 8 ). There is further evidence that exercise training is safe based on a recent meta-analysis of adverse events and effects reported in randomized controlled trials (RCTs) ( 9 ). This collectively has supported the statement that “…exercise may be the single most effective non-pharmacological symptomatic treatment for multiple sclerosis.” ( 10 ). Exercise training can be administered alongside medications for comprehensive disease management through MS clinical care professionals. However, this requires clear, up-to-date, evidence-based prescriptive guidelines ( 11 , 12 ). The first evidence-based prescriptive guidelines for exercise training in MS were published in 2013 and were developed through a two-stage process ( 13 ). The first stage involved a systematic review of the relevant literature ( 14 ) that provided the evidence for the second stage of guideline formation ( 13 ). This process yielded the MS prescriptive exercise training guidelines recommending that adults (aged 18–65 years) with mild-to-moderate MS-related disability engage in 30 minutes or more of moderate intensity aerobic activity twice per week, and strength training targeting major muscle groups twice per week. The recommended prescription of exercise training was based on promoting improvements in fitness and perhaps improvements in fatigue, mobility and quality of life ( 13 ). There is now a timely opportunity for updating the exercise training guidelines for MS based on several reasons. First, the original guidelines were based on a systematic review of evidence of mediocre quality from a limited number of studies, including both RCT and non-randomized trials ( 13 ). The past decade’s growing body of published RCTs examining the effects of exercise training on outcomes in adults with MS provides a robust evidence base for updating the guidelines, drawing on expansive and higher-level evidence from these studies ( 15 ). Second, the increasing number of exercise training RCTs across the disability spectrum in MS might further allow for the extension of recommendations among people with MS who have severe disability. Moreover, the expanded number of outcomes included in the RCTs may permit a broader indication for the prescriptive exercise training guidelines. This is of particular importance, as recent systematic reviews published on the effects of exercise among people with MS have focused only on a few, specific outcomes ( 16 – 18 ). For guidelines formation and update, it is crucial to adopt a broader approach which includes a large range of health and disease-related outcomes, thereby fully supporting implementation of the guidelines in public health policies ( 19 ). Finally, we note that the existing guidelines were largely branded as Canadian and this has limited uptake ( 20 ) and potentially reduced the effects on physical activity levels for the global MS population. Aim Our overarching aim is to update the 2013 exercise training prescriptive guidelines for MS, and the initial, foundational step involves a systematic, structured review of the available evidence from RCTs. To that end, the objectives of this systematic review are: To recommend the type and dose of exercise training necessary to improve fitness, biomarkers of health and disease, physical and cognitive functions, symptoms of MS, quality of life, and/or participation in activities of daily life among adults with MS presenting with mild, moderate, or severe disability. To identify the type, frequency, intensity, and/or duration of exercise training that elicit benefits across levels of mild, moderate, or severe disability. Methods and analysis The current protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines ( 21 ). The completed PRISMA-P checklist is provided in Appendix 1. The protocol for the review is further registered with PROSPERO International Prospective Register of Systematic Reviews, under registration number CRD42025628825. The most recent version of the Cochrane Handbook for Systematic Reviews of Interventions ( 22 ) was consulted when elaborating this protocol, ensuring that it satisfied the highest standard of methodological rigor. The resulting systematic review will adhere to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 statement ( 23 ). As the goal of the systematic review involves updating exercise training guidelines ( 13 ), the Appraisal of Guidelines Research and Evaluation instrument (AGREE II), specifically items 7 to 9, will be respected ( 24 ). Eligibility Criteria Study selection will be guided by a comprehensive list of inclusion and exclusion criteria, following a specific order of importance. The Cochrane Handbook recommends the use of review population, intervention, comparator and outcome (PICO) elements to pre-establish clear eligibility criteria ( 22 ). As per recommendation ( 25 ), we added one element, namely study design, to these criteria (Table 1 ). In addition, included studies will need to have a retrievable full-text and be written in English, French or Dutch. Conference abstracts will be excluded, but we will investigate whether these are linked to full-text publications. If necessary, conference abstract authors will be contacted for information on the progress of the study. Table 1 Review of PICOS to determine main eligibility criteria PICOS Element Inclusion Criteria Exclusion Criteria Population Study sample is made up of adults (aged 18 years and above) with any type(s) of MS. All disability levels (mild, moderate or severe) are included. Study sample includes adults without MS in clearly separate group. Study sample is only partly made up of adults (aged 18 years and above) with any type(s) of MS, and adults without MS are in the same group. Study sample includes pediatric forms of MS. Study sample is made up of animal models of MS. Intervention Study intervention consists of any modality of exercise training, defined by the World Health Organization as “a subcategory of physical activity that is planned, structured, repetitive and purposeful in the sense that the improvement or maintenance of one or more components of physical fitness* is the objective.” ( 6 ) A majority (at least 3 of 4) of the exercise intervention’s FITT parameters, namely frequency, intensity, time and type, are defined. Study intervention consists of a single bout of exercise only. Study intervention consists of exercise training targeting one specific body function such as pelvic floor or inspiratory/expiratory muscle training. Study intervention is supplemented by one or more additional, non-exercise study intervention(s) such as relaxation, massage, diet or pharmaceutical approach, which the control group does not receive. Study intervention consists of a therapeutic intervention only targeting disability and functioning, including robotic and bodyweight-supported gait training. Comparators At least one of the study comparator(s) consist of non-exercise controls, including sham exercise interventions, non-active or education program, standard/usual care, no treatment or waitlist. Study comparator(s) is identical to exercise intervention but with different type of delivery method such as remote delivery. Study comparator(s) receive a pharmacology-based treatment that the intervention group does not receive. Outcomes Outcome measures relate to at least one of the following: fitness*, biomarkers, physical and cognitive function, symptoms, quality of life or participation in activities of daily life. Outcomes have been measured before and at least once after the intervention delivery. Outcome measures are solely qualitative. Study design Design follows methodology of RCTs. Design follows other types of methodology including case report, case study or cross-sectional. * Physical fitness includes cardiorespiratory fitness, muscular strength, muscular endurance, body composition and flexibility ( 33 ). Search strategy and information sources The search strategy will be developed by the research team in collaboration with an experienced university librarian. The search itself will be conducted by the librarian. The 8 following electronic bibliographic databases will be searched: PubMed, EMBASE, PEDro, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Rehabilitation & Sports Medicine Source from inception to date of search. To compose a comprehensive search, we will start by creating a table of keywords which include our main search terms (the population and intervention of interest) as well as synonyms and closely related terms. These keywords will be identified by relying on the research team’s expertise, and identifying search terms used in similar previously published systematic reviews ( 14 ). We will then identify relevant subject headings available in each of the different databases. These key words and subject heading will then be combined by using the Boolean operators AND/OR and adapted or structured according to each database’s characteristics. As recommended by the Cochrane Handbook, we will add pre-established and highly sensitive search filters to search for RCTs ( 22 ). No search restriction will be made (for example, related to age range of the recruited samples, or language of the reports). The proposed search strategy for PubMed is provided in Appendix 2. The studies identified and included through these databases will further be used as a base to undertake forward citations searches in Google scholar in order to identify grey literature sources including reports, dissertations and theses. We will conduct hand searches of the reference lists from included studies, as well as that of previous reviews on the same topics, to complete our search and strive to identify all relevant evidence. Finally, to further minimize risk of publication bias, we will search international trial registries, namely clinicaltrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) and the European Union Clinical Trials Register (EudraCT), for recent or ongoing trials and contact authors for information on the study and its data. Data management and screening procedure All identified records will be imported by the university librarian into Covidence software (Veritas Health Innovation, Melbourne, Australia) and duplicate citations will be removed by using the Covidence automated deduplication algorithm. Two review authors will independently screen the titles and abstracts for relevance. In this initial screen, records will be excluded if they clearly do not align to the population and intervention of interest, if they do not follow the design of an RCT and if they do not include any outcomes of quantitative nature. The number of records removed at this stage will be documented. In case of any uncertainty, the record will be marked as "maybe" in Covidence, and moved to the next screening stage. Conflicts will be solved via discussion which included a third author. Next, the full-text of the remaining studies will be retrieved, and two authors will independently review them to further determine eligibility according to our detailed list of inclusion and exclusion criteria (Table 1 ). Study authors will be contacted where necessary if relevant information on eligibility is missing. If the full-texts cannot be retrieved, or if the full-text displays evidence of the presence of one or more exclusion criteria, they will be removed. The reason for removing these studies will be documented through Covidence and be used to create a complete PRISMA Flow Chart (23). Any discrepancies will be discussed and resolved with a third review author. Overall agreement of full-text inclusion or exclusion between reviewers will be computed by Cohen’s Kappa, using Covidence’s tool for calculating inter-rater reliability. Data extraction Data of interest will be extracted from the included studies by a team of 9 authors with knowledge of the topic, study design, data analysis and statistics ( 22 ). Extraction of each study information will be conducted by two authors, working independently from one another. One author will extract data from all included studies, while second authors will vary so that each second author extracts approximately 12% of the total number of included studies. All authors will be trained in using the data extraction form prior to data extraction ( 22 ). These authors will not be blinded to the journal or to the authors of the reports. Any discrepancies will be recorded and resolved through discussion with a third review author. Data will be extracted into a piloted study-specific data collection form using Microsoft Excel, and will include: study identification; study methods and designs; study sample demographics; intervention and control protocols, combining elements from the Frequency, intensity, time, type (FITT) exercise-prescription framework ( 26 ) and from the Template for Intervention Description and Replication (TIDieR) checklist and guide ( 27 ); all quantitative outcomes related to fitness, biomarkers of health, physical and cognitive function, symptoms of MS, quality of life or participation in activities of daily life; results as change in outcomes after the intervention. Table 2 contains more details regarding this data. Any key missing data will initially be marked as “not reported”, and attempts will be made to obtain clarifications by contacting the corresponding authors of the articles a maximum of three times, each separated by a two-week interval. If no response is received, the items will remain “not reported” in the final table. Multiple reports of the same study will be extracted independently then linked together for subsequent analysis ( 22 ). Table 2 Items for data extraction Domain of Interest Items to Extract Additional Information Study identification Author last name (year of publication) Manuscript title, journal name Country/countries where study occurred If not provided in manuscript’s main text, we will record country of first author’s affiliation. Clinical trial registry ID Conflicts of interest Study methods Study design If multicentric, we will identify the number of recruiting centers. Number of groups for randomization, Randomization process Sample size calculation If provided in manuscript, we will record both the number and the method used for calculating it. Year(s) of study recruitment If provided in manuscript, we will record both start and end date. Study aims Study hypotheses Study sample demographics Inclusion/exclusion criteria Number of participants Items will be extracted per group/condition. Age Sex MS type Time since diagnosis Disability level* Intervention protocol Frequency Intensity Time We will record both session and overall program duration. Type We will record the name or phrase used by the authors to describe the intervention and subsequently classify its type as “aerobic”, “resistance”, “combined” or “other. Tailoring mechanisms We will record any process used to tailor or adapt the intervention FITT protocol to the participant. Intervention provider Mode of delivery Location of delivery Control protocol Frequency If the manuscript states that the control received standard/usual care, no treatment or was placed on a wait list, without providing any additional information, we will only fill out “type”. Intensity Time Type Tailoring mechanisms Intervention provider Mode of delivery Location of delivery Outcomes Fitness For each outcome of interest, we will record the testing procedure/instrument used together with the timing of the testing. Biomarkers of health and disease Physical function Cognitive function Symptoms of MS Quality of life Participation in activities of daily life Results Loss to follow-up We will record the number of participants lost during the intervention in all groups. Fitness For each outcome of interest, we will record pre, post, and follow-up (if applicable) results. Symbols will be used to identify whether the change reached statistical significance (time and/or group comparison). Items will be extracted per group/condition. Biomarkers of health and disease Physical function Cognitive function Symptoms of MS Quality of life Participation in activities of daily life *Disability level will preferably be recorded as Expanded Disability Status Scale (EDSS) or Patient Determined Disease Steps (PDDS). These will then be classified as mild (EDSS 0–4.0 or PDDS 0–3), moderate (EDSS 4.5–6.5 or PDDS 4–6) or severe (EDSS or PDDS 7 and above) ( 34 ). If unavailable, other indicators or descriptors of disability will be used. Methodological quality and risk of bias Methodological quality of the included studies will be determined using the Tool for the Assessment of Study quality and Reporting in Exercise (TESTEX), specifically developed for trials focusing on exercise-based intervention ( 28 ). The tool is made up of 12 items with a total maximum score is 15 as some items (6 and 8) can obtain multiple points ( 28 ). TESTEX has shown to possess good to excellent reliability ( 28 ). We will record the presence or absence of each item and subitem on a standardized table-template and calculate a total score for each of the included studies. Based on a recent review’s thresholds, we will classify studies obtaining scores ranging from 12–15, 9–11, 6–8, < 6, as excellent, good, fair or poor, respectively ( 29 ). We will assess risk of bias using the revised Cochrane risk-of-bias tool for RCTs (RoB 2), as recommended by the Cochrane Handbook ( 22 ). The RoB 2 encompasses fives domains from which study bias may arise, namely the randomization process, deviations from the intended intervention protocols, missing outcomes data, measurement of the outcomes and selection of the reported results. For cluster RCTs, it is recommended to add a sixth domain to assess bias related to the timing of recruitment. These domains are then joined by algorithms that include mappings of the possible combination of responses, and produce one of three possible overall risk of bias judgements: low, high or some concerns ( 22 , 30 ). Domain-specific as well as overall risk of biases will be recorded in a full risk-of-bias table, together with text and sources to support each judgment ( 22 ). Similar to the extraction process, methodological quality and risk of bias of studies will be assessed by the same team of authors, of which one will assess all studies, and the remaining 8 will each assess 12.5% of the included studies. As recommended by Cochrane, a sample of three papers will be used to pilot both quality and risk-of-bias assessments and ensure reliability among the authors ( 22 ). Data analysis The extracted data and methodological quality/risk of bias assessment will be analyzed according to the ultimate goal of this systematic review, (i.e. to provide evidence to inform the update of exercise training guidelines for people with MS)( 13 ). We aim to recommend a type and dose of exercise training necessary to improve fitness, biomarkers, physical and cognitive functions, symptoms of MS, quality of life and participation in activities of daily life among adults with MS across the disability spectrum. To that end, we will include heterogenous samples, exercise intervention protocols, and a broad range of outcomes and our analysis will be of qualitative nature. No quantitative synthesis will be performed. This is similar to the analysis conducted by a systematic review undertaken to inform the initial MS guidelines ( 13 ) and the 2018 exercise training guidelines for adults with spinal cord injury ( 31 , 32 ). We will start by providing a qualitative synthesis of participant characteristics and intervention protocols (FITT parameters), as well as overall methodological quality and risk-of-bias of the included studies. Next, we will qualitatively synthesize the study results per outcome of interest, namely fitness (including cardiorespiratory fitness, muscular strength, muscle endurance, body composition, and flexibility), biomarkers of health and disease (including blood samples), physical and cognitive function, symptoms of MS (including fatigue and depression), quality of life and participation in activities of daily life. Within this analysis, the different FITT parameters of the included studies will be highlighted. Finally, as we aim to identify FITT parameters that require modification for optimizing exercise training to varying levels of disability (mild, moderate or severe), we will conduct a final narrative synthesis by separately considering the disability levels of the included samples. Within this analysis, the FITT protocols of the included studies will be further highlighted. Certainty of evidence The certainty of evidence provided for the outcomes of interest (fitness, biomarkers of health, physical and cognitive function, symptoms of MS, quality of life and participation in activities of daily life) will be evaluated through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines ( 22 ). All RCTs will start at a level of high certainty, and be downgraded to moderate, low or very low certainty due to presence of risk of bias, inconsistency, indirectness, imprecision and publication risk of bias ( 22 ). The grading of evidence certainty will be conducted independently by two authors and appraisal of each domain will be justified and documented. Any discrepancies will be discussed and solved through consensus by a third author. Discussion By adhering to this robust protocol, which upholds high standards of research methodology, our systematic review aims to provide a solid base of evidence regarding the effects of exercise training on fitness, biomarkers, physical and cognitive function, symptoms, quality of life and participation in activities of daily life among people living with MS. The qualitative analysis, including the appraisal of the methodological quality and risk-of-bias of the included studies, will deliver valuable insights into the FITT parameters and how to modify these according to disability level. However, some limitations, such as heterogeneity between the study protocols and outcome measures, vague/incomplete or unclear reporting of protocols, and lack of RCTs conducted among people presenting with severe MS-related disability, may impact this and our ability to undertake detailed analyses within these specific sub-groups. If that is the case, authors will discuss ways to merge certain sub-groups together, when appropriate. These decisions, as well as any other deviations from the protocol resulting from these limitations or due to other, unforeseen factors will be noted and justified in the full systematic review. The evidence gathered and analyzed will be crucial for our next step, namely updating the exercise guidelines for MS, published in 2013 ( 13 ). These updated guidelines will serve to inform people with MS, their families and/or their caregivers on the benefits of exercise training. The prescriptive guidelines will further provide health care professionals and MS services organization or advocates with clear information to promote exercise training among patients with MS, and to facilitate implementation of exercise training programs into MS-care. Finally, this review will guide future research within the field of exercise training for MS by establishing the state of the art and identifying remaining research gaps. Abbreviations AGREE II Appraisal of Guidelines Research and Evaluation instrument FITT frequency, intensity, type, time GRADE Grading of Recommendations Assessment, Development and Evaluation MS multiple sclerosis PRISMA P Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols RCT randomized controlled trial ROB2 Risk of Bias Tool TESTEX Tool for the Assessment of Study quality and Reporting in Exercise TIDieR Template for Intervention Description and Replication Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Not applicable Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Dr. Louise Declerck was supported by a Fellowship of the Belgian American Educational Foundation. Authors’ contributions: LD engaged in conceptualization, methodology, writing- original draft, writing- review and editing. 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Available from: https://www.riskofbias.info/ Martin Ginis KA, van der Scheer JW, Latimer-Cheung AE, Barrow A, Bourne C, Carruthers P, et al. Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline. Spinal Cord. 2018;56(4):308–21. van der Scheer JW, Martin Ginis KA, Ditor DS, Goosey-Tolfrey VL, Hicks AL, West CR, et al. Effects of exercise on fitness and health of adults with spinal cord injury. Neurology. 2017;89(7):736–45. Medicine AC. of S. ACSM’s Fitness Assessment Manual. Lippincott Williams & Wilkins; 2021. 369 p. Ahmad H, van der Mei I, Taylor BV, Lucas RM, Ponsonby AL, Lechner-Scott J, et al. Estimation of annual probabilities of changing disability levels in Australians with relapsing-remitting multiple sclerosis. Mult Scler J. 2019;25(13):1800–8. Supplementary Files Appendix1PRISMAPchecklist.docx Appendix2.docx Cite Share Download PDF Status: Published Journal Publication published 11 Feb, 2026 Read the published version in Systematic Reviews → Version 1 posted Reviewers agreed at journal 05 May, 2025 Reviewers invited by journal 02 May, 2025 Editor assigned by journal 07 Mar, 2025 First submitted to journal 03 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6148397","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":451128681,"identity":"3a52c47a-80cc-4feb-841d-2c740de49f16","order_by":0,"name":"Louise Declerck","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtUlEQVRIiWNgGAWjYBACPoYEBoYHDDZyDMwgLhsRWthAWhIY0oxJ1nI4sYGBaC3syQc/JFQwp284zvyA4UPZYSK08DxLlkg4w5a74TCbAeOMc8RokcgxY0hs4wFq4WFg5m0jSkv+N4bEfxLpBiAtf4nTksPGkNhgkADWwkiUFp5nxhIJxxIMZwL9crDnXDphLfzsyQ8/fKj5L893/vDDBz/KrAlrQQEHSFQ/CkbBKBgFowAXAACSDzXv6BB69gAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0006-2410-333X","institution":"University of Illinois Chicago","correspondingAuthor":true,"prefix":"","firstName":"Louise","middleName":"","lastName":"Declerck","suffix":""},{"id":451128682,"identity":"77e371ba-98de-4670-83d3-d175def4e496","order_by":1,"name":"Kathleen Martin Ginis","email":"","orcid":"","institution":"The University of British Columbia","correspondingAuthor":false,"prefix":"","firstName":"Kathleen","middleName":"Martin","lastName":"Ginis","suffix":""},{"id":451128683,"identity":"f400bfa6-5003-4276-81d7-9942b9c802ad","order_by":2,"name":"Amy Latimer Cheung","email":"","orcid":"","institution":"Queen's University","correspondingAuthor":false,"prefix":"","firstName":"Amy","middleName":"Latimer","lastName":"Cheung","suffix":""},{"id":451128684,"identity":"f35c7e74-7162-413b-8408-205f758fce19","order_by":3,"name":"Brenda Jeng","email":"","orcid":"","institution":"University of Illinois Chicago","correspondingAuthor":false,"prefix":"","firstName":"Brenda","middleName":"","lastName":"Jeng","suffix":""},{"id":451128685,"identity":"be47fc24-7e32-4f4e-9bf0-f955f0edf75d","order_by":4,"name":"Peixuan Zheng","email":"","orcid":"","institution":"University of Illinois Chicago","correspondingAuthor":false,"prefix":"","firstName":"Peixuan","middleName":"","lastName":"Zheng","suffix":""},{"id":451128686,"identity":"527f243d-00b0-462d-adaf-3fd5e03f7632","order_by":5,"name":"Trinh L T Huynh","email":"","orcid":"","institution":"University of Illinois Chicago","correspondingAuthor":false,"prefix":"","firstName":"Trinh","middleName":"L T","lastName":"Huynh","suffix":""},{"id":451128687,"identity":"0c409936-927d-4bc4-a928-85b034c040c1","order_by":6,"name":"Amelia Brunskill","email":"","orcid":"","institution":"University of Illinois Chicago","correspondingAuthor":false,"prefix":"","firstName":"Amelia","middleName":"","lastName":"Brunskill","suffix":""},{"id":451128688,"identity":"7485f31a-e739-4b11-9236-2206d1dd82de","order_by":7,"name":"Robert W Motl","email":"","orcid":"","institution":"University of Illinois Chicago","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"W","lastName":"Motl","suffix":""}],"badges":[],"createdAt":"2025-03-03 17:48:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6148397/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6148397/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13643-026-03095-z","type":"published","date":"2026-02-11T15:58:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102785766,"identity":"30a8c445-c2e8-4260-bdd3-024102e739e2","added_by":"auto","created_at":"2026-02-16 16:09:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":710448,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6148397/v1/0a207615-cc60-4598-883c-6d36a19e0b06.pdf"},{"id":82177120,"identity":"c3259af7-aec8-447b-ac5a-a2264806b11f","added_by":"auto","created_at":"2025-05-07 11:18:38","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":32460,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1PRISMAPchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-6148397/v1/49581cef0179736085988409.docx"},{"id":82177117,"identity":"5996be70-c1f0-4489-8964-1007f6bb2ed8","added_by":"auto","created_at":"2025-05-07 11:18:35","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":13804,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6148397/v1/8f339bd4c5bb75b8f4192486.docx"}],"financialInterests":"","formattedTitle":"Effects of exercise training among adults with multiple sclerosis Protocol for a systematic review that informs an updated prescriptive guideline","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMultiple sclerosis (MS) is a chronic, immune-mediated and neurodegenerative disease of the central nervous system (CNS) with an estimated prevalence of 1\u0026nbsp;million adults in the United States and 2.9\u0026nbsp;million adults worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The extent and location of damage within the CNS result in outcomes including declines in physiological conditioning as well as physical and cognitive functions, and worsening of symptoms such as fatigue, depression, and anxiety (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Those outcomes, in turn, can have significant negative impact on health, well-being, quality of life and participation in daily activities in MS (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The disease itself is managed through medications that target immune system components including signaling proteins and cells, and reduce rates of relapses, lesions, and disease progression (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Nevertheless, people with MS still demonstrate the aforementioned outcomes based on (a) residual CNS damage and/or smoldering disease and (b) alterations in health behaviors resulting in prevalent and influential comorbidity. This underscores the importance of adjuvant therapeutic approaches for the management of MS and its life-altering outcomes that can be administered alongside medications.\u003c/p\u003e \u003cp\u003eExercise training, defined as planned, structured, and repetitive physical activity undertaken for improving or maintaining fitness (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), represents a key approach for rehabilitation and symptom management in MS (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). There is broad consensus that exercise training is beneficial for individuals with MS across a range of outcomes from cells through quality of life and societal participation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). There is further evidence that exercise training is safe based on a recent meta-analysis of adverse events and effects reported in randomized controlled trials (RCTs) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). This collectively has supported the statement that \u0026ldquo;\u0026hellip;exercise may be the single most effective non-pharmacological symptomatic treatment for multiple sclerosis.\u0026rdquo; (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Exercise training can be administered alongside medications for comprehensive disease management through MS clinical care professionals. However, this requires clear, up-to-date, evidence-based prescriptive guidelines (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe first evidence-based prescriptive guidelines for exercise training in MS were published in 2013 and were developed through a two-stage process (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The first stage involved a systematic review of the relevant literature (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) that provided the evidence for the second stage of guideline formation (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This process yielded the MS prescriptive exercise training guidelines recommending that adults (aged 18\u0026ndash;65 years) with mild-to-moderate MS-related disability engage in 30 minutes or more of moderate intensity aerobic activity twice per week, and strength training targeting major muscle groups twice per week. The recommended prescription of exercise training was based on promoting improvements in fitness and perhaps improvements in fatigue, mobility and quality of life (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is now a timely opportunity for updating the exercise training guidelines for MS based on several reasons. First, the original guidelines were based on a systematic review of evidence of mediocre quality from a limited number of studies, including both RCT and non-randomized trials (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The past decade\u0026rsquo;s growing body of published RCTs examining the effects of exercise training on outcomes in adults with MS provides a robust evidence base for updating the guidelines, drawing on expansive and higher-level evidence from these studies (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Second, the increasing number of exercise training RCTs across the disability spectrum in MS might further allow for the extension of recommendations among people with MS who have severe disability. Moreover, the expanded number of outcomes included in the RCTs may permit a broader indication for the prescriptive exercise training guidelines. This is of particular importance, as recent systematic reviews published on the effects of exercise among people with MS have focused only on a few, specific outcomes (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). For guidelines formation and update, it is crucial to adopt a broader approach which includes a large range of health and disease-related outcomes, thereby fully supporting implementation of the guidelines in public health policies (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Finally, we note that the existing guidelines were largely branded as Canadian and this has limited uptake (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) and potentially reduced the effects on physical activity levels for the global MS population.\u003c/p\u003e"},{"header":"Aim","content":"\u003cp\u003eOur overarching aim is to update the 2013 exercise training prescriptive guidelines for MS, and the initial, foundational step involves a systematic, structured review of the available evidence from RCTs. To that end, the objectives of this systematic review are:\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo recommend the type and dose of exercise training necessary to improve fitness, biomarkers of health and disease, physical and cognitive functions, symptoms of MS, quality of life, and/or participation in activities of daily life among adults with MS presenting with mild, moderate, or severe disability.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo identify the type, frequency, intensity, and/or duration of exercise training that elicit benefits across levels of mild, moderate, or severe disability.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003cp\u003e\u003c/p\u003e "},{"header":"Methods and analysis","content":"\u003cp\u003eThe current protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The completed PRISMA-P checklist is provided in Appendix 1. The protocol for the review is further registered with PROSPERO International Prospective Register of Systematic Reviews, under registration number CRD42025628825. The most recent version of the Cochrane Handbook for Systematic Reviews of Interventions (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) was consulted when elaborating this protocol, ensuring that it satisfied the highest standard of methodological rigor. The resulting systematic review will adhere to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 statement (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). As the goal of the systematic review involves updating exercise training guidelines (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), the Appraisal of Guidelines Research and Evaluation instrument (AGREE II), specifically items 7 to 9, will be respected (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eStudy selection will be guided by a comprehensive list of inclusion and exclusion criteria, following a specific order of importance. The Cochrane Handbook recommends the use of review population, intervention, comparator and outcome (PICO) elements to pre-establish clear eligibility criteria (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). As per recommendation (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), we added one element, namely study design, to these criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, included studies will need to have a retrievable full-text and be written in English, French or Dutch. Conference abstracts will be excluded, but we will investigate whether these are linked to full-text publications. If necessary, conference abstract authors will be contacted for information on the progress of the study.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eReview of PICOS to determine main eligibility criteria\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePICOS Element\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInclusion Criteria\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExclusion Criteria\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy sample is made up of adults (aged 18 years and above) with any type(s) of MS.\u003c/p\u003e \u003cp\u003eAll disability levels (mild, moderate or severe) are included.\u003c/p\u003e \u003cp\u003eStudy sample includes adults without MS in clearly separate group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy sample is only partly made up of adults (aged 18 years and above) with any type(s) of MS, and adults without MS are in the same group.\u003c/p\u003e \u003cp\u003eStudy sample includes pediatric forms of MS.\u003c/p\u003e \u003cp\u003eStudy sample is made up of animal models of MS.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy intervention consists of any modality of exercise training, defined by the World Health Organization as \u0026ldquo;a subcategory of physical activity that is planned, structured, repetitive and purposeful in the sense that the improvement or maintenance of one or more components of physical fitness* is the objective.\u0026rdquo; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA majority (at least 3 of 4) of the exercise intervention\u0026rsquo;s FITT parameters, namely frequency, intensity, time and type, are defined.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy intervention consists of a single bout of exercise only.\u003c/p\u003e \u003cp\u003eStudy intervention consists of exercise training targeting one specific body function such as pelvic floor or inspiratory/expiratory muscle training.\u003c/p\u003e \u003cp\u003eStudy intervention is supplemented by one or more additional, non-exercise study intervention(s) such as relaxation, massage, diet or pharmaceutical approach, which the control group does not receive.\u003c/p\u003e \u003cp\u003eStudy intervention consists of a therapeutic intervention only targeting disability and functioning, including robotic and bodyweight-supported gait training.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComparators\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAt least one of the study comparator(s) consist of non-exercise controls, including sham exercise interventions, non-active or education program, standard/usual care, no treatment or waitlist.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy comparator(s) is identical to exercise intervention but with different type of delivery method such as remote delivery.\u003c/p\u003e \u003cp\u003eStudy comparator(s) receive a pharmacology-based treatment that the intervention group does not receive.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome measures relate to at least one of the following: fitness*, biomarkers, physical and cognitive function, symptoms, quality of life or participation in activities of daily life.\u003c/p\u003e \u003cp\u003eOutcomes have been measured before and at least once after the intervention delivery.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOutcome measures are solely qualitative.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDesign follows methodology of RCTs.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDesign follows other types of methodology including case report, case study or cross-sectional.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cb\u003e*\u003c/b\u003ePhysical fitness includes cardiorespiratory fitness, muscular strength, muscular endurance, body composition and flexibility (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \n\u003ch3\u003eSearch strategy and information sources\u003c/h3\u003e\n\u003cp\u003eThe search strategy will be developed by the research team in collaboration with an experienced university librarian. The search itself will be conducted by the librarian. The 8 following electronic bibliographic databases will be searched: PubMed, EMBASE, PEDro, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Rehabilitation \u0026amp; Sports Medicine Source from inception to date of search.\u003c/p\u003e \u003cp\u003eTo compose a comprehensive search, we will start by creating a table of keywords which include our main search terms (the population and intervention of interest) as well as synonyms and closely related terms. These keywords will be identified by relying on the research team\u0026rsquo;s expertise, and identifying search terms used in similar previously published systematic reviews (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). We will then identify relevant subject headings available in each of the different databases. These key words and subject heading will then be combined by using the Boolean operators AND/OR and adapted or structured according to each database\u0026rsquo;s characteristics. As recommended by the Cochrane Handbook, we will add pre-established and highly sensitive search filters to search for RCTs (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). No search restriction will be made (for example, related to age range of the recruited samples, or language of the reports). The proposed search strategy for PubMed is provided in Appendix 2.\u003c/p\u003e \u003cp\u003eThe studies identified and included through these databases will further be used as a base to undertake forward citations searches in Google scholar in order to identify grey literature sources including reports, dissertations and theses. We will conduct hand searches of the reference lists from included studies, as well as that of previous reviews on the same topics, to complete our search and strive to identify all relevant evidence. Finally, to further minimize risk of publication bias, we will search international trial registries, namely clinicaltrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) and the European Union Clinical Trials Register (EudraCT), for recent or ongoing trials and contact authors for information on the study and its data.\u003c/p\u003e\n\u003ch3\u003eData management and screening procedure\u003c/h3\u003e\n\u003cp\u003eAll identified records will be imported by the university librarian into Covidence software (Veritas Health Innovation, Melbourne, Australia) and duplicate citations will be removed by using the Covidence automated deduplication algorithm.\u003c/p\u003e \u003cp\u003eTwo review authors will independently screen the titles and abstracts for relevance. In this initial screen, records will be excluded if they clearly do not align to the population and intervention of interest, if they do not follow the design of an RCT and if they do not include any outcomes of quantitative nature. The number of records removed at this stage will be documented. In case of any uncertainty, the record will be marked as \"maybe\" in Covidence, and moved to the next screening stage. Conflicts will be solved via discussion which included a third author. Next, the full-text of the remaining studies will be retrieved, and two authors will independently review them to further determine eligibility according to our detailed list of inclusion and exclusion criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Study authors will be contacted where necessary if relevant information on eligibility is missing. If the full-texts cannot be retrieved, or if the full-text displays evidence of the presence of one or more exclusion criteria, they will be removed. The reason for removing these studies will be documented through Covidence and be used to create a complete PRISMA Flow Chart (23). Any discrepancies will be discussed and resolved with a third review author. Overall agreement of full-text inclusion or exclusion between reviewers will be computed by Cohen\u0026rsquo;s Kappa, using Covidence\u0026rsquo;s tool for calculating inter-rater reliability.\u003c/p\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eData of interest will be extracted from the included studies by a team of 9 authors with knowledge of the topic, study design, data analysis and statistics (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Extraction of each study information will be conducted by two authors, working independently from one another. One author will extract data from all included studies, while second authors will vary so that each second author extracts approximately 12% of the total number of included studies. All authors will be trained in using the data extraction form prior to data extraction (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). These authors will not be blinded to the journal or to the authors of the reports. Any discrepancies will be recorded and resolved through discussion with a third review author.\u003c/p\u003e \u003cp\u003eData will be extracted into a piloted study-specific data collection form using Microsoft Excel, and will include:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003estudy identification;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003estudy methods and designs;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003estudy sample demographics;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eintervention and control protocols, combining elements from the Frequency, intensity, time, type (FITT) exercise-prescription framework (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) and from the Template for Intervention Description and Replication (TIDieR) checklist and guide (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e);\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eall quantitative outcomes related to fitness, biomarkers of health, physical and cognitive function, symptoms of MS, quality of life or participation in activities of daily life;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eresults as change in outcomes after the intervention.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e contains more details regarding this data. Any key missing data will initially be marked as \u0026ldquo;not reported\u0026rdquo;, and attempts will be made to obtain clarifications by contacting the corresponding authors of the articles a maximum of three times, each separated by a two-week interval. If no response is received, the items will remain \u0026ldquo;not reported\u0026rdquo; in the final table. Multiple reports of the same study will be extracted independently then linked together for subsequent analysis (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eItems for data extraction\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDomain of Interest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eItems to Extract\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdditional Information\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eStudy identification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuthor last name (year of publication)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eManuscript title, journal name\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry/countries where study occurred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIf not provided in manuscript\u0026rsquo;s main text, we will record country of first author\u0026rsquo;s affiliation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinical trial registry ID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConflicts of interest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eStudy methods\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIf multicentric, we will identify the number of recruiting centers.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of groups for randomization, Randomization process\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSample size calculation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIf provided in manuscript, we will record both the number and the method used for calculating it.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear(s) of study recruitment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIf provided in manuscript, we will record both start and end date.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy aims\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy hypotheses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eStudy sample demographics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInclusion/exclusion criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of participants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eItems will be extracted per group/condition.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMS type\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime since diagnosis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDisability level*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eIntervention protocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrequency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntensity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWe will record both session and overall program duration.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eType\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWe will record the name or phrase used by the authors to describe the intervention and subsequently classify its type as \u0026ldquo;aerobic\u0026rdquo;, \u0026ldquo;resistance\u0026rdquo;, \u0026ldquo;combined\u0026rdquo; or \u0026ldquo;other.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTailoring mechanisms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWe will record any process used to tailor or adapt the intervention FITT protocol to the participant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntervention provider\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMode of delivery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLocation of delivery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eControl protocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrequency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eIf the manuscript states that the control received standard/usual care, no treatment or was placed on a wait list, without providing any additional information, we will only fill out \u0026ldquo;type\u0026rdquo;.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntensity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eType\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTailoring mechanisms\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntervention provider\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMode of delivery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLocation of delivery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFitness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eFor each outcome of interest, we will record the testing procedure/instrument used together with the timing of the testing.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBiomarkers of health and disease\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhysical function\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCognitive function\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSymptoms of MS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuality of life\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParticipation in activities of daily life\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eResults\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoss to follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWe will record the number of participants lost during the intervention in all groups.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFitness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eFor each outcome of interest, we will record pre, post, and follow-up (if applicable) results.\u003c/p\u003e \u003cp\u003eSymbols will be used to identify whether the change reached statistical significance (time and/or group comparison).\u003c/p\u003e \u003cp\u003eItems will be extracted per group/condition.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBiomarkers of health and disease\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhysical function\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCognitive function\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSymptoms of MS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuality of life\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParticipation in activities of daily life\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Disability level will preferably be recorded as Expanded Disability Status Scale (EDSS) or Patient Determined Disease Steps (PDDS). These will then be classified as mild (EDSS 0\u0026ndash;4.0 or PDDS 0\u0026ndash;3), moderate (EDSS 4.5\u0026ndash;6.5 or PDDS 4\u0026ndash;6) or severe (EDSS or PDDS 7 and above) (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). If unavailable, other indicators or descriptors of disability will be used.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMethodological quality and risk of bias\u003c/h2\u003e \u003cp\u003eMethodological quality of the included studies will be determined using the Tool for the Assessment of Study quality and Reporting in Exercise (TESTEX), specifically developed for trials focusing on exercise-based intervention (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The tool is made up of 12 items with a total maximum score is 15 as some items (6 and 8) can obtain multiple points (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). TESTEX has shown to possess good to excellent reliability (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). We will record the presence or absence of each item and subitem on a standardized table-template and calculate a total score for each of the included studies. Based on a recent review\u0026rsquo;s thresholds, we will classify studies obtaining scores ranging from 12\u0026ndash;15, 9\u0026ndash;11, 6\u0026ndash;8, \u0026lt;\u0026thinsp;6, as excellent, good, fair or poor, respectively (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe will assess risk of bias using the revised Cochrane risk-of-bias tool for RCTs (RoB 2), as recommended by the Cochrane Handbook (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The RoB 2 encompasses fives domains from which study bias may arise, namely the randomization process, deviations from the intended intervention protocols, missing outcomes data, measurement of the outcomes and selection of the reported results. For cluster RCTs, it is recommended to add a sixth domain to assess bias related to the timing of recruitment. These domains are then joined by algorithms that include mappings of the possible combination of responses, and produce one of three possible overall risk of bias judgements: low, high or some concerns (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Domain-specific as well as overall risk of biases will be recorded in a full risk-of-bias table, together with text and sources to support each judgment (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSimilar to the extraction process, methodological quality and risk of bias of studies will be assessed by the same team of authors, of which one will assess all studies, and the remaining 8 will each assess 12.5% of the included studies. As recommended by Cochrane, a sample of three papers will be used to pilot both quality and risk-of-bias assessments and ensure reliability among the authors (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eThe extracted data and methodological quality/risk of bias assessment will be analyzed according to the ultimate goal of this systematic review, (i.e. to provide evidence to inform the update of exercise training guidelines for people with MS)(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). We aim to recommend a type and dose of exercise training necessary to improve fitness, biomarkers, physical and cognitive functions, symptoms of MS, quality of life and participation in activities of daily life among adults with MS across the disability spectrum. To that end, we will include heterogenous samples, exercise intervention protocols, and a broad range of outcomes and our analysis will be of qualitative nature. No quantitative synthesis will be performed. This is similar to the analysis conducted by a systematic review undertaken to inform the initial MS guidelines (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) and the 2018 exercise training guidelines for adults with spinal cord injury (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe will start by providing a qualitative synthesis of participant characteristics and intervention protocols (FITT parameters), as well as overall methodological quality and risk-of-bias of the included studies. Next, we will qualitatively synthesize the study results per outcome of interest, namely fitness (including cardiorespiratory fitness, muscular strength, muscle endurance, body composition, and flexibility), biomarkers of health and disease (including blood samples), physical and cognitive function, symptoms of MS (including fatigue and depression), quality of life and participation in activities of daily life. Within this analysis, the different FITT parameters of the included studies will be highlighted. Finally, as we aim to identify FITT parameters that require modification for optimizing exercise training to varying levels of disability (mild, moderate or severe), we will conduct a final narrative synthesis by separately considering the disability levels of the included samples. Within this analysis, the FITT protocols of the included studies will be further highlighted.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCertainty of evidence\u003c/h3\u003e\n\u003cp\u003eThe certainty of evidence provided for the outcomes of interest (fitness, biomarkers of health, physical and cognitive function, symptoms of MS, quality of life and participation in activities of daily life) will be evaluated through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). All RCTs will start at a level of high certainty, and be downgraded to moderate, low or very low certainty due to presence of risk of bias, inconsistency, indirectness, imprecision and publication risk of bias (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The grading of evidence certainty will be conducted independently by two authors and appraisal of each domain will be justified and documented. Any discrepancies will be discussed and solved through consensus by a third author.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBy adhering to this robust protocol, which upholds high standards of research methodology, our systematic review aims to provide a solid base of evidence regarding the effects of exercise training on fitness, biomarkers, physical and cognitive function, symptoms, quality of life and participation in activities of daily life among people living with MS. The qualitative analysis, including the appraisal of the methodological quality and risk-of-bias of the included studies, will deliver valuable insights into the FITT parameters and how to modify these according to disability level. However, some limitations, such as heterogeneity between the study protocols and outcome measures, vague/incomplete or unclear reporting of protocols, and lack of RCTs conducted among people presenting with severe MS-related disability, may impact this and our ability to undertake detailed analyses within these specific sub-groups. If that is the case, authors will discuss ways to merge certain sub-groups together, when appropriate. These decisions, as well as any other deviations from the protocol resulting from these limitations or due to other, unforeseen factors will be noted and justified in the full systematic review.\u003c/p\u003e \u003cp\u003eThe evidence gathered and analyzed will be crucial for our next step, namely updating the exercise guidelines for MS, published in 2013 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These updated guidelines will serve to inform people with MS, their families and/or their caregivers on the benefits of exercise training. The prescriptive guidelines will further provide health care professionals and MS services organization or advocates with clear information to promote exercise training among patients with MS, and to facilitate implementation of exercise training programs into MS-care. Finally, this review will guide future research within the field of exercise training for MS by establishing the state of the art and identifying remaining research gaps.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAGREE II\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAppraisal of Guidelines Research and Evaluation instrument\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFITT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efrequency, intensity, type, time\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGRADE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGrading of Recommendations Assessment, Development and Evaluation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emultiple sclerosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRISMA P\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erandomized controlled trial\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROB2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk of Bias Tool\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTESTEX\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTool for the Assessment of Study quality and Reporting in Exercise\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTIDieR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTemplate for Intervention Description and Replication\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Dr. Louise Declerck was supported by a Fellowship of the Belgian American Educational Foundation.\u003c/p\u003e\u003ch2\u003eAuthors\u0026rsquo; contributions:\u003c/h2\u003e \u003cp\u003eLD engaged in conceptualization, methodology, writing- original draft, writing- review and editing. KMG engaged in conceptualization, methodology and reviewing the methods. ALC engaged in conceptualization, methodology and reviewing the methods. BJ, PZ and TLTH engaged in writing-review and editing. AB engaged in methodology and writing- review and editing. RWM engaged in conceptualization, methodology, and writing- review and editing\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e \u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e \u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNumber of people with MS. | Atlas of MS [Internet]. [cited 2024 Dec 18]. 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Arch Phys Med Rehabil. 2013;94(9):1800\u0026ndash;e18283.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLearmonth YC, Pilutti LA, Herring MP, Motl RW, Chan B, Metse AP. Safety of exercise training in multiple sclerosis: a protocol for an updated systematic review and meta-analysis. Syst Rev. 2021;10(1):208.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBl\u0026aacute;zquez-Fern\u0026aacute;ndez A, Navarro-L\u0026oacute;pez V, Marcos-Ant\u0026oacute;n S, Cano-de-la-Cuerda R. Effects of Physical Exercise on Neurofilament Light Chain and Glial Fibrillary Acidic Protein Level in Patients with Multiple Sclerosis: A Systematic Review and Bayesian Network Meta-Analysis. J Clin Med. 2025;14(3):839.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDu L, Xi H, Zhang S, Zhou Y, Tao X, Lv Y et al. Effects of exercise in people with multiple sclerosis: a systematic review and meta-analysis. Front Public Health [Internet]. 2024 Apr 10 [cited 2025 Feb 28];12. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.frontiersin.org/journals/public-health/articles/\u003c/span\u003e\u003cspan address=\"https://www.frontiersin.org/journals/public-health/articles/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fpubh.2024.1387658/full\u003c/span\u003e\u003cspan address=\"10.3389/fpubh.2024.1387658/full\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeratto L, Bressy L, Agostino S, Malandrone F, Brichetto G, Ponzano M. The effect of exercise on mental health and health-related quality of life in individuals with multiple sclerosis: A Systematic review and meta-analysis. 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BMJ. 2015;349:g7647.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins J, Thomas J, Chandler J, Cumpston M, Li T, Page M et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024) [Internet]. Cochrane. 2024. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.training.cochrane.org/handbook\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10(1):89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmir-Behghadami M, Janati A, Population. Intervention, Comparison, Outcomes and Study (PICOS) design as a framework to formulate eligibility criteria in systematic reviews. Emerg Med J. 2020;37(6):387\u0026ndash;387.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray CA, et al. Exercise and Hypertension. Med Sci Sports Exerc. 2004;36(3):533.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ. 2014;348:g1687.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmart NA, Waldron M, Ismail H, Giallauria F, Vigorito C, Cornelissen V, et al. 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Lippincott Williams \u0026amp; Wilkins; 2021. 369 p.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmad H, van der Mei I, Taylor BV, Lucas RM, Ponsonby AL, Lechner-Scott J, et al. Estimation of annual probabilities of changing disability levels in Australians with relapsing-remitting multiple sclerosis. Mult Scler J. 2019;25(13):1800\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"exercise, multiple sclerosis, guidelines, evidence-based, recommendations, neurological rehabilitation","lastPublishedDoi":"10.21203/rs.3.rs-6148397/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6148397/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eBackground: \u003c/u\u003eResearch demonstrates that exercise training is both safe and beneficial for individuals with multiple sclerosis (MS). There is a timely opportunity for updating the guidelines for exercise training in MS, as the number of RCTs examining the effects of exercise training on a range of functional and biomedical outcomes among adults with MS has increased substantially in the past decade. The evidence for updating the guidelines should be gathered through rigorous methodology, thereby ensuring a comprehensive analysis. This systematic review of the literature will evaluate the type and dose of exercise training necessary to improve fitness, biomarkers of health and disease, physical and cognitive functions, symptoms of MS, quality of life, and/or participation in activities of daily life among adults with MS presenting with mild, moderate, or severe disability.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMethods: \u003c/u\u003eThis protocol for a systematic review follows the PRISMA-P guidelines and was registered on Prospero. We will undertake a systematic and comprehensive search will be conducted across 8 electronic bibliographic databases. Retrieved references will be screened by two authors based on pre-established inclusion and exclusion criteria. Relevant data will be extracted into piloted tables and synthesized qualitatively. Methodological quality of the included studies will be determined using the Tool for the Assessment of Study quality and Reporting in Exercise (TESTEX). Risk of bias will be assessed through the revised Cochrane risk-of-bias tool for RCTs (RoB 2). Finally, the certainty of evidence provided for the outcomes of interest will be evaluated through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eDiscussion: \u003c/u\u003eThe evidence gathered and analyzed through this review will be crucial for our next step of updating the exercise guidelines for MS. These updated guidelines will provide people with MS, their families and/or their caregivers, as well as health care professionals and MS services organization or advocates, with clear information to promote exercise training among patients with MS. This will subsequently facilitate implementation of exercise training programs into MS-care.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eRegistration details: \u003c/u\u003ePROSPERO registration number CRD42025628825\u003c/p\u003e","manuscriptTitle":"Effects of exercise training among adults with multiple sclerosis Protocol for a systematic review that informs an updated prescriptive guideline","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 11:18:30","doi":"10.21203/rs.3.rs-6148397/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-05-05T20:13:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-02T13:41:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-07T06:51:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2025-03-03T12:47:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"003a87fe-6892-4da0-b41f-76627dad3cb3","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:07:51+00:00","versionOfRecord":{"articleIdentity":"rs-6148397","link":"https://doi.org/10.1186/s13643-026-03095-z","journal":{"identity":"systematic-reviews","isVorOnly":false,"title":"Systematic Reviews"},"publishedOn":"2026-02-11 15:58:21","publishedOnDateReadable":"February 11th, 2026"},"versionCreatedAt":"2025-05-07 11:18:30","video":"","vorDoi":"10.1186/s13643-026-03095-z","vorDoiUrl":"https://doi.org/10.1186/s13643-026-03095-z","workflowStages":[]},"version":"v1","identity":"rs-6148397","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6148397","identity":"rs-6148397","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}