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Abstract
Introduction Multiple sclerosis (MS) causes a broad range of symptoms, with physical function being one of the most disabling consequences according to patients themselves. Exercise effectively improves lower extremity physical function. Nonetheless, it is unknown which exercise modality is most effective and it remains challenging to keep persons with MS adhering to exercise over a longer period. Therefore, the present study aims to investigate how exercise booster sessions (EBS) influence the sustainability of exercise-induced effects on physical function, and furthermore, to investigate which exercise modality (aerobic training or resistance training) is most effective in terms of improving physical function.
Materials and methods This study is a multi-arm, parallel-group, open-label multicentre randomised controlled trial investigating the effects of EBS. Participants (n=150) are initially randomised to 12 weeks of either resistance training+usual care, aerobic training+usual care or usual care. After 12 weeks of intervention, participants in the exercise groups will again be randomised to either EBS+usual care or usual care during a 40-week follow-up period. The primary outcome is physical function (composite score based on 6-min walk test and five-time sit to stand), and the secondary outcomes are fatigue, cognition, physical activity, symptoms of depression and quality of life.
Ethics and dissemination The study is approved by the Central Denmark Region Committees on Health Research Ethics (1-10-72-237-21) and is registered at the Danish Data Protection Agency (2016-051-000001) and at Clinicaltrials.gov (NCT04913012). All study findings will be published in scientific peer-reviewed journals and presented at scientific conferences.
Trial registration number NCT04913012.
- Multiple sclerosis
- REHABILITATION MEDICINE
- Physical Therapy Modalities
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The present study is a large-scale randomised controlled trial investigating exercise booster sessions in persons with multiple sclerosis.
The present study offers head-to-head data on which exercise modality is the most effective in terms of improving physical function.
It is a limitation that no blinding is performed, thus increasing the risk of bias.
Introduction
Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system, causing demyelination and axonal loss.1 As a result, symptoms such as mobility impairment, fatigue and depression frequently appear,1–3 all of which are known to be positively affected by exercise.4–6 Importantly, preservation of mobility is rated as one of the most important aspects by persons with MS (PWMS),7 making interventions that can effectively improve mobility warranted. Over the past 20 years, exercise has gained much attention and is now considered a cornerstone in MS rehabilitation, being both safe and effective at improving mobility (ie, walking capacity).8 Although aerobic training (AT) and resistance training (RT)—the two most commonly applied exercise modalities in PWMS9—have been suggested to be equally effective in terms of improving walking capacity and physical function,8 no head-to-head exercise studies comparing interventions and involving PWMS have been performed, despite the obvious clinical interest in such a comparison.
While AT primarily targets the cardiovascular system eliciting improvements in aerobic capacity, RT primarily targets the neuromuscular system eliciting improvements in muscle strength.8
To benefit from the positive effect of exercise, one must adhere over time. Yet, long-term maintenance of exercise efforts remains a major challenge in PWMS.10 The current knowledge based on preservation of exercise effects is limited by rare reporting of follow-up data across most randomised controlled exercise trials (RCTs) in PWMS, thus providing little insight into the sustainability of exercise-induced effects.9 Furthermore, to our knowledge, only one RCT11 with an intervention duration exceeding 26 weeks exists, making it difficult to conclude on the long-term benefits of exercise.12
From research involving older individuals, it is well known that cessation of an exercise intervention leads to a loss of physical function in the following period (weeks, months).13 14 However, the sparse findings from MS studies are divergent, with studies reporting preserved physical function after 1215 16 and 24 weeks of follow-up.17 As these studies failed to assess important determinants for preservation of exercise-induced effects such as recording of the physical activity level as well as participation in exercise outside the research study, it remains uncertain if the participants change behaviour after an exercise intervention and/or if certain types of exercise induce longer lasting effects.
Exploring the sustainability of exercise-induced effects holds vital importance for several reasons. First, it sheds light on the potential long-term benefits individuals with compromised mobility, such as PWMS, can derive from structured exercise interventions. Understanding the sustainability of these effects provides valuable insights into optimising exercise strategies, aiding healthcare professionals in tailoring interventions. Second, by discerning the factors influencing the persistence of exercise-induced benefits, it becomes possible to develop targeted and personalised approaches, enhancing adherence and promoting sustained physical well-being.
An emerging concept that may hold the potential to better preserve exercise-induced effects is supervised ‘exercise booster sessions’ (EBS); defined as a number of supervised high-intensity exercise sessions delivered at a markedly lower frequency compared with how a traditional exercise programme is normally implemented. By placing EBS regularly during the follow-up period, the idea is to boost the effects of the preceding exercise intervention by offering high-quality exercise sessions and by motivating participants to sustain their exercise routines. Although EBS have recently attracted much attention in clinical practice, it is still a new and understudied concept, with only four existing RCTs focusing on the effect of EBS in different populations.18–21 Results from the existing studies are inconsistent, with some failing to report any effect of EBS,18–20 whereas one study report a positive effect.21 These studies reported few details on exercise intensity and volume, and did not evaluate any neurological patients such as PWMS, as they primarily focused on patients with osteoarthritis.22 Furthermore, none of the studies investigated AT.
Taken together, a need exists for more in-depth studies examining the effects of EBS on preservation of potential effects on physical function of an exercise intervention in populations with reduced mobility and in need of rehabilitation (eg, PWMS). To further expand our knowledge on EBS in PWMS, it seems prudent to also involve a head-to-head comparison of exercise modalities, specifically AT versus RT as emphasised above, thus allowing evaluation of the sustainability of effects induced by different exercise modalities.
Therefore, the primary purpose of the present study is to compare how 40 weeks of either AT EBS plus usual care, RT EBS plus usual care or usual care alone, influence the sustainability of effects on functional capacity and physiological key indicators, induced by a preceding 12-week exercise intervention.
Our secondary purposes are to:
compare the effects of either 12 weeks of AT or RT on physical function in PWMS (ie, head-to-head comparison of AT and RT).
compare the sustainability of exercise-induced effects in the groups not receiving EBS from week 12 to week 52 (ie, head-to-head comparison of 40 weeks of follow-up effects after AT or RT).
investigate the effects of 40 weeks of AT EBS plus usual care and RT EBS plus usual care on fatigue, cognition, depression and quality of life compared with the groups not receiving EBS.
The primary hypothesis is that participants receiving AT EBS plus usual care or RT EBS plus usual care during the follow-up period will have superior physical function at follow-up compared with the participants receiving usual care only.
Our secondary hypotheses are that:
there is no difference in physical function after 12 weeks of either AT or RT.
there is no difference in the sustainability of exercise-induced effects in the groups not receiving EBS from week 12 to week 52.
participants receiving 40 weeks of AT EBS plus usual care or RT EBS plus usual care will have reduced their fatigue and symptoms of depression and improved their cognition and quality of life, as compared with the groups not receiving EBS.
Methods
Design and setting of the study
The present study is a multi-arm, parallel-group, open-label, multicentre RCT investigating the effects of EBS on functional capacity. In the first 12 weeks of the study, the participants (n=150) are randomised to either AT, RT or usual care. After testing at 12 weeks, the exercise groups will once again undergo a randomisation process, where participants are randomised to either 40 weeks of EBS or 40 weeks of usual care (see figure 1).
Conceptual figure. *Participants randomised to EBS will receive two exercise sessions every fifth week during the 40 weeks follow-up period. For more information on specific outcomes at the tests, see table 1. EBS, exercise booster sessions; HR, heart rate; RM, repetition maximum.
The intervention is carried out in Aarhus at Aarhus University, in Copenhagen at the University of Copenhagen, in Odense at University of the Southern Denmark and in Esbjerg at a private physiotherapy clinic. Outcome assessments are conducted at both Aarhus and Copenhagen University. The duration of the study is 52 weeks, with an outcome assessment at baseline (T0), after 12 weeks (T1) and after 52 weeks (T2).
The study started recruitment on 1 November 2021 and is expected to be completed in October 2024.
Recruitment and eligibility
Participants are recruited via Danish regional MS clinics (Aarhus University Hospital, Odense University Hospital, Hospital of Southwest Jutland and the Danish Multiple Sclerosis Center in Copenhagen). Furthermore, there is recruitment through social media and events hosted by the Danish MS Society. Prior to enrolment, participants are screened via a phone interview, where basic information is collected, and it is ensured that the medical status of the participant meets the inclusion/exclusion criteria (see table 1). As one purpose of the study is to investigate the difference between AE and RT on physical function, participants randomised into one of these groups are requested not to perform the other exercise modality during the intervention period if this exercise modality was not performed prior to inclusion (it is considered unethical to ask participants to skip existing exercise habits).
Inclusion and exclusion criteria
If the participant meets the inclusion/exclusion criteria at the phone interview, the participant is invited to a baseline assessment, whereafter the participant is assigned to a group according to the randomised allocation list.
Randomisation
Following T0 testing, participants are randomised according to a computer-generated randomisation list (2(AT):2(RT):1(usual care)). Cluster randomisation at the level of intervention sites is performed, with groups of four participants allocated to an intervention at a specific site. Following T1, participants in both exercise groups are again randomised according to a computer-generated allocation list (1(Boost):1(usual care)).
This randomisation process was primarily chosen due to pragmatic reasons, which is also why there is no blinding of assessors in the present study.
Assessors and exercise supervisors
There will be three assessors at the Aarhus test site and two assessors at the Copenhagen test site. All assessors will have undergone the same extensive teaching and training in order to assure the quality of assessment. As the project is running over a long period of time at many different sites, it is expected that approximately 20 exercise supervisors will take part in the project. All supervisors will undergo comprehensive training before supervising exercise sessions.
Interventions
The interventions are developed by exercise physiologists (LT-M, LGH and UD) and are based on principles similar to previous studies showing an effect on cardiorespiratory fitness11 and muscle strength,17 respectively. In addition to the delivered supervised interventions, participants are encouraged to continue their regular physical activities.
All interventions are delivered in a supervised manner by trained student assistants. The frequency is 5 sessions/2 weeks over a 12-week period, resulting in a total of 30 sessions (see online supplemental appendix). The intervention consists of either AE or RT, which is performed in a progressive manner. After the exercise interventions, participants randomised to EBS receive 2 sessions every fifth week over 40 weeks resulting in a total of 14 sessions (as week 40 is the week for T3 testing).
Supplemental material
Both session and content adherence are monitored during the intervention period. Should a participant be unable to meet the prescribed exercise intensity, this will be noted, and the training session is adjusted accordingly.
If a participant is unable to attend any sessions over a 3-week period, the intervention is terminated, and the participant is considered a drop out.
Aerobic training
The AT intervention is performed on either bicycle ergometer, rowing ergometer, cross trainer or recumbent stepper and consists of continuous training (1/3 of the sessions) and interval training (2/3 of the sessions). The duration of the continuous sessions is 40–45 min with a target intensity of 65%–80% of maximum heart rate (HR max) as determined by the maximal incremental exercise test, and the interval sessions consist of 30–50 min with target intensities between 65%–90% of HR max. By motivating them, the trained supervisors will ensure that participants do their best to reach the target intensity.
Resistance training
The RT intervention consists of exercises primarily focusing on the lower limb. In each exercise session, the participants perform the following exercises: leg press, seated calf raises, leg curl, leg extensions, chest press and lateral pull-down. The duration of the sessions is 45–60 min with target intensities between 15 and 8 repetition maximum.
Exercise booster sessions
The EBS is delivered with a frequency of two sessions every fifth week. The intensity of the sessions corresponds to the intensity applied during weeks 6–8 of the initial exercise programmes (see online supplemental appendix).
Outcomes and assessments
Assessors are not blinded to any outcome; nor are participants blinded to the interventions. An overview of all outcomes can be seen in table 2.
Outcomes
Primary outcome
The primary outcome of the study is functional capacity, measured as a composite score based on the 6-min walk test (6MWT)23 and the five-time sit to stand test (5STS).24 This outcome is assessed at T0, T1 and T2. A Z score (the mean subtracted from the individual score divided by the SD) is calculated for both the 6MWT and the 5STS. The two Z scores are added, and the average of these is the composite score.
As part of the study aim is to compare AT and RT, this composite score is chosen based on the assumption that an increase in aerobic capacity favour improvements in 6MWT8 25 whereas an increased neuromuscular strength favour improvements in 5STS.17
Functional capacity is chosen as the primary outcome for several reasons. First, patients report preservation of mobility as one of the most important aspects of living with MS.7 Second, physical impairment is associated with lowered quality of life26 27 and causes a greater societal economic burden.28 29 Third, both AT and RT exercise have been proven effective in terms of improving physical function.8 As the present study aims to investigate the effects of EBS on sustainability of exercise-induced effects on physical function, an exercise-induced effect following the initial 12 weeks exercise intervention of the study is needed.
The 6MWT is assessed on a 30-m track evaluating walking endurance.23 Participants are instructed to walk as far as possible,30 and a change exceeding 21.6 m in walking distance is considered a clinically meaningful change.31
The 5STS evaluates the muscle mechanical function of the lower extremities. Participants are asked to rise and sit down as fast as possible on a chair without armrest.24 The test is done twice, and the best result was used for evaluation.
Secondary outcomes
Physical function
Physical function is also measured by the timed 25-foot walk test (T25FWT), 9-hole Peg Test (9HPT), six spot step test (SSST) and the timed up and go (TUG).
The T25FWT is completed in a corridor with a marked 7.62 m track. Participants are instructed to walk 25 feet as quickly as possible in a safe manner.32 The test is performed twice, and the average of the two tests (in seconds) is recorded as the result. It is a validated quantitative measurement of lower limb ambulatory performance in PWMS,33 where a change exceeding 20% is considered a clinically meaningful change.34
For the 9HPT, participants are instructed to insert pegs one by one into nine holes and then remove them again one by one as fast as possible. This is done twice with both the dominant and the non-dominant hand, and the average time of each hand (in seconds) is recorded as the result.32 It is a quantitative measure of manual dexterity and upper extremity function, where a change exceeding 20% is considered a clinically meaningful change.35
In the SSST, the participant is instructed to walk a 5-m rectangular track in a crisscross manner, while shoving five wooden blocks out of circles marked on the floor. This is done with one foot alternating between the lateral and medial sides of the foot.
The participant is instructed to do this safely and as fast as possible. The test is performed four times (two times with each foot), and the average time (in seconds) is recorded. The SSST requires, in contrast to the T25FWT, a more complex movement pattern including changes in direction, balance and coordination.36 Despite the complex movement pattern, an acceptable test–retest agreement and reliability have been shown.37 38
In the TUG, the participant is instructed to rise from a chair, walk 3 m, turn, walk back and sit down again. It evaluates more functional components of mobility and has shown good reliability and is easily performed.39
Aerobic capacity
Participants perform an incremental exercise test until exhaustion on a bicycle ergometer (SRM, Jülich, Germany). Prior to the test, the flow and gas analysers are calibrated using a 3 L syringe (Hans Rudolph, series 5530, Shawnee, Kansas, USA) and certified reference gasses (4.00% CO2 and 16.5% O2). Saddle and handlebars are adjusted according to the participant’s anthropometrics, and body mass and fat percentage are measured using a calibrated personal scale (Tanita SC-330, Tokyo, Japan.)
The test starts with a 5-min warm up at 60 W followed by increments of 10 W/min (women) and 15 W/min (men) until voluntary exhaustion. Participants are throughout the test verbally encouraged to continue as long as possible. The cadence throughout the test is at a self-chosen level between 50 and 95 revolutions/min. Expired gas is collected in a mixing bag. The rate of oxygen uptake (VO2), carbon dioxide release (VCO2) and respiratory exchange ratio is determined continuously by an online respiratory gas exchange analyser (Oxigraf O2CPX, Oxigraf, Sunnyvale, California, USA) and expressed as 10 s averages using Indoor 8.00 software (Innovision ApS, Glamsbjerg, Denmark).
Both work rate (W) (SRM software, SRM, Jülich, Germany) and HR (Wahoo Tickr2, Wahoo fitness, Atlanta, USA) are continuously monitored during the test.
Following the test, participants are asked to rate their perceived exhaustion after voluntary exhaustion using the 6–20 Borg Scale.40 The highest recorded 30 s VO2 average attained during the test is considered the VO2-max.
Based on the expected maximal power output estimated from age, sex, disability and body size, individual power output adjustments can be made after the 5-min warm-up to expectedly exhaust the subjects within 8–12 min after warm-up.41
An incremental exercise test has been shown to be a reliable and valid method for testing VO2-max in PWMS, and a change exceeding 10% is considered the smallest reliable change.42
Muscle strength measurements
After a 5-min warm-up on an ergometer bicycle (MonarkLT2, Monark, Sweden), participants are seated (hip angle of 90°), depending on the test site, either in an isokinetic dynamometer (Aarhus) (Humac Norm, CSMi, Stoughton, Massachusetts, USA) or in a custom build dynamometer enabling isometric muscle strength testing via a strain gauge (Copenhagen). Their non-dominant leg is attached to the dynamometer lever arm. The test is performed with arms across at the chest, and the upper body is strapped to the chair to ensure that only the knee extensors affected the torque outcome. The lever arm is fixed at a 90° angle for the test. The participants are then instructed to maximally extend their knee with full force for 3–5 s while being verbally encouraged. The participants have three trials interspersed by 1–2 min of rest.
Following the isometric test, participants belonging to the test site (Aarhus) also perform three isokinetic knee extensions at 180°/s over a 90° range of motion (starting from 90° and ending at 0°). Prior to the actual test, participants have three familiarisation trials.
For both the isometric and the isokinetic tests, the trial with the highest peak force value is selected for further analysis. If a participant has three consecutive trials with consecutive increase in peak force, a fourth trial is given.
Physical activity—measured by accelerometry
To objectively assess physical activity, participants wear a thigh-worn accelerometer (Axivity, AX3, Axivity, Newcastle, UK) for 7 consecutive days following T0, T1 and T2. The device is attached mid-thigh to the non-dominant leg using 5×9 cm self-adhesive tape (Fixomull Stretch, BSN Medical, Hamburg, Germany).
Raw data are sampled using 100 Hz±8 g and subsequently downloaded and analysed using custom-built software (Propero by Jan Christian Brønd, Odense, Denmark).43 The vector magnitude counts are analysed in 30 s epochs over a time span of 18 hours. For the data to be considered valid, 8 hours of accepted data per day over a period of 4 days is a minimum.
Physical activity level is presented as counts per minute.
Cognitive function
Cognitive function is assessed using the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), both primarily measuring processing speed,32 44 but for the PASAT, also attention, executive control and working memory.32 To minimise a potential learning effect, alternate forms of both tests are used. A change greater than 0.5 SD of the studied population is considered a clinically meaningful change for the PASAT,45 and a change of four points or greater from baseline is considered clinically meaningful for the SDMT.46
Patient-reported outcomes
Prior to tests of physical function at T0, T1 and T2, participants are instructed to fill out a number of questionnaires on MS specific symptoms, general health status, and physical activity level. Patient-reported outcomes are considered important, as it puts the patient at the centre and is the first step of patient-centred therapeutic management.47
MS-specific questionnaires
To assess the participant’s own perception of their walking ability, the Multiple Sclerosis Walking Scale-12 (MSWS-12) is used.48 Each question in the MSWS-12 has five different answers (score range 1–5), and the total score is transformed to a score from 0 to 100, with a higher score indicating greater impairment. Previously, the MSWS-12 has proven more sensitive than objective walking tests in detecting walking-related impairment early in the disease course.49 A change in the MSWS-12 score exceeding 10.7 points is considered clinically meaningful.31
Fatigue is one of the most debilitating MS symptoms and is, in the present study, assessed by the Multiple Sclerosis Fatigue Impact Scale (MFIS),50 where the score ranges from 0 to 84 with a higher score indicating higher levels of fatigue. A change of 3.86 is considered clinically meaningful.51
General health status
To assess health-related quality of life, the EQ-5D-5L is used.52 It measures five dimensions: mobility, self-care, daily activities, pain/discomfort and anxiety/depression. Each dimension consists of one item with five possible answers (no, slight, moderate, severe problems, unable to do so). Furthermore, the EQ-5D-5L also includes a visual analogue scale where health status is rated from 0 (worst imaginable health) to 100 (best imaginable health). The EQ-5D-5L has previously been suggested to be used in MS research to allow comparison across studies.53
To measure generic physical and mental health, the Short-Form Health Survey with 36 questions is used.54 The questionnaire has both a physical and a mental component, and for both components, a higher score indicates a better health status. Each item in the questionnaire will be scored using norm-based T-scores and transformed to 0–100 range scores, according to official guidelines.55
Societal costs
To measure if the interventions have an effect on societal costs, two different questionnaires are used. A nine-item questionnaire (Health Utilisation Questionnaire (HUQ)) measures health utilisation by assessing healthcare and medicine usage.56 To measure productivity loss of paid work due to absence, presenteeism and loss related to unpaid work, the iMTA Productivity Cost Questionnaire (IPCQ) is used.57
Falls
More than 50% of all PWMS report falls within the last 3–6 months,58 59 constituting it as a major health issue in PWMS.60 To quantify falls, participants are asked to retrospectively answer if they have had falls within the last year, and if so, the number of falls and the associated injuries are recorded. Furthermore, the Falls efficacy scale (FES) is used to measure the fear of falling. This is a 7-item questionnaire where each item has 4 possible answers (not concerned at all, slightly concerned, quite concerned or very concerned)61 corresponding to a score from 1 to 4. The total score is calculated by summing all answers.
Anxiety and depression symptoms
Both anxiety and depression are common symptoms in PWMS,62 63 and to measure this, the Hospital Anxiety and Depression Scale (HADS) is used.64
Self-reported physical activity
To measure the self-reported physical activity level, the Baecke Physical Activity Questionnaire is used. This quantifies the habitual physical activity in three indices: occupational (at work), sport (structured exercise) and leisure (leisure time). Each index is scored from 1 to 5, with 5 indicating the highest level of physical activity.65
Patient and public involvement
There has been no patient involvement in the design of the study. Patients are involved in the recruitment of participants by assisting in the recruitment through social media (MS-specific Facebook groups).
Each participant receives individual feedback after the intervention and all participants will be invited to a lecture at the end of the study, where the overall results of the project will be presented.
Power analysis
The power calculation is based on the primary purpose of the study, which is to investigate the effect of frequently applied EBS. To estimate the number of participants, a two-sample two-sided power calculation was conducted. Based on previous studies,15–17 a mean difference in functional capacity between the group receiving usual care and the group receiving AT or RT EBS+usual care, regardless of exercise intervention, is expected to be 6% with a SD of ±10%.
The level of significance was set as 5% and a statistical power of 80%. According to the power calculation, groups of 60 participants (expected drop-out rate of 30% is included) are needed. In addition to this, we consider it of clinical relevance to include a control group not receiving any intervention. To match the size of the EBS interventions groups, it was decided that the control group should be 30 participants.
Therefore, the total sample size is 150.
Data management and statistical analysis
All data collected in the project is directly entered into the Research Electronic Data Capture (RedCap) for safe storage.66 67 This includes drop-outs and reasons here-fore and potential adverse events. The patient-reported outcomes are entered directly into RedCap by participants through a link sent by email at T0, T1 and T2. Only the principal investigator (LT-M), UD and LGH will have access to data at the completion of the study.
Baseline demographics are presented as mean±SD if they follow a normal distribution and as medians and IQRs if they are not normally distributed. It is checked by Q/Q plots and histograms if data follow a normal distribution and if not, data are transformed accordingly. Furthermore, outcome measures at T0 versus T1 and T1 versus T2 are analysed using a multivariate-repeated measurements mixed effects regression model with participant ID as a random effect and group and time as fixed effects. A priori defined potential confounding variables (age, gender and time since diagnosis) are included in the model. All analyses are performed as intention to treat.
Strength and limitations
One of the major strengths of the present study is the large sample size (n=150), which is based on an expected drop-out rate of 30%. This is relatively high, as a systematic review has found drop-out rates in exercise interventions in PWMS range from 0 to 47.9 Additionally, the study has a control group, in which participants are not offered any intervention in addition to usual care throughout the study. This feature allows a direct comparison of our interventions with real-world conditions.
Furthermore, the EBS concept still holds a high degree of novelty, as few studies have investigated this previously, and none of these are in a neurodegenerative population.22 Finally, the long follow-up period of 40 weeks provides insight into how well the effect of 12 weeks of either AT or RT is preserved, which has not been directly compared in PWMS previously.
The study also holds some limitations. First, none of the assessors are blinded to the interventions, which potentially can lead to bias. However, as the primary outcome is an objective functional outcome, the lack of blinding most likely has a minimal impact. Additionally, an inherent limitation in exercise trials is that the exercise therapists and the participants cannot be blinded to the intervention due to the nature of an exercise intervention. This could potentially lead to performance bias in the patient-reported outcomes.
Second, our study design does not provide information on the active component in EBS (motivation or physiological response). To assess this aspect, participants should optimally be required not to perform any exercise other than the EBS to isolate this. However, due to ethical reasons, this was not considered possible. Hence, it remains uncertain if the active ingredient during the follow-up period is the EBS itself or the motivational boost a participant could gain from knowing they are in the intervention group.
Third, there is a risk of potential selection bias, as participants voluntarily participate in the study. This means that the results from the study might not be generalisable for the whole group of PWMS. Moreover, the participants in the present study might already before entering the study be among the most active, as one would expect these would be more likely to participate in a study like this. However, one of the inclusion criteria was that people were not allowed to exercise more than twice weekly, as this ensured room for improvement.
Fourth, it is challenging to make AT and RT interventions fully comparable, as the modalities differ in nature. It is only possible to match the two modalities completely in frequency, whereas both intensity and progression are matched as well as possible.
Perspectives
To our knowledge, the present study is the first head-to-head comparison of the effects potentially elicited by the two most applied exercise modalities in PWMS, AT and RT.12 Furthermore, this is the first study reporting EBS in a population with neurodegenerative condition.
If EBS is found to be an effective way of preserving exercise-induced effects on physiological key indicators (muscle strength and aerobic capacity) and/or functional capacity, the study has provided novel and clinically important information, which easily can be implemented in a ‘real-world’ setting.
One of the major challenges in the field of rehabilitation is to keep people engaged and motivated to exercise over a longer period. The present study addresses this problem by applying EBS after the cessation of a period with supervised exercise.
In summary, this is the first study performing a head-to-head comparison of the effects of the two most applied exercise modalities in PWMS and is also the first study to report EBS in a neurodegenerative population. If we find that one exercise modality is more effective in improving physical function, this is a finding of major clinical importance. Likewise, if we find EBS to be an effective intervention at maintaining, or even improving, physical function after an exercise intervention, this will offer an implementable solution that holds the potential for changing current clinical practice.
Ethical aspects and dissemination
This study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials guidelines.68 The project has been approved by the Central Denmark Region Committees on Health Research Ethics (Journal No. 1-10-72-237-21) and is registered at the Danish Data Protection Agency (2016-051-000001) and at Clinicaltrials.gov (NCT04913012). The study conforms to the principles of the Declaration of Helsinki. Participants sign informed consent (standard formula from the Danish National Research Ethics Committee). Results will be published in international peer-reviewed journals, regardless of positive, negative or neutral findings.
Supplemental material
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @HvidLars
Contributors The manuscript was drafted by LT-M, LGH and UD. The trial was developed by LT-M, LGH, HD and UD. During the execution of the study, JL-J has been responsible for the testing in Copenhagen. FS, JRC, RR, TS, KBS, VP and HHC have all assisted with inclusion of participants, provided clinical information on participants and general guidance on clinical matters. All coauthors have commented upon and approved the present manuscript before submission. LT-M is the guarantor.
Funding The study is funded by TrygFonden (Grant number 154868), Helsefonden (Grant number 21-B-0236), Scleroseforeningen (Grant number A42692), JaschaFonden (Grant number 2021-0120), Fogs Fond and Fonden af 1870. None of the funders played a role in the study design, in the writing of the manuscript and nor will they in the data collection, analysis and interpretation of data and in the publication process.
Competing interests LT-M, HD, RR, KBS and JL-J declare no conflict of interest. LGH has received travel grants and/or teaching honorary from Biogen and Sanofi Genzyme. UD has received research support, travel grants and/or teaching honorary from Biogen, Merck Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on scientific meetings of Biogen and Sanofi Genzyme. HHC reports non-financial support from Merck, non-financial support from Teva, non-financial support from Biogen, non-financial support from Roche and non-financial support from Novartis outside the submitted work and personal support from the Warwara Larsen Foundation. FS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. VP has received travel grants from Merck and Sanofi and research support from Roche. JRC has received speaker honoraria from Biogen. RR has served on scientific advisory boards, received speaker honoraria and received support for congress participation from Merck, Sanofi, Roche, Medtronic and Ipsen. TS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi. TS received unrestricted research grants to his research institution from Biogen, Merck and Roche, and is currently engaged in sponsor-initiated research projects by Eisai, Lundbeck, Roche and Sanofi.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
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