Exercise therapy for fatigue in multiple sclerosis

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

Primary objectives

The primary objectives of this review are as follows.

1.1 To determine the immediate (i.e. postintervention; 1.1a) and long‐term (i.e. follow‐up; 1.1b) benefits of exercise therapy, when compared to a control group, on self‐reported fatigue in people with MS; and

1.2 To specifically determine the immediate and long‐term benefits of exercise therapy, when compared to a control group, on self‐reported fatigue when only clinical trials are considered in which (1.2a) self‐reported fatigue was the primary outcome and (1.2b) only people with MS with predefined levels of self‐reported fatigue were included.

Secondary objectives

The following secondary objectives will be pursued; each relevant to people with MS, clinicians and academics.

Safety

2.1 To determine the safety of exercise therapy, when compared to a control group, as determined by an exploratory review of reported adverse effects over the course of the intervention phase.

2.2 To confirm the safety of exercise therapy, when compared to a control group, as determined by a confirmatory review of reported MS exacerbations, falls, and overuse injuries over the course of the intervention phase.

Intervention characteristics

3.1 Determine the immediate and long‐term differential impact of different exercise therapy modalities on self‐reported fatigue (e.g. aerobic training).

3.2 Explore the relationship between dose of exercise therapy (an agglomeration of frequency, time per session, and program duration) and the immediate and long‐term benefits of exercise therapy on fatigue.

3.3 Explore the relationship between features of exercise therapy programs (e.g. progression, overload, specificity) and the immediate and long‐term benefits of exercise therapy on fatigue.

Participant characteristics

4.1 Determine the impact of baseline fatigue levels on the immediate and long‐term benefits of exercise therapy on fatigue.

4.2 Determine the impact of baseline levels of disease severity (i.e. Expanded Disability Status Scale [EDSS]) on the immediate and long‐term benefits of exercise therapy on fatigue.

Study design characteristics

5.1 Determine the impact of the specific self‐reported fatigue measure (e.g. Fatigue Severity Scale) on the immediate and long‐term benefits of exercise therapy on fatigue.

5.2 Determine the impact of methodological quality (i.e. risk of bias) and (self‐reported) pilot studies, on the immediate and long‐term benefits of exercise therapy on fatigue.

5.3. Determine the impact of the type of control group on the immediate and long‐term benefits of exercise therapy on fatigue.

Background

Multiple sclerosis (MS) is the leading chronic, progressive, neurological condition among young adults. Globally, a total of 2.8 million people are estimated to live with MS (35.9 per 100,000 population), and the prevalence of MS is increasing across world regions (Atlas of MS 3rd Edition; Coetzee 2020; Walton 2020). The etiology of MS is poorly understood and mainly based on theories in which autoimmunity is assumed to be the initiator of the disease (outside‐in) or alternatively, an underlying process of slow neurodegeneration driving a subsequent immune response from inside‐out (Sen 2020). In the absence of a cure for MS, disease‐modifying treatments aimed at limiting MS exacerbations or disease progression are the first line of care, but have limited effectiveness in reducing disabling symptoms (Hubbard 2021). Consequently, most people with MS will experience significant disability, activity limitations, and participation restrictions during their lifetime that impact quality of life.

Fatigue has been reported to be one of the most prevalent (> 80%) and, more importantly, most debilitating symptoms of MS (Broch 2021; Enoka 2021; Rooney 2019; Valentine 2021). Consequently, the study of fatigue and its management has been identified as a priority for further research (Zackowski 2021). The pathophysiology of fatigue in MS is poorly understood, and likely multifactorial (Zackowski 2021). In combination with disease‐modifying medication, clinical practice guidelines suggest using a variety of rehabilitation interventions for managing MS‐related fatigue, including exercise therapy (Zackowski 2021). However, while there is compelling evidence for the benefits of exercise therapy on a variety of key factors important in the health and well‐being of people with MS, including general physical and mental health (Gascoyne 2020; Langeskov‐Christensen 2015), the evidence for the benefits of exercise therapy on self‐reported fatigue, specifically, has been equivocal and heterogeneous at best (Heine 2015). Moreover, the evidence for the benefits of exercise therapy on self‐reported fatigue has mostly been drawn from studies which were not specifically designed to assess the impact of exercise therapy of fatigue in people with MS with predefined levels of fatigue (Heine 2015).

Description of the condition

Fatigue is a multidimensional construct and, with that, difficult to define (Beckerman 2020). One of the definitions widely adopted is that fatigue is “a subjective lack of physical and/or mental energy that is perceived by the individual (or caregiver) to interfere with usual and desired activities” (MS Council 1998). Fatigue can have both a central (i.e. nervous system) and peripheral origin (e.g. muscle atrophy), and be caused by primary (i.e. directly attributable to MS) or secondary mechanisms (e.g. comorbidity, depression) (Chaudhuri 2004; Kos 2008). Collectively, these causative mechanisms can lead to a perceived level of fatigue that impacts day‐to‐day participation and quality of life, as well as objectively‐assessed reduced performance (i.e. fatigability) on both physical and mental parameters (Enoka 2021). In the present review, we focus on the perceived experience of fatigue in people with MS, commonly assessed using patient‐reported outcome measures, and from here on referred to as self‐reported fatigue.

Description of the intervention

Exercise can be described as a series of movements with the aim of training or developing the body by a routine practice, or as a physical training to promote good physical health (Heine 2015). As an extension of that, exercise can be considered as exercise therapy when such movements are used as part of a treatment goal within allied health care and rehabilitation. Ideally, albeit not always apparent (Schlagheck 2021), exercise therapy is based on key exercise training principles to optimize benefits, including principles of overload, reversibility, progression, individualization, periodization, and specificity. Importantly, the type of exercise modalities that are used within a therapy setting, and who the most qualified or applicable provider may be, vary globally. In some health care settings, exercise therapy may be based on exercise types like yoga or dancing, while in other settings, exercise therapy may be composed of aerobic or resistance training (Heine 2019).

How the intervention might work

The poorly understood and multifactorial etiology of fatigue in people with MS allows for a multitude of pathways through which exercise therapy may positively affect self‐reported fatigue (Langeskov‐Christensen 2017). Cardiovascular, physiological, immunologic, neuroendocrine, and neurotrophic changes associated with exercise may alleviate primary MS fatigue, while exercise may improve secondary MS fatigue through symptomatic improvement of deconditioning, sleep disorders, and depression (Langeskov‐Christensen 2017). In addition, there may be other benefits of exercise therapy that could reduce self‐reported fatigue, including increased self‐efficacy or social support.

Why it is important to do this review

In 2015, a Cochrane Review on the effects of exercise therapy for self‐reported fatigue identified 45 clinical trials, studying 69 different exercise interventions (Heine 2015). The collective evidence suggested a significant heterogeneous (I² = 58%) positive effect (standardized mean difference (SMD) ‐0.53, 95% confidence interval (CI) ‐0.73 to ‐0.33; P value < 0.01) in favor of exercise therapy when compared to a control group. However, important limitations were identified that contributed to the heterogeneity between studies, particularly the lack of inclusion of participants with predefined levels of fatigue at baseline, as well as a lack of studies in which fatigue was the primary outcome measure (Heine 2015). In addition, different effect sizes for the benefits of exercise therapy on fatigue were identified for different types of exercise interventions (e.g. endurance training, resistance training). Between 2015 and 2021, a multitude of new (phase 3 and 4) clinical trials have been published that can add to the existing body of evidence for the effect and clinical relevance of exercise therapy on self‐reported fatigue in people with MS. Furthermore, the added body of evidence will allow for specific sensitivity analyses to explore sources of heterogeneity between studies, including the methodological limitations identified in the 2015 Cochrane Review (Heine 2015), and elsewhere (Heine 2016).

Objectives

Primary objectives

The primary objectives of this review are as follows.

1.1 To determine the immediate (i.e. postintervention; 1.1a) and long‐term (i.e. follow‐up; 1.1b) benefits of exercise therapy, when compared to a control group, on self‐reported fatigue in people with MS; and

1.2 To specifically determine the immediate and long‐term benefits of exercise therapy, when compared to a control group, on self‐reported fatigue when only clinical trials are considered in which (1.2a) self‐reported fatigue was the primary outcome and (1.2b) only people with MS with predefined levels of self‐reported fatigue were included.

Secondary objectives

The following secondary objectives will be pursued; each relevant to people with MS, clinicians and academics.

Safety

2.1 To determine the safety of exercise therapy, when compared to a control group, as determined by an exploratory review of reported adverse effects over the course of the intervention phase.

2.2 To confirm the safety of exercise therapy, when compared to a control group, as determined by a confirmatory review of reported MS exacerbations, falls, and overuse injuries over the course of the intervention phase.

Intervention characteristics

3.1 Determine the immediate and long‐term differential impact of different exercise therapy modalities on self‐reported fatigue (e.g. aerobic training).

3.2 Explore the relationship between dose of exercise therapy (an agglomeration of frequency, time per session, and program duration) and the immediate and long‐term benefits of exercise therapy on fatigue.

3.3 Explore the relationship between features of exercise therapy programs (e.g. progression, overload, specificity) and the immediate and long‐term benefits of exercise therapy on fatigue.

Participant characteristics

4.1 Determine the impact of baseline fatigue levels on the immediate and long‐term benefits of exercise therapy on fatigue.

4.2 Determine the impact of baseline levels of disease severity (i.e. Expanded Disability Status Scale [EDSS]) on the immediate and long‐term benefits of exercise therapy on fatigue.

Study design characteristics

5.1 Determine the impact of the specific self‐reported fatigue measure (e.g. Fatigue Severity Scale) on the immediate and long‐term benefits of exercise therapy on fatigue.

5.2 Determine the impact of methodological quality (i.e. risk of bias) and (self‐reported) pilot studies, on the immediate and long‐term benefits of exercise therapy on fatigue.

5.3. Determine the impact of the type of control group on the immediate and long‐term benefits of exercise therapy on fatigue.

Methods

Criteria for considering studies for this review

Types of studies

We will consider randomized controlled trials (RCTs) or randomized cross‐over trials, including cluster‐randomized controlled trials. Studies will be eligible if at least one of the study arms consists of a control group, which could be either usual care, treatment as usual, a sham intervention, or no intervention (Levack 2019). We will not include studies in which exercise therapy is compared solely with another experimental intervention (e.g. energy conservation management, another type of exercise therapy).

Types of participants

We will include studies in which participants were aged 18 years or over, with a clinical confirmed diagnosis of MS (any subtype) according to applicable diagnostic criteria (e.g. Polman 2005; Thompson 2018). We will exclude studies in people with neuromyelitis optica or clinically isolated syndrome (CIS).

Types of interventions

There is no established typology for exercise interventions. Therefore, we will include all interventions that fit the review teams' description of exercise therapy, based on consensus. Importantly, the team will take a broad and inclusive perspective towards what constitutes 'exercise', with the aim for this review to be relevant across various contexts. However, at least one of the exercise principles needs to be included, as proposed by Schlagheck 2021.

Principle	Criteria for this review
Specificity: training adaptations are specific to the organ system or muscles trained with exercise.	Appropriate population targeted and modality selected based on primary outcome.
Progression: over time, the body adapts to exercise. For continued improvement, the volume or intensity of training must be increased.	Stated exercise program was progressive and outlined training progression.
Overload: for an intervention to improve fitness, the training volume must exceed current habitual physical activity and/or training levels.	Rationale provided that program was of sufficient intensity/exercise prescribed relative to baseline capacity.
Initial values: improvements in the outcome of interest will be greatest in those with lower initial values.	Selected population with low level of primary outcome measure or baseline physical activity levels.
Reversibility: once a training stimulus is removed, fitness levels will eventually return to baseline.	Performed follow‐up assessment on participants who decreased or stopped exercise training after conclusion of intervention.
Diminishing returns: the expected degree of improvement in fitness decreases as individuals become more fit, thereby increasing the effort required for further improvements. Also known as the ‘ceiling effect’.	Performed follow‐up assessment of primary outcomes on participants who continued to exercise after conclusion of intervention.

Identifying intervention subtypes

In a previous version of this review (Heine 2015), the international classification of functioning (ICF) was used to classify exercise therapy interventions into five different domains: endurance, muscle power, task‐oriented, mixed, or other (Heine 2015). While for some exercise types, use of the ICF was straightforward based on the respective working mechanisms (e.g. aerobic exercise), use of the ICF was more challenging for a subset of interventions (e.g. yoga‐based interventions, hippotherapy). Hence, for this updated review, we propose an alternative approach where we aim to extract the different exercise interventions first, prior to stratifying them into intervention type clusters, based on their various design features and modalities. This 'bottom‐up' internal consensus procedure may promote homogeneity within each subgroup, and additional insight into specific working mechanisms that may be more beneficial in addressing self‐reported fatigue.

Special note on eHealth interventions

We will consider exercise interventions that are provided through eHealth solutions, on the premise that a trained health care professional (e.g. physician, physiotherapist, exercise specialist, community health worker) is involved in the initiation, set‐up, conduct, or evaluation of the exercise program. In other words, we will exclude stand‐alone eHealth applications that are studied without the involvement of a health care professional (i.e. exercise self‐management) within the allied health and rehabilitation space. While we do not disregard their value and potential benefits to people with MS, they are beyond the scope of this review.

Control intervention

We will include clinical trials in which the control group was withheld active treatment, as well as control groups in which participants were provided standardized or unstandardized treatment as usual (Levack 2019). Eligible controls are described below.

• Active treatment withheld (e.g. no treatment, wait‐list control, placebo, or attention controls)

• In treatment as usual with a standardized protocol, the quantity, duration, intensity and type of usual care that the control group receives is prespecified (Levack 2019).

• In treatment as usual without a standardized protocol, no restrictions are placed on what control participants do or do not receive as part of their care (Levack 2019).

We will perform secondary analyses that can highlight the impact of the type of control group on the summary effect estimate. We will exclude studies in which multiple exercise therapy interventions are studied, without the presence of a defined control group (e.g. endurance training versus resistance training).

Types of outcome measures

We will assess primary and secondary outcomes postintervention (i.e. the immediate benefit or harm), as well as at the follow‐up time point most distant to the baseline assessment (i.e. the long‐term benefit or harm).

Primary outcomes

1. Self‐reported fatigue

   1. We will include self‐reported measures, primarily developed for the evaluation of (a component of) self‐reported fatigue. Examples of such measures are the Fatigue Severity Scale (Krupp 1989), Modified Fatigue Impact Scale (Fisk 1994), or Multidimensional Fatigue Index (Smets 1995).

   2. However, we will also consider subscales of measures not developed for the assessment of self‐reported fatigue per se, yet with a subscale that assesses (a component) of fatigue. An example of such an outcome is the vitality subscale for the Short Form 36 (SF‐36). In line with the original Cochrane Review, we will only consider such subscales if the respective study authors specifically noted that these were included to assess self‐reported fatigue.

Secondary outcomes

1. Any adverse events: we will assess the potential harms of exercise therapy by reviewing the reported adverse events that occurred during the intervention period in both the experimental and control group(s), for which the causal relation between the intervention and the event is at least a reasonable possibility (Higgins 2022; chapter 19).

2. Exercise‐specific adverse events: in addition to this exploratory approach, we will specifically focus on the following three type of adverse events that are, or may have been, a concern in relation to (the self‐efficacy to engage in) exercise therapy (Crank 2017).

   1. MS exacerbations (i.e. relapse)

   2. Reported falls

   3. Overuse injury

Search methods for identification of studies

Electronic searches

The Information Specialist will search the following data sources from October 2014 to date, to ensure all articles published in succession of the Cochrane Review published in 2015 are identified (Heine 2015). Search strategies are give in Appendix 1; Appendix 2; Appendix 3; Appendix 4; and Appendix 5.

1. The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue)

2. MEDLINE (PubMed) (1966 to date)

3. EMBASE (Embase.com) (1974 to date)

4. CINAHL (Cumulative Index to Nursing and Allied Health Literature)

5. SPORTDiscus

6. PEDro

7. Clinical trials registries (www.clinicaltrials.gov, and WHO International Clinical Trials Registry Platform [ICTRP]).

Additional databases to be searched by the authors include Scielo (1997 to date).

We will not apply any language restrictions to the search, or restrictions in terms of publication status. In case studies arise in languages outside of those spoken by the review team (i.e. English, Dutch) we will consult Cochrane for assistance.

Searching other resources

To identify other relevant studies we will:

1. screen reference lists of review articles on the topic (e.g. Andreu‐Caravaca 2021; García‐Muñoz 2020; Ghahfarrokhi 2021; Moss‐Morris 2021; Razazian 2020; Schlagheck 2021; Shohani 2020; Torres‐Costoso 2022; Yeh 2020), as well as reference lists of included studies;

2. conduct forward‐citation hashing in Google Scholar for articles included in the original review (Heine 2015); and

3. contact experts in the field to identify any additional trials not identified through the search strategies (Dalgas 2020).

Data collection and analysis

Selection of studies

In line with the Cochrane conflict of interest policy, the two reviewers primarily responsible for study selection (EE, EAG) have not been involved in any of the clinical trials that we anticipate could be included in this review. After the search results have been deduplicated, study selection will follow a three‐tiered process. Firstly, all titles will be randomly allocated to one of two reviewers (EE, EAG) for an initial rapid screening to filter out any citations clearly not eligible for inclusion (e.g. editorials, reviews). Secondly, both reviewers (EE, EAG) will independently screen all remaining titles and abstracts for eligibility. Finally, both reviewers (EE, EAG) will independently conduct full‐text screening of articles. In case of any persisting disagreements between the two reviewers, they will consult a third reviewer (MH) to reach consensus. Review authors will conduct study selection through the online and open‐access platform CADIMA (Kohl 2018). Prior to data extraction, we will link reports on the same study and include them as a single study rather than multiple reports.

Data extraction and management

For each included study, a member of the review team will document the following information on a predefined and pilot‐tested form.

1. Study design features (country of origin, assessment schedule)

2. Study‐specific inclusion and exclusion criteria

3. Sample characteristics (number included, number analyzed, age, gender, type of MS, disease duration, baseline measure of disease severity [i.e. Expanded Disability Status Scale, EDSS]).

4. Description of the experimental intervention(s) using the Consensus on Exercise Reporting Template (CERT) (Slade 2016), as well as a dichotomous recording of key exercise principles adopted (i.e. yes/no/unknown).

5. Classification of the control group into (1) active treatment withheld, (2) active treatment as usual ‐ standardized, or (3) active treatment as usual ‐ unstandardized (Levack 2019; see Description of the intervention)

6. The self‐reported fatigue measure(s) used, which fatigue measure (if applicable) was the primary outcome (extracted from published study protocol, trial registry or when used for power calculations), directionality of the outcome reported, baseline measures of central tendency and variability [e.g. mean and SD] per study arm, outcome data postintervention, as well as the follow‐up assessment furthest in time from the postintervention assessment.

7. Harm data, including the number of MS exacerbations, falls, and overuse injuries reported (stratified by study arm).

A team member will cross‐reference the initial data extraction (as opposed to full data extraction by two reviewers independently) to retain rigor while maintaining efficiency, except for the outcome data, baseline levels of fatigue and EDSS (Item 3, 6 and 7 in the list above), which two reviewers will extract independently.

Some data relevant to this update (e.g. baseline fatigue levels) were not extracted at the time of the original review (Heine 2015). Hence, we will extract these data retrospectively from the studies that were included in the 2015 version. Where needed, we will contact corresponding authors to provide additional (unpublished when applicable) relevant information.

Assessment of risk of bias in included studies

Two members of the review team will independently perform a risk of bias assessment for each included study, using the Cochrane risk of bias tool 2.0 (RoB 2) (Sterne 2019). We will put special procedures in place to ensure that review authors are not allocated to review the risk of bias for studies in which they were involved themselves. In case of any disagreements, the two review authors will seek consensus and consult a third review author if disagreements persist. We will re‐evaluate studies that were included in the original review by Heine 2015 using RoB 2, to ensure the same standards apply to all studies included.

Continuous data

We will pool continuous data (self‐reported fatigue) of individual studies using a random‐effects model, adjusting for between‐study variance. As heterogeneity is implicit, due to differences in exercise therapy types, intervention structure, and patient populations among others, we will use a random‐effects model independent of statistical parameters for heterogeneity. In addition, based on our experience with the original review (Heine 2015), we anticipate heterogeneity in the self‐report measures for fatigue adopted, so will use a standardized mean difference (SMD), including 95% confidence intervals (CIs). Albeit, in subsequent subgroup analyses (Objective 5.1) looking at specific fatigue measures in relation to the immediate and long‐term benefits of exercise therapy, we could adopt the mean difference rather than SMD.

There is no recommended method for combining studies that reported change scores and studies that reported postintervention scores when calculating the SMD (Higgins 2022; Chapter 10). Hence, we will include both in the meta‐analysis but present them as separate subgroups for transparency. If a study presents both, we will prioritize postintervention data over change scores. Where needed, we will use the built‐in Review Manager tool for data manipulation to extract data in a format useable for meta‐analysis.

Count data

For count data (i.e. number of people with adverse events, MS exacerbations, falls, and overuse injuries over the intervention window), we will extract the number of participants and number of events per arm and calculate risk ratios (RRs) with 95% CIs for each trial. For the primary analysis, we will assume that if no adverse events were reported, adverse events did not occur. However, we will conduct a sensitivity analysis in which studies that did not report adverse events will be excluded.

We will present summary effect sizes (SES) graphically using forest plots.

Unit of analysis issues

We will include studies with a randomized cross‐over design, but will only use the data up to the moment of cross‐over in any meta‐analyses. When applicable, we will consult a statistician to determine the impact of trials using a cluster‐randomized design, or other unit of analysis issues, on the effect estimates.

Multiple exercise interventions or fatigue measures

In the case of multiple exercise interventions within the same study (i.e. multi‐arm trials), or multiple self‐report measures for fatigue within the same RCT, we will follow the mathematical procedures outlined in section 6.5.2.10 of the Cochrane Handbook to combine these into a single metric (e.g. a single effect measure for both exercise interventions combined, or a single outcome for fatigue across multiple self‐reported fatigue measures) (Higgins 2022). However, in case a specific measure for fatigue was considered the primary outcome for that specific study, while other fatigue measures were secondary, we will only include the primary fatigue measure in the analysis and disregard the secondary fatigue measures for that specific study. Subsequently, moving to subgroup analyses where we explore the impact of different measures of fatigue used, we could reconsider data presented for the secondary fatigue measures. Similarly, for subgroup analyses based on the type of intervention, we will consider each type of intervention individually. If more than one intervention from a specific study is included in a subgroup analysis (e.g. they both fall within the same subgroup of exercise interventions), we will divide the number of participants for the comparison (i.e. control condition) by the number of interventions from that specific study to ensure that each participant is represented in the analysis only once.

Dealing with missing data

We will only analyze the available data, thereby ignoring missing data under the assumption that they are missing at random (section 10.12 in the Cochrane Handbook (Higgins 2022). However, the amount and nature (e.g. randomness) of missing data is part of the risk of bias evaluation, and can be addressed as such.

Assessment of heterogeneity

To assess heterogeneity across studies, we will inspect the distribution of point estimates for the effect measure and the overlap in their confidence intervals on the forest plot. We will use the I² statistic to check the statistical consistency, defined as the ratio of between‐study variation compared to the overall variation (Higgins 2022).

Assessment of reporting biases

We will use a contour‐enhanced funnel plot to estimate the influence of unpublished studies on the overall effect estimate (i.e. publication bias) as well as the impact of small studies on the overall effect estimate. We will address the latter, in part, through a sensitivity analysis in which we exclude from the meta‐analysis pilot studies and studies without a priori sample size calculations.

Data synthesis

The following primary analyses are planned.

Objective 1.1a: the immediate (postintervention) treatment effect of exercise therapy versus a control condition on self‐reported fatigue, based on continuous outcome data (i.e. postintervention mean or [standardized] mean difference, in conjunction with measures of variance). Subsequently, we will conduct a Sensitivity analysis including only studies with fatigue as a primary outcome.

Objective 1.1b: the long‐term (follow‐up) treatment effect of exercise therapy versus a control condition on self‐reported fatigue, based on continuous outcome data (i.e. follow‐up mean or [standardized] mean difference, in conjunction with measures of variance). We will use meta‐regression to determine the impact of follow‐up period on the effect estimate.

Objective 2.1 and 2.2: the relative risk for either an adverse event (exploratory approach), defined as any untoward medical occurrence, as well as confirmatory analyses specific for falls, MS exacerbations, and overuse injuries, when participating in the exercise therapy group, versus a control condition based on risk ratios (including 95% confidence intervals) (chapter 19 of the Cochrane Handbook;Higgins 2022).

We will consult the Cochrane Handbook as required, to ensure optimal extraction of key data and data manipulation where applicable (Higgins 2022).

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses are planned for both immediate and long‐term effect estimates for self‐reported fatigue.

• A subgroup analysis stratified by the type of exercise intervention provided (objective 3.1). As alluded to earlier, such a stratification will be developed from the bottom‐up, based on the various interventions identified during the review process. There are multiple sources of evidence that indicate that some exercise therapy types may be more beneficial relative to other types of exercise therapy (Heine 2015; Moss‐Morris 2021).

• A subgroup analysis based on the self‐report measure used (e.g. Fatigue Severity Scale) for the assessment of fatigue (objective 5.1). Where possible, the summary effect size for a specific self‐report measure will be mirrored against published values for the minimally clinically important difference (MCID) for that specific measure. Various fatigue measures differ in terms of conceptual focus (e.g. fatigue severity versus impacts) and dimensional structure (e.g. unidimensional, multidimensional) (Kamudoni 2022).

• A subgroup analysis based on the type of control group (active treatment as usual versus treatment withheld) on the effect estimate (objective 5.3). This subgroup analysis will allow us to quantify the impact of 'contrast' between exercise therapy and the comparator on the estimated effect size.

We will use exploratory meta‐regression to assess the potential impact of the following factors on the immediate and long‐term effect estimate for self‐reported fatigue (Section 10.11.4 of the Cochrane Handbook; Higgins 2022).

• The impact of baseline fatigue levels for the study sample (objective 4.1). Through this regression analysis, we will be able to test the hypothesis that there is an association between the benefits of exercise therapy and the level of fatigue prior to exercise therapy participation.

• The impact of MS severity at baseline (i.e. Expanded Disability Status Score) for the study sample (objective 4.2). Through this regression analysis, we will be able to test the hypothesis that there is an association between the level of disability at baseline and the benefits of exercise therapy on self‐reported fatigue.

• The physiological benefits (e.g. aerobic capacity) of exercise therapy are closely related to the level and adequacy of exposure to the exercise stimulus. Hence, the impact of exercise 'dose' or exposure (objective 3.2), as determined by multiplying frequency (sessions per week) by session duration (minutes) by program length (weeks), will be associated with the benefits of exercise therapy on self‐reported fatigue. This analysis, however, does not account for the exercise therapy intensity or adequate personalization of exercise prescription.

We will exclude studies that report baseline imbalances in either fatigue or disease severity from these analyses. In addition, we cannot include studies in which baseline values for fatigue or disability are not provided, but the difference over time for each study arm has been presented, unless the study authors provide additional data. These analyses should be considered exploratory, as individual participant data synthesis for these objectives would be more appropriate, though is beyond the scope of this review.

Sensitivity analysis

The following sensitivity analyses are planned. In these analyses, studies that meet specific criteria are retained in the analysis while others are removed. As such, these sensitivity analyses will provide insight into the impact of specific study design features on the estimated immediate and long‐term benefits of exercise therapy on self‐reported fatigue.

• A sensitivity analysis of trials in which self‐reported fatigue was defined as the primary outcome measure (objective 1.2a), and included subjects with a predefined level of fatigue (objective 1.2b). As alluded to earlier, the lack of specificity in the study of exercise therapy for self‐reported fatigue has been an important limitation (Heine 2015; Heine 2016).

• A sensitivity analysis which excludes studies with moderate to high risk of bias, as well as pilot studies. This will allow us to determine the impact of methodological quality on the effect estimate (objective 5.2).

• A sensitivity analysis which only includes studies adhering to three or more of the principles for exercise training (objective 3.3). The benefits of exercise therapy on self‐reported fatigue, among others, may be influenced by the quality or dosage of the exercise prescription (Schlagheck 2021).

• While we will exclude equivalence (or superiority) studies on the relative benefits of different exercise therapy modalities, we cannot ignore the fact that, in many settings, exercise or physical activity components may be part of usual care. Hence, in studies were exercise therapy is compared against usual care, contrast between intervention and comparator may be limited by the presence of exercise as an essential component of usual care. Hence, when applicable, we will conduct a sensitivity analysis that excludes studies in which an exercise component was part of the 'active treatment as usual'. This is a sensitivity analysis supplement to the subgroup analysis in which the impact of the type of control condition is determined.

• A sensitivity analysis which excludes pilot‐studies and studies without a priori sample size calculations. This is to assess the impact of small studies on overall effect size.

• In terms of count data (objective 2.1 and 2.2), we plan to undertake a sensitivity analysis which excludes studies that did not specifically report adverse effects as an outcome of interest (as opposed to the assumption that these studies encountered zero adverse effects [e.g. falls] during the study period) (Higgins 2022; chapter 19). Adverse effects are only analyzed during the intervention window.

Summary of findings and assessment of the certainty of the evidence

Three reviewers will evaluate the overall quality of the evidence using the GRADE system, as recommended by Cochrane, and present these in summary of findings tables (Higgins 2022; chapter 14). The summary of findings table will include a total of seven outcomes (aligned to key primary and secondary Objectives), and we will provide a rationale for each assumed risk to the certainty of findings. The seven outcomes are as follows.

1.1a) Postintervention self‐reported fatigue (i.e. immediate benefits)

1.1b) Self‐reported fatigue at follow‐up (i.e. long‐term benefits)

1.2a) Postintervention self‐reported fatigue (i.e. immediate benefits) when only studies in which fatigue was a primary outcome are considered.

1.2b) Postintervention self‐reported fatigue (i.e. immediate benefits) for studies in which predefined levels of fatigue was an inclusion criterion.

2.1a) Adverse events during the intervention window (i.e. immediate risk).

2.2a) MS exacerbations during the intervention window (i.e. immediate risk).

2.2b) Falls during the intervention window (i.e. immediate risk).

Appendices

Appendix 1. Search strategies ‐ PubMed

#39 #37 AND #38

#38 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab]) NOT (animals [mh] NOT humans [mh])

#37 #19 AND #36

#36 #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35

#35 physical fitness[title/abstract] OR occupational therapy[title/abstract] OR physical rehabilitation[title/abstract] OR physical endurance[title/abstract] OR physical stimulation[title/abstract] OR physical education[title/abstract] OR physical training[title/abstract] OR physical medicine[title/abstract] OR physical therap*[title/abstract] OR "recovery of function"[title/abstract] OR endurance training[title/abstract] OR resistance training[title/abstract] OR strength training[title/abstract] OR endurance program*[title/abstract] OR resistance program*[title/abstract] OR strength program*[title/abstract] OR fitness program*[title/abstract] OR aerobic training[title/abstract] OR balance training[title/abstract] OR gait training[title/abstract]

#34 "Resistance Training"[Mesh]

#33 "Endurance Training"[Mesh]

#32 "Recovery of Function"[Mesh]

#31 "Physical Education and Training"[Mesh]

#30 "Physical Stimulation"[Mesh]

#29 "Physical Endurance"[Mesh]

#28 "Physical and Rehabilitation Medicine"[Mesh]

#27 "Occupational Therapy"[Mesh]

#26 "Physical Fitness"[Mesh]

#25 Movement[title/abstract]

#24 "Movement"[Mesh]

#23 "Exercise Movement Techniques"[Mesh]

#22 "Physical Therapy Modalities"[Mesh]

#21 Exercise[title/abstract]

#20 "Exercise"[Mesh]

#19 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18

#18 "Multiple Sclerosis"[Mesh:noexp]

#17 "encephalomyelitis"[Title/Abstract]

#16 "transverse myelitis"[Title/Abstract]

#15 "clinically isolated syndrome"[Title/Abstract]

#14 "demyelinating disorder"[Title/Abstract]

#13 adem[Title/Abstract]

#12 "demyelinating disease"[Title/Abstract]

#11 "devic disease"[Title/Abstract]

#10 "optic neuritis"[Title/Abstract]

#9 "neuromyelitis optica"[Title/Abstract] OR "neuro‐myelitis optica"[Title/Abstract]

#8 "multiple sclerosis"[Title/Abstract]

#7 "Myelitis, Transverse"[Mesh]

#6 "Encephalomyelitis, Acute Disseminated"[Mesh]

#5 "Demyelinating Autoimmune Diseases, CNS"[Mesh:noexp]

#4 "Optic Neuritis"[Mesh]

#3 "Demyelinating Diseases"[Mesh:noexp]

#2 "Multiple Sclerosis, Relapsing‐Remitting"[Mesh]

#1 "Multiple Sclerosis, Chronic Progressive"[Mesh]

Appendix 2. Search strategies ‐ Central

#36 #18 AND #35

#35 {OR #19‐#34}

#34 (physical fitness OR occupational therapy OR physical rehabilitation OR physical endurance OR physical stimulation OR physical education OR physical training OR physical medicine OR physical therap* OR "recovery of function" OR endurance training OR resistance training OR strength training endurance program* OR resistance program* OR strength program* OR fitness program* OR aerobic training OR balance training OR gait training):ti,ab,kw

#33 MeSH descriptor: [Resistance Training] explode all trees

#32 MeSH descriptor: [Endurance Training] explode all trees

#31 MeSH descriptor: [Recovery of Function] explode all trees

#30 MeSH descriptor: [Physical Education and Training] explode all trees

#29 MeSH descriptor: [Physical Stimulation] explode all trees

#28 MeSH descriptor: [Physical Endurance] explode all trees

#27 MeSH descriptor: [Physical and Rehabilitation Medicine] this term only

#26 MeSH descriptor: [Occupational Therapy] explode all trees

#25 MeSH descriptor: [Physical Fitness] explode all trees

#24 (movement):ti,ab,kw

#23 MeSH descriptor: [Movement] this term only

#22 MeSH descriptor: [Exercise Movement Techniques] explode all trees

#21 MeSH descriptor: [Physical Therapy Modalities] this term only

#20 (exercise):ti,ab,kw

#19 MeSH descriptor: [Exercise] this term only

#18 {OR #1‐#17}

#17 encephalomyelitis:ti,ab,kw

#16 "transverse myelitis":ti,ab,kw

#15 "clinically isolated syndrome":ti,ab,kw

#14 "demyelinating disorder":ti,ab,kw

#13 adem:ti,ab,kw

#12 "demyelinating disease":ti,ab,kw

#11 "devic disease":ti,ab,kw

#10 "optic neuritis":ti,ab,kw

#9 ("neuromyelitis optica" OR "neuro‐myelitis optica"):ti,ab,kw

#8 "multiple sclerosis":ti,ab,kw

#7 MeSH descriptor: [Myelitis, Transverse] explode all trees

#6 MeSH descriptor: [Encephalomyelitis, Acute Disseminated] explode all trees

#5 MeSH descriptor: [Demyelinating Autoimmune Diseases, CNS] this term only

#4 MeSH descriptor: [Optic Neuritis] explode all trees

#3 MeSH descriptor: [Demyelinating Diseases] this term only

#2 MeSH descriptor: [Multiple Sclerosis, Relapsing‐Remitting] explode all trees

#1 MeSH descriptor: [Multiple Sclerosis] this term only

Appendix 3. Search strategies ‐ CINAHL and SPORTDiscuss

S35 S33 AND S34

S34 (MH randomized controlled trials OR MH double‐blind studies OR MH single‐blind studies OR MH random assignment OR MH pretest‐posttest design OR MH cluster sample OR TI (randomised OR randomized) OR AB (random*) OR TI (trial) OR (MH (sample size) AND AB (assigned OR allocated OR control)) OR MH (placebos) OR PT (randomized controlled trial) OR AB (CONTROL W5 GROUP) OR MH (CROSSOVER DESIGN) OR MH (COMPARATIVE STUDIES) OR AB (CLUSTER W3 RCT)) NOT ((MH ANIMALS+ NOT MH HUMAN) OR (MH (ANIMAL STUDIES) NOT MH (HUMAN)) OR (TI (ANIMAL MODEL) NOT MH (HUMAN)))

S33 S17 AND S32

S32 S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31

S31 TI ( (physical fitness OR occupational therapy OR physical rehabilitation OR physical endurance OR physical stimulation OR physical education OR physical training OR physical medicine OR physical therap* OR "recovery of function" OR endurance training OR resistance training OR strength training OR endurance program* OR resistance program* OR strength program* OR fitness program* OR aerobic training OR balance training OR gait training) ) OR AB ( (physical fitness OR occupational therapy OR physical rehabilitation OR physical endurance OR physical stimulation OR physical education OR physical training OR physical medicine OR physical therap* OR "recovery of function" OR endurance training OR resistance training OR strength training OR endurance program* OR resistance program* OR strength program* OR fitness program* OR aerobic training OR balance training OR gait training) )

S30 (MH "Resistance Training")

S29 (MH "Endurance Training")

S28 (MH "Physical Education and Training")

S27 (MH "Physical Stimulation")

S26 (MH "Physical Endurance")

S25 (MH "Occupational Therapy")

S24 (MH "Physical Fitness")

S23 TI Movement OR AB Movement

S22 (MH "Movement")

S21 (MH "Therapeutic Exercise")

S20 (MH "Physical Therapy")

S19 TI Exercise OR AB Exercise

S18 (MH "Exercise")

S17 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16

S16 TI encephalomyelitis OR AB encephalomyelitis

S15 TI "transverse myelitis" OR AB "transverse myelitis"

S14 TI "clinically isolated syndrome" OR AB "clinically isolated syndrome"

S13 TI "demyelinating disorder" OR AB "demyelinating disorder"

S12 TI adem OR AB adem

S11 TI "demyelinating disease" OR AB "demyelinating disease"

S10 TI "devic disease" OR AB "devic disease"

S9 TI "optic neuritis" OR AB "optic neuritis"

S8 TI "neuromyelitis optica" OR AB "neuromyelitis optica" OR TI "neuro‐myelitis optica" OR AB "neuro‐myelitis optica"

S7 TI "multiple sclerosis" OR AB "multiple sclerosis"

S6 (MH "Myelitis, Transverse")

S5 (MH "Encephalomyelitis, Acute Disseminated")

S4 (MH "Demyelinating Autoimmune Diseases, CNS")

S3 (MH "Optic Neuritis")

S2 (MH "Demyelinating Diseases")

S1 (MH "Multiple Sclerosis")

Appendix 4. Search strategies ‐ Embase

#40 #36 NOT #39

#39 #37 OR #38

#38 (‘animal experiment’/de NOT (‘human experiment’/de OR ‘human’/de))

#37 ((rat:ti,tt OR rats:ti,tt OR mouse:ti,tt OR mice:ti,tt OR swine:ti,tt OR porcine:ti,tt OR murine:ti,tt OR sheep:ti,tt OR lambs:ti,tt OR pigs:ti,tt OR piglets:ti,tt OR rabbit:ti,tt OR rabbits:ti,tt OR cat:ti,tt OR cats:ti,tt OR dog:ti,tt OR dogs:ti,tt OR cattle:ti,tt OR bovine:ti,tt OR monkey:ti,tt OR monkeys:ti,tt OR trout:ti,tt OR marmoset*:ti,tt) AND ‘animal experiment’/de)

#36 #34 AND #35

#35 'crossover procedure':de OR 'double‐blind procedure':de OR 'randomized controlled trial':de OR 'single‐blind procedure':de OR random*:de,ab,ti OR factorial*:de,ab,ti OR crossover*:de,ab,ti OR ((cross NEXT/1 over*):de,ab,ti) OR placebo*:de,ab,ti OR ((doubl* NEAR/1 blind*):de,ab,ti) OR ((singl* NEAR/1 blind*):de,ab,ti) OR assign*:de,ab,ti OR allocat*:de,ab,ti OR volunteer*:de,ab,ti

#34 #16 AND #33

#33 #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32

#32 'physical fitness':ab,ti OR 'occupational therapy':ab,ti OR 'physical rehabilitation':ab,ti OR 'physical endurance':ab,ti OR 'physical stimulation':ab,ti OR 'physical education':ab,ti OR 'physical training':ab,ti OR 'physical medicine':ab,ti OR 'physical therap*':ab,ti OR 'recovery of function':ab,ti OR 'endurance training':ab,ti OR 'resistance training':ab,ti OR 'strength training':ab,ti OR 'endurance program*':ab,ti OR 'resistance program*':ab,ti OR 'strength program*':ab,ti OR 'fitness program*':ab,ti OR 'aerobic training':ab,ti OR 'balance training':ab,ti OR 'gait training':ab,ti

#31 'resistance training'/exp

#30 'endurance training'/exp

#29 'convalescence'/exp

#28 'physical education'/exp

#27 'physical stimulation'/exp

#26 'endurance'/exp

#25 'rehabilitation medicine'/exp

#24 'occupational therapy'/exp

#23 'fitness'/exp

#22 Movement:ab,ti

#21 'movement (physiology)'/exp

#20 'kinesiotherapy'/exp

#19 'physiotherapy'/exp

#18 exercise:ab,ti

#17 'exercise'/exp

#16 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15

#15 encephalomyelitis:ab,ti

#14 'transverse myelitis':ab,ti

#13 'clinically isolated syndrome':ab,ti

#12 'demyelinating disorder':ab,ti

#11 adem:ab,ti

#10 'demyelinating disease':ab,ti

#9 'devic disease':ab,ti

#8 'optic neuritis':ab,ti

#7 'neuromyelitis optica':ab,ti OR 'neuro‐myelitis optica':ab,ti

#6 'multiple sclerosis':ab,ti

#5 'transverse myelitis'/exp

#4 'acute disseminated encephalomyelitis'/exp

#3 'optic neuritis'/exp

#2 'demyelinating disease'/de

#1 'multiple sclerosis'/exp

Appendix 5. Search Strategies ‐ Pedro, Scielo, WHO ICTRP & ClinicalTrials.gov

Exercise OR "physical therapy modalities" OR "exercise movement techniques" OR movement OR "physical fitness" OR "occupational therapy" OR "physical rehabilitation" OR "physical endurance" OR "physical stimulation" OR "physical education" OR "physical training" OR "physical medicine" OR "physical therapy" OR "recovery of function" OR "endurance training" OR "resistance training" OR "strength training" OR "endurance program*" OR "resistance program*" OR "strength program*" OR "fitness program*" OR "aerobic training" OR "balance training" OR "gait training"

AND

"Multiple sclerosis" OR "optic neurit*" OR encephalomyelitis OR "myelooptic neuropathy" OR myelitis OR neuromyelitis OR "neuro‐myelitis" OR "clinically isolated syndrome" OR devic OR devics OR demyelinating

Contributions of authors

MH: conceptualization, methodology, writing ‐ original draft, funding acquisition

MR: resources, project administration, funding acquisition, writing ‐ review & editing

EAG: writing ‐ review & editing

EE: writing ‐ review & editing

HB: writing ‐ review & editing, funding acquisition

IP: writing ‐ review & editing

VG: writing ‐ review & editing, funding acquisition

GK: writing ‐ review & editing, funding acquisition

EW: writing ‐ review & editing, funding acquisition

Sources of support

Internal sources

• No sources of support provided

External sources

• National Multiple Sclerosis Foundation, Netherlands

  OZ2021‐002

Declarations of interest

MH: reports being involved in a study that is eligible for inclusion in the work; the study was funded by ZonMW / Fonds NutsOHRA, but the researchers retained complete control over the study design, methods, data analysis and reporting.

MR: reports being involved in a study that is eligible for inclusion in the work; the study was funded by ZonMW / Fonds NutsOHRA, but the researchers retained complete control over the study design, methods, data analysis and reporting.

EAG: has declared no conflicts of interest.

EE: has declared no conflicts of interest.

HB: reports being involved in a study that is eligible for inclusion in the work; the study was funded by ZonMW / Fonds NutsOHRA, but the researchers retained complete control over the study design, methods, data analysis and reporting.

IP: reports being involved in a study that is eligible for inclusion in the work; the study was funded by ZonMW / Fonds NutsOHRA, but the researchers retained complete control over the study design, methods, data analysis and reporting.

VG: reports being involved in a study that is eligible for inclusion in the work; the study was funded by ZonMW / Fonds NutsOHRA, but the researchers retained complete control over the study design, methods, data analysis and reporting.

GK: has declared no conflict of interest.

EW: has declared no conflict of interest.

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