Contemporary Clinical Trials 41 (2015) 280–286

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Contemporary Clinical Trials journal homepage: www.elsevier.com/locate/conclintrial

Experimental protocol of a randomized controlled clinical trial investigating exercise, subclinical atherosclerosis, and walking mobility in persons with multiple sclerosis Garett Griffith a, Rachel E. Klaren b, Robert W. Motl b, Tracy Baynard a, Bo Fernhall a,⁎ a b

Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois at Chicago, IL, USA Exercise Neuroscience Research Laboratory, Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, IL, USA

a r t i c l e

i n f o

Article history: Received 19 November 2014 Received in revised form 6 February 2015 Accepted 9 February 2015 Available online 14 February 2015 Keywords: Multiple sclerosis Aerobic exercise Subclinical atherosclerosis Walking mobility

a b s t r a c t Background: This randomized controlled trial (RCT) will investigate the effects of a home-based aerobic exercise training regimen (i.e., cycle ergometry) on subclinical atherosclerosis and walking mobility in persons with multiple sclerosis (MS) and minimal disability. Methods/design: This RCT will recruit 54 men and women who have an Expanded Disability Status Scale characteristic of the 1st stage of MS (i.e., 0–4.0) to participate in a 3 month exercise or stretching intervention, with assessments of subclinical atherosclerosis and walking mobility conducted at baseline, week 6 (midpoint), and week 12 (conclusion) of the program. The exercise intervention will consist of 3 days/week of cycling, with a gradual increase of duration followed by an increase in intensity across the 3 month period. The attention-control condition will incorporate stretching activities and will require the same contact time commitment as the exercise condition. Both study groups will participate in weekly video chat sessions with study personnel in order to monitor and track program adherence. Primary outcomes will consist of assessments of vascular structure and function, as well as several walking tasks. Additional outcomes will include questionnaires, cardiorespiratory fitness assessment, and a 1-week free-living physical activity assessment. Discussion: This investigation will increase understanding of the role of aerobic exercise as part of a treatment plan for managing subclinical atherosclerosis and improving walking mobility persons in the 1st stage of MS. Overall, this study design has the potential to lead to effective aerobic exercise intervention strategies for this population and improve program adherence. © 2015 Elsevier Inc. All rights reserved.

1. Introduction & background Multiple sclerosis (MS) is a neurological disease of the central nervous system with a prevalence of 1 per 1000 persons in the US [1]. Life expectancy is reduced by ~10 years in populations with MS, but the disease itself is rarely the cause of premature death [2]. Co-morbidities, including cardiovascular

⁎ Corresponding author at: Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois at Chicago, 808 South Wood Street, 169 CMET, Chicago, IL 60612-7305, USA. E-mail address: [email protected] (B. Fernhall).

http://dx.doi.org/10.1016/j.cct.2015.02.003 1551-7144/© 2015 Elsevier Inc. All rights reserved.

disease (CVD), are a leading cause of mortality in MS and epidemiological studies have demonstrated an increased risk of CVD in persons with MS compared with the general population [2–4]. Vascular co-morbidities have been associated with diagnostic delays and worsening of mobility disability, and mobility disability itself is a hallmark feature of disease progression in MS [5,6]. Such observations underscore the importance of identifying approaches for managing CVD and its associated consequences for mobility disability. Physical activity, particularly aerobic exercise training, may have beneficial effects on CVD and mobility disability in MS. Physical activity is inversely and independently associated with

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symptoms of CVD [7], markers of subclinical atherosclerosis [8], and mobility disability [9] in persons with MS. There are currently no data examining the effects of aerobic exercise training on subclinical atherosclerosis in persons with MS, although aerobic exercise training has improved mobility disability [10]. Importantly, aerobic exercise training has improved subclinical atherosclerosis in the general population [11,12], and markers of subclinical atherosclerosis are predictive of CVD mortality and morbidity [13–17]. Collectively, aerobic exercise training might improve both subclinical atherosclerosis and mobility disability in persons with MS. One major limitation of exercise programs delivered among persons with MS involves the degree of supervision of the intervention. For example, supervised exercise training in a center has improved walking mobility in persons with MS, whereas unsupervised exercise programs in the home have not yielded the same effect, perhaps based on poor compliance [10]. This undermines the potential of providing an effective therapy for those with MS who cannot undertake supervised, center-based exercise programs. Accordingly, home-based exercise programs that adopt strategies for maximizing compliance might present a novel and efficacious approach. Such strategies include using exercise equipment with Internet access for monitoring program compliance, along with support from behavioral interventionists using strategies for behavior change based on an established theory, such as social-cognitive theory (SCT) [18]. This randomized controlled trial (RCT) will examine the effect of a 12-week, home-based aerobic exercise training intervention (i.e., cycle ergometer) versus a minimal exercise, attention-control condition (i.e., stretching) on markers of subclinical atherosclerosis and mobility disability among persons with MS who have minimal disability. The exercise training program will be delivered using Expresso Nuvo cycle ergometers (Sunnyvale, CA) that allow for monitoring of compliance based on Internet access along with weekly support from a behavior interventionist and strategies from previous research in MS [19,20]. Such a study will address gaps in knowledge by implementing a home-based exercise program with provisions for maximizing and monitoring compliance with the exercise training. This study will further establish the scientific basis of aerobic exercise training for improving markers of subclinical atherosclerosis and mobility disability. The protocol utilizes an innovative design, by applying the use of cycle ergometry while evaluating potential improvements in gait and mobility. Therefore, the study may help to isolate potential independent effects of aerobic exercise conditioning and general lower body conditioning, not specific to gait, on mobility parameters. Data from this study should advance our understanding of home-based exercise as a behavioral approach for managing vascular co-morbidities and worsening of mobility disability in MS. 2. Methods 2.1. Study design, overview, & hypotheses The proposed study and data collection will take place in the Integrative Physiology Laboratory at the University of Illinois at Chicago. The study will use a two-arm RCT design to examine the effect of a home-based exercise training program versus a

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minimal exercise, attention-control condition on measures of subclinical atherosclerosis and mobility disability in individuals with MS who have Expanded Disability Status Scale (EDSS) scores characteristic of the 1st stage of MS (i.e., scores of 0–4.0). Fig. 1 illustrates the study sequence. Randomization will take place upon completion of the first study visit, and subjects will have an equal chance to draw each of the two possible study arms. Subjects will draw from a pool containing an equal number of “exercise” or “stretching” cards. This method of randomization was chosen in order to eliminate potential selection bias. The home-based exercise regimen includes cycle ergometry as an aerobic mode of training, and is performed three days per week with a gradual progression of duration and intensity across a 12-week period. The attention-control involves stretching using the same frequency and duration across a 12-week period. Participants in both conditions will further take part in weekly one-on-one behavioral coaching sessions via Skype. These sessions will be based on SCT and will focus on self-efficacy, goal setting, self-monitoring, and strategies and facilitators of behavioral change [20]. We will collect subclinical atherosclerosis and mobility disability data before, during (i.e., midpoint), and immediately after the 12-week intervention. We will use a 2 (condition) by 3 (time) mixedfactor, analysis of variance with intent-to-treat principles for testing the effect of the intervention on outcomes. Our central hypothesis is that a 12-week aerobic exercise training program will reduce both subclinical atherosclerosis and mobility disability. The primary outcomes for subclinical atherosclerosis will be carotid intima-media thickness (IMT), aortic pulse wave velocity (PWV), endothelial function, and arterial stiffness. The primary outcomes for mobility disability will be timed 25-foot walk (T25FW), 6-minute walk (6 MW), gait kinematics, and free-living accelerometry. Additional secondary outcomes include a fasting blood lipid profile and inflammatory biomarkers. We further hope to explore the possible association between changes in subclinical atherosclerosis and walking mobility following exercise training. We hypothesize that improvements in subclinical atherosclerosis will be associated with improvements in walking mobility. 2.2. Participants We plan to enroll a sample of 54 men and women with MS in the Chicago, IL area who have EDSS scores between 0–4.0. We selected this EDSS range to ensure that our participants are still capable of engaging in sufficient physical activity that is necessary for accruing physiological adaptations. Recruitment will occur through the MS Center at the University of Illinois Hospital and Health Sciences System and presentations at MS support groups. Additional recruitment strategies will be to advertise in local newspapers, television, and radio outlets as needed. We will further contact participants from our previous research who reside within the proximity. Participants will be asked to contact the Integrative Physiology Laboratory for further information about the study and screening for inclusion. Inclusion criteria are: being physically inactive (defined as less than 2 days of aerobic exercise per week), body mass index b 40 kg/m2, EDSS score of 0–4.0 and being independently ambulatory (walking without an assistive device, such as a cane or orthotic), relapse free in the past 30 days, confirmed

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3-Month Exercise or Stretching Program

Recruitment

Screening

Enrollment

• Support Groups • Physician • 54 subjects • UIC MS Center Clearance Form • Scheduled for Visit 1 • Advertisements • Neurologist Confirmation of Diagnosis

Visit 1

Visit 2

Visit 3

• Cardiovascular • Scheduled 6 • Scheduled 6 and Walking Weeks after Visit Weeks after Visit Mobility 1 2 Assessments • Same • Same • Physical Activity Assessments as Assessments as Assessment Visit 1 Visits 1 and 2 • Randomization

Fig. 1. Study sequence.

diagnosis of MS, no underlying clinically diagnosed cardiovascular disease, be on a stable MS modifying therapy (i.e., no change over the previous 6 months), and physician approval for undertaking exercise testing and training. Importantly, Internet access is not an inclusion criterion, as we will provide this to the participants as part of the intervention when necessary. We will only include persons with relapsing– remitting MS, as disability progression is influenced by clinical course before reaching an EDSS milestone of 4.0. We will include persons regardless of the Functional System Score that primarily drives the EDSS score, but will record this information for inclusion as an effect modifier and/or covariate in the data analyses. We will further include persons irrespective of MSmodifying medications and symptomatic agents (i.e., antispastic agents and potassium channel blockers), but we collect this information (i.e., drug, dosage, and timing) on each testing session for descriptive purposes, consideration in testing of the outcomes, and inclusion as a potential covariate in the statistical analyses.

free software program (G*Power 3.1.2 ,Düsseldorf, Germany) and assumptions of reliability for the within-subjects factor = .8, two-tailed α = .05, and β = .20 (i.e., 80% power). The power analysis indicated that the minimal total sample size for testing the time × condition interaction on carotid intima media thickness, aortic pulse wave velocity, and endothelial function should be nearly 30 participants. The cumulative effect size pooled across studies of aerobic exercise training and T25FW and 6 MW performance for persons with MS was d = 0.75 based on a re-analysis of data in a published metaanalysis [10]. This additional power analysis indicated that the minimal total sample size for testing the time × condition interaction on walking mobility should be 46 participants. Overall, the proposed sample size of 54 subjects should yield appropriate statistical power for testing the aims of the project, given there is a likelihood of some attrition caused by illness, injury, disease activity, other patient factors, and relocation. We anticipate a 15% dropout rate based on a recent systematic review of patients with MS participating in exercise training programs [24].

2.3. Sample size 2.4. Measures We estimated the sample size for detecting a condition [2 levels of between-subjects factor: intervention vs. control] × time [3 levels of within-subjects factor: 0, 6, & 12 weeks] interaction on the primary outcomes of carotid intima media thickness, aortic pulse wave velocity, and endothelial function. To do this, we first generated an overall effect size that was based on an average of effect sizes from studies of aerobic exercise training and aortic pulse wave velocity and endothelial function for persons with chronic conditions other than MS [21–23]. This yielded an average effect size of d = 3.5 for the power analysis. We calculated this effect size from studies in populations other than MS, but that included similar exercise prescriptions as our planned study. This approach was undertaken because of a lack of data available for patients with MS. Importantly, the patients in those studies had similar profiles of general physical inactivity as those described for patients with MS before any interventions. We further note that cross sectional evidence in patients with MS supports this approach as valid, considering the association between physical activity and subclinical atherosclerosis appears to be similar in patients with MS as in these other patient populations [8]. The power analysis itself was conducted using an open source

2.4.1. Aortic blood pressure Radial artery pressure waveforms will be obtained in the supine position from a 10-second epoch using applanation tonometry and a high-fidelity strain gauge transducer (Millar Instruments, Houston, TX). Using a generalized validated transfer function [25,26], a central aortic pressure waveform will be reconstructed from the aforementioned radial artery pressure waveform (SphygmoCor, AtCor Medical, Sydney, Australia). Only high-quality recordings, defined as an indevice quality operator index N 80% will be included in the analysis [27]. This index is derived from a weighted algorithm that examines average pulse height (average height of the pulse waveforms measured), pulse height variation (amount of variation in the height of the pulse waveforms measured), and the diastolic variation (an index of baseline pressure consistency during the measurement attained from the variation in the diastolic inflection point of the pulse waveform) [27]. All measurements will be made in duplicate, and the mean value will be used for subsequent analysis. Reproducibility of measures attained from this technique has previously been shown to be high [28].

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2.4.2. Intima media thickness All IMT measurements will be made with a high definition ultrasound (Aloka, SSD 5500) using a high frequency (7– 13 MHz) linear probe. The IMT of the common carotid artery is defined as the distance between the leading edge of the lumenintima interface to the leading edge of the media-adventitia interface of the far wall of the carotid artery, following standard guidelines [29]. All measurements will be made at the end of diastole. The IMT will be measured using edge detection software, where a 5 mm segment of the artery will be identified, and IMT will be measured over the entire 5 mm segment providing average and peak IMT of the segment. All measurements will be conducted approximately 1 cm proximal to the carotid bifurcation. This technique is highly reproducible with a CV of b 3% in our laboratory. 2.4.3. Regional arterial stiffness — Pulse wave velocity All measurements will be conducted following the guidelines of the Clinical Application of Arterial Stiffness Task Force III [30]. A high-fidelity strain gauge transducer (Millar Instruments, Houston, TX) will be used to obtain the pressure waveform from: 1) the right common carotid artery to the right femoral artery, and 2) the right femoral artery and the ipsilateral superior dorsalis pedis artery. Distances from the carotid artery sampling site to the femoral artery, carotid artery to the suprasternal notch, and femoral artery to the superior dorsalis pedis artery will be measured as straight lines above the body with a tape measure. The distance from the carotid artery to the sterna notch will then be subtracted from the carotid–femoral segment length. PWV is determined from the foot-to-foot pressure wave velocity. The foot of the pressure wave will be identified using an algorithm that detects the initial upstroke via a line tangent to the initial systolic upstroke point of the pressure tracing and an intersecting horizontal line through the minimum point [31]. This algorithm has been shown to be highly reproducible [31]. The peak of an in-phase R wave, as attained from sequential ECG monitoring (CM5 configuration) will be used as a timing marker. The time delay between a minimum of 10 simultaneously recorded flow waves is averaged. PWV will be calculated from the distances between measurement points and the measured time delay (Δt) between proximal and distal foot waveforms as follows: PWV ¼ D=Δt

  −1 ms ;

where D is distance in meters and Δt is the time interval in seconds. Values attained from the carotid to femoral artery will be taken as an index of central stiffness while values from the femoral to superior dorsalis pedis artery are taken as an index of peripheral stiffness. Integral software assesses the quality of measure (SphygmoCor, AtCor Medical, Sydney, Australia) and only those PWV values with a standard deviation b 10% will be included in the subsequent analysis. All measurements will be made in duplicate, and the mean value used for sequent analysis. This technique has been shown to be highly reproducible [28]. 2.4.4. Carotid artery compliance and β-stiffness index Carotid artery diameter will be measured via ultrasonography (SSD-5500, Aloka, Tokyo, Japan). The cephalic portion of the

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carotid artery will be imaged in longitudinal section, 1–2 cm proximal to the bifurcation, using a high frequency (7.5– 13 MHz) linear array probe. Simultaneous blood pressure of the contralateral carotid artery will be determined using applanation tonometry. Image analysis and calculation of the arterial compliance (AC) will be carried out using an automated wall detection echo-tracking system: AC ¼ πðD1  D1 −D0 Þ=4ðP1 –P0 Þ; where D1 and D0 are the maximum and minimum diameters, respectively, and P1 and P0 are the highest and lowest blood pressures, respectively. In addition to arterial compliance, β-stiffness index (β) will be calculated as a means of adjusting for AC for changes in distending pressure. 2.4.5. Conduit artery function — Brachial artery reactivity Brachial artery vasodilatory function will be assessed noninvasively by measurement of brachial artery dilation using ultrasonography (SSD-5500, Aloka, Tokyo, Japan). The brachial artery will be imaged in longitudinal section, 5–10 cm proximal to placement of a blood pressure cuff that will be placed just below the antecubital fossa, using a high frequency (7.5– 13 MHz) linear array probe. Brachial artery diameter and flow velocity will be analyzed for 1 min at baseline. Endotheliumdependent, flow-mediated dilation (FMD) of the brachial artery will then be measured for 3 min following an ischemic stimulus (inflation of a blood pressure cuff around the forearm to 250 mm Hg for 5 min). On cuff deflation the resultant FMD will be calculated as diameter change from baseline, expressed as a percentage change in diameter. Analysis of FMD will be carried out using an automated edge-detection software system. Responses will be calculated as percentage change in brachial artery diameter from baseline. The computerized image analysis system with edge-detection software reduces observer error significantly over manual methods and allows the detection of changes in endothelial function with substantially fewer subjects. This method conforms to the guidelines set out for the ultrasound measurement of endotheliumdependent FMD of the brachial artery. Images will be saved off-line and anatomical landmarks will be used as reference points to ensure that subsequent measurements are made in identical regions of the artery. 2.4.6. Microvascular function — Forearm resistance artery vasodilatory capacity Vasodilatory capacity of forearm resistance arteries will be assessed, as previously described by our group [32,33], using reactive hyperemia and strain-gauge plethysmography (EC-6, DE Hokonson, Inc., Bellevue, Washington). With the subject in the supine position, a mercury-in-silastic strain gauge will be placed around the forearm. A rapidly inflating venous occlusion cuff will be placed around the upper arm. A second blood pressure cuff will be placed over the venous occlusion cuff on the upper arm and inflated to a pressure of 250 mm Hg for 5 min. Thirty seconds prior to release of the upper arm cuff, the wrist cuff will be inflated to a pressure of 250 mm Hg, occluding circulation in the hand. After 5 min of occlusion, the BP cuff in the upper arm will be released. This will be followed immediately by rapid inflation of the venous occlusion cuff to 50 mm Hg for 7 s followed by 8 s of deflation. With these

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15 second cycles occurring over the following 3 minute period, changes in forearm volume will be assessed as an index of vasodilatory capacity. 2.4.7. Inflammatory biomarkers and fasting blood chemistries Forty milliliters of blood will be drawn from the antecubital fossa into vacutainer serum EDTA tubes after a 10–12 hour overnight fast. Samples will be centrifuged at 4 °C at 2500 rpm for 20 min and the serum will be removed and stored at −80 °C for subsequent analysis. A solid phase high sensitive enzymelinked immunosorbent (ELISA) assay will be used to determine levels of C-reactive protein (Diagnostic Automation Inc., Calabasas, CA). Interleukin 6 will be assessed using a commercially available high-sensitivity sandwich ELISA (Amersham Biosciences GE Healthcare, UK; Molecular Innovation Inc., Southfield, MI; SPI Bio, France; BioSource International, Inc., Camarillo, CA). TNF-α levels will be measured by enzymelinked immunosorbent assay kits (R&D Systems Inc., Minneapolis, MN). Serum lipoprotein profile (total cholesterol, triglycerides, LDL, and HDL) and plasma glucose will be assessed using the Cholestech LDX (Hayward, CA). The National Cholesterol Education Program Adult Treatment Panel III update will be used to classify our participants for descriptive purposes and to account for potential covariates. 2.4.8. Mobility disability The study will include performance-based measures of mobility disability. The timing of all assessments will be standardized, such that testing will commence 2 h after reported administration of medications that might influence mobility disability (e.g., antispastic agents or potassium channel blockers). The T25FW [34,35] and 6 MW [34,36] represent standard performance-based measures of mobility and will be the primary outcomes of interest for this clinical trial. We will measure gait kinematics and free living mobility and physical activity using ProtoKinetics (Havertown, PA) technology and ActiGraph accelerometry (Pensacola, FL), respectively [37]. 2.4.9. Aerobic capacity Aerobic capacity will be measured as peak oxygen consumption (VO2peak) using an incremental exercise test on an electronically-braked, computer-controlled cycle ergometer (Lode BF, Groningen, The Netherlands) and an open-circuit spirometry system (TrueOne, Parvo Medics, Sandy, UT) for analyzing expired gases. The participants will perform a 1 minute warm-up at 0 W. The initial work rate for the exercise test will be 0 W, and the work rate continuously increases at a rate of 15 W·min−1 until the participant reaches volitional fatigue or cannot maintain 60 rpm. VO2peak will be expressed in ml·kg−1·min−1 based on the highest recorded 15 second VO2 value when two of three criteria are satisfied: (1) respiratory exchange ratio ≥ 1.10; (2) peak heart rate within 10 beats·min−1 of age-predicted maximum; or (3) peak rating of perceived exertion ≥ 17. 2.4.10. Dietary control To control the influence of diet on our cardiovascular measures, we will ask subjects to complete a 3-day dietary recall on their first visit to the laboratory. Participants will then

be asked (and reminded) to follow the same diet 3 days prior to each subsequent visit. The 3-day recall will be completed during each testing period to validate compliance. Macronutrient and micronutrient analyses will be conducted using Diet Analysis Plus software (Independence, KY). Additionally, all arterial testing will occur 4 hours postprandially to further minimize any effects of the last meal. 2.5. Intervention condition The home-based exercise stimulus will incorporate cycle ergometry as an aerobic mode of training and will be delivered over a 12-week period. The regimen itself was developed based on the guidelines for exercise prescription for older adults provided by the American College of Sports Medicine [38]. We selected the use of cycle ergometry as the exercise mode because our goal is to evaluate the effect of aerobic exercise training on walking ability through the mediating effects of subclinical atherosclerosis, without involving an exercise mode that includes walking as a training mode. The regimen has been standardized and manualized for reproducibility and in-home delivery. The regimen will be delivered 3 days per week and the structured exercise portion of the sessions initially last for 10 min and progressively increase up to 30 min in duration, based on the patient response and following ACSM criteria for progression. The sessions will begin and end with 5 min of warm-up and cool-down, which consist of pedaling at 0 W. The aerobic training focuses on large, dynamic movements of the lower extremities using leg cycling ergometry on an Expresso S3u Novo cycle and progresses in duration (10–30 min) and intensity (40–60% VO2peak) over the 12-week intervention period. All subjects start at 10 min of exercise at 40% of VO2peak as determined by the exercise test, for the first week, in order to individualize the exercise prescription. Progression initially targets duration by weekly progression of 5 min until 30 min of exercise has been achieved, followed by progression of intensity by 5% per week until 60% is attained, based on patient tolerance of the increased workload. We further ask that participants not undertake additional exercise (i.e., not join a gym and begin exercising) over the duration of the study and this will be documented through an exercise history [39] and free-living accelerometry. 2.6. Attention control condition The alternative treatment condition involves a stretching program as our minimal exercise, attention control. This program will be delivered using the same frequency and duration as the intervention. The first session will be conducted under supervision of visiting study personnel as described above. The stretching exercises will be based on a manual provided by the National Multiple Sclerosis Society (National Multiple Sclerosis Society, New York: NMSS 2004). More exercises and sets will be progressively included over the course of the 3-month period and this too has been standardized and manualized for reproducibility. We provide the same materials and Internet coaching for the attention control as for the intervention group, but focus on stretching and not on increasing aerobic exercise. We ask that participants not undertake additional exercise (i.e., not join a gym and begin exercising) over the duration of the study and this will be

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documented through an exercise history and free-living accelerometry. 2.7. Procedure 2.7.1. Approach for monitoring compliance Technological advances and the Internet have afforded opportunities for monitoring and maximizing compliance with a home-based exercise program in persons with MS. Expresso S3u Novo cycles provide a novel experience that is engaging and motivating by providing realistic rides and in-ride games over 30 virtual courses, virtual riders and customized pacers, and Internet workout features that allow for virtual exercise with partners, and Internet portal for uploading performance data and monitoring compliance and progression over time. We are unaware of research that has incorporated this methodology into an RCT of exercise training in general or MS, but this allows for a high degree of compliance monitoring, including parameters of duration, intensity, and frequency of exercise. 2.7.2. Maximizing compliance Two members of the study team will visit each subject to set up the cycle ergometer and the computer. The subject will then be instructed on the use of the devices and taught the exercise protocol. The first exercise session will be completed under the direction of study personnel. Subjects will be further provided with a toll-free phone number to call study personnel for assistance if needed. Strategies based on SCT and our previous research for maximizing compliance with the intervention will be incorporated. This includes the provision of materials focusing on self-efficacy, outcome expectations, impediments, and goal-setting. Such materials will be delivered through weekly Internet video chats through Skype with participants by a trained, experienced exercise-behavior change coach. The content of the video chats will be semi-structured, such that it delivers essential materials, but allows for modification based on the specific participant needs and experiences. This approach has been developed based on recent research [39]. The “coaching” takes 5–10 min and involves reviewing weekly goals and progress with participants, dialogue on current weekly content and a discussion of training parameters and experiences. We further inquire about adverse and serious adverse events during each chat and such events will be immediately discussed among the team for corrective action. 2.8. Statistical analyses The data analysis will be performed using PASW Statistics 18.0 (Chicago, IL). The data will initially be examined for normality violations, outliers, errors, and pattern of missing values; missing data will be replaced using multiple imputation techniques in SPSS. The data analysis itself will follow intentto-treat principles. The effect of the aerobic exercise training intervention on arterial structure and function variables as well as mobility disability outcomes will be examined using condition by time mixed-factor multivariate analysis of variance (MANOVA), followed by inspection of univariate F-ratios per outcome variable. Condition will be a between subjects factor and time will be a within-subjects factor. Interactions and main effects will be further decomposed using post-hoc analyses with

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a correction of alpha. Effect sizes associated with univariate F-statistics will be expressed as eta-squared (η2). Effect sizes based on a difference in mean scores will be expressed as Cohen's d. Bivariate correlation analysis will be used for examining the relationship between changes in arterial structure and functional variables and change in walking mobility outcomes.

3. Discussion This RCT will explore the effects of a 12-week home-based exercise training intervention versus a minimal exercise, attention-control on markers of subclinical atherosclerosis and mobility disability in persons with MS. The intervention and expected outcomes of this RCT represent a novel approach for managing subclinical atherosclerosis and mobility disability among persons in the 1st stage of MS (i.e., EDSS scores 0–4.0). The progression of mobility disability is a two-staged process, and when a person enters the second stage of MS (defined as an EDSS score of N 4), the disability progression is considered irreversible (Confavreux, Brain 2003). To that end, treatment and rehabilitation in MS largely focuses on stopping or slowing the eventual progression of mobility disability by targeting those within the 1st stage of MS (EDSS score b 4.0). Comorbidities are common in MS and the presence of comorbidities, especially vascular comorbidities, is associated with diagnostic delays and increased levels of mobility disability upon diagnosis [40]. Vascular comorbidities are further associated with more rapid progression of mobility disability over time in MS [40]. This is disconcerting given that patients with MS have similar or increased risk of CVD mortality compared to the general population [4,41,42], especially in the first year after diagnosis [43]. Physical fitness and physical activity are associated with neurological disability in MS [44] and supervised exercise training improves walking mobility [10], but it is unknown if home-based aerobic exercise training affects vascular structure and function and has not been shown to alter mobility disability. Our contribution from this study is expected to be a detailed understanding of how a home-based, aerobic exercise training program independently affects vascular structure and function and mobility disability in MS. The completion of this study will contribute fundamental missing information regarding the effect of home-based exercise training on subclinical atherosclerosis and mobility disability in persons with MS, and the cycling exercise intervention may elucidate potential independent effects of aerobic exercise conditioning on walking mobility. This will contribute to the development and application of exercise therapeutic approaches to reduce the disease burden and impact mortality and morbidity in persons with MS. This contribution is significant because it is an important step in the process of understanding how therapeutic interventions such as exercise training and physical activity will affect vascular structure and function and how such interventions impact mobility disability. Furthermore, this project will provide information on how home-based exercise training can be used to prevent or improve CVD risk and worsening of mobility disability in MS, potentially providing a significant increase in the number of individuals with MS who could be targeted for intervention.

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