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.
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
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