Remotely-delivered exercise training program for improving physical and cognitive functions among older adults with multiple sclerosis: Protocol for an NIH stage-I randomized controlled trial

Abstract

Background:

Older adults with multiple sclerosis (MS) present with low physical activity participation, cognitive and ambulatory dysfunctions, and compromised quality of life (QOL).

Objective:

We propose a NIH Stage-I, randomized controlled trial (RCT) that examines the feasibility and efficacy of a 16-week theory-based, remotely-delivered, exercise training program for improving cognitive and physical functions in older adults with MS who have moderate mobility disability without severe cognitive impairment.

Methods:

This Stage-I study utilizes a parallel-group RCT design. Participants (N = 50; age ≥ 50 years) will be randomly assigned into exercise training (combined aerobic and resistance exercise) or active control (flexibility and stretching) conditions. The conditions will be undertaken within a participant’s home/community over a 16-week period, and monitored remotely and supported by Zoom-based chats guided by social cognitive theory (SCT) via a behavioral coach. Participants will receive training manuals and equipment, one-on-one behavioral coaching, action-planning calendars, self-monitoring logs, and SCT-based newsletters. The primary outcomes include feasibility (e.g., recruitment and retention rates), exercise behavior and physical activity; other outcomes include physical function (lower-extremity function, mobility, walking), cognition (processing speed, learning and memory, executive function), MS symptoms, QOL, and vascular function. We will collect outcome data at baseline (Week 0), post-intervention (Week 16), and follow-up (Week-32). Data analysis will follow intent-to-treat principles using linear mixed-effects models.

Discussion:

This Stage-I trial adopts an innovative approach for exercise training via telerehabilitation and is convenient and accessible for older adults with MS. If successful, the study will provide foundations for future research using remotely-delivered exercise intervention for managing the consequences of aging with MS.

Trial Registration Number: NCT05930821

1. Introduction

Multiple sclerosis (MS) is an immune-mediated and neurodegenerative disease of the central nervous system with onset mostly occurring in early adulthood (between 20 and 50 years of age) [1,2]. The development and early initiation of disease-modifying therapies have increased the life expectancy of persons with MS over the past decades, thereby expanding the prevalence of the disease in older adulthood [3,4]. Recent epidemiological data indicate that individuals aged 55 years or older account for nearly half of the estimated one million cases of MS in the United States [5]. The effect of aging occurs in conjunction with MS disease progression and results in a faster rate of disability accumulation over time [6]. Older adults with MS often present with advanced cognitive decline (e.g., slowed processing speed, impaired learning and memory) and poor physical functioning (e.g., decreased walking speed and endurance) [7–9]. These dysfunctions are further associated with compromised quality of life, loss of independence for activities of daily living, and reduced physical activity (PA) participation [4]. The common approach for managing MS involves disease-modifying drugs, yet this first-line approach for medical management has little efficacy in older MS age groups [10,11] and there is little known about rehabilitation in older adults with MS [6].

PA and exercise training have been increasingly recognized as promising rehabilitation approaches for restoring function in MS and aging populations [12]. Interventions involving exercise training as a form of PA in young and middle-aged adults with MS have yielded favorable effects on reducing fatigue and improving quality of life, cognitive function, and physical fitness [12]. Older adults with MS who engaged in higher levels of PA demonstrated better cardiorespiratory fitness [13], cognitive performance [14], and walking mobility [9] based on cross-sectional evidence. Despite the potential benefits, older adults with MS engage in less PA compared with younger MS patients and age-matched cohorts from the general population [15]. An earlier study showed that older adults with MS spent approximately 12.6 min/day in moderate-to-vigorous PA (MVPA) and only 14% of them met the public health guidelines (i.e., ≥30 min/day of MVPA) [15]. Such inactivity may be attributed to disease-related disability as well as environmental and social barriers (e.g., poor access to recreational facilities, training costs, and travel demands) [12], and likely increases the burden of disease in this aging segment of MS. This collectively supports the importance of establishing feasible and efficacious interventions that overcome barriers, increase PA participation, and restore function for successful aging with MS.

Home-based exercise training may be a valuable approach for successful aging with MS. Compared with traditional interventions delivered in highly supervised, controlled settings (e.g., clinics or laboratories), home-based exercise programs can be accomplished within an individual’s home or community and might offer better generalizability but could result in lower adherence due to lack of supervision. Previous systematic reviews suggest that home-based PA interventions seem to present high adherence rates among individuals with dementia or other chronic conditions [16,17], but evidence remains limited in MS [18]. Several recently proposed randomized controlled trials (RCTs) have focused on evaluating the efficacy of home-based exercise training programs in persons living with MS [19–21]. For example, Project GEMS (Guidelines for Exercise in MS) [22] involved a 4-month home-based exercise training program supported by telerehabilitation emphasizing aerobic and resistance training consistent with guidelines for MS [23]. The program was safe and had initial feasibility with a compliance rate (71%) for exercise training, moderate increase in self-reported PA (d = 0.57), and strong satisfaction (mean scores >4 out of 5) [22]. However, the existing research on home-based exercise training does not focus on older MS age groups, and these intervention programs have rarely been designed and tested in those with cognitive and mobility dysfunction [20] that are highly prevalent in this population [24,25].

The current study involves an NIH Stage-I trial [26] that examines the feasibility and initial efficacy of a 16-week home-based, combined exercise (aerobic and resistance) training intervention in older adults (≥50 years) with MS who have moderate mobility disability without severe cognitive impairment. Feasibility will be evaluated based on process (e.g., recruitment and retention rates), resource, management, and scientific outcomes (e.g., safety outcomes) following established criteria in previous intervention programs for MS [21,27]. In particular, we hypothesize that the intervention will be feasible to (a) achieve our recruitment goals (n = 50; 25 per condition) within a two-year period, (b) retain at least 80% of participants through the 16-week study period, and (c) safe with fewer than 10% of participants reporting adverse events. We will determine the preliminary efficacy of the intervention on exercise behavior, free-living PA, physical function, cognition, MS symptoms, quality of life (QOL), and vascular function compared with a social contact, attention control condition; this aspect will inform outcome selection for a Stage-II trial examining efficacy of the approach. We hypothesize improvements in these outcomes immediately after the 16-week exercise training program compared with the control condition, and such changes will be sustained during a 16-week follow-up period.

2. Methods

2.1. Study design and procedures

The proposed NIH Stage-I trial will utilize a parallel group, assessor-blinded, RCT design. NIH Stage-I trials are appropriate when testing a modification, adaptation, or refinement of an existing intervention and examining its feasibility and initial efficacy in a new population [26]. Participants (N = 50) will be randomly assigned (1:1) into the exercise training condition (GEMS program) or the active control condition (flexibility and stretching, or FLEX-MS program) using computerized random numbers with allocation concealment and matching on age (≤5 years) and sex. The standardized approaches for the GEMS and FLEX-MS programs will be delivered through the UIC Exercise Neuroscience Research Laboratory (ENRL) over a 16-week period via Zoom-based chats by a trained behavioral coach who is uninvolved in random assignment and outcome assessment. There will be a 16-week follow-up period with no interaction with the behavioral coach for determining sustainability of the behavioral intervention. Participants will receive remuneration for completing the intervention program and all data assessments. Outcome data will be collected by treatment-blinded assessors using a series of non-invasive laboratory assessments on three occasions (Week 0-Baseline, Week 16-Immediate post-intervention, & Week 32-Follow-up). The study protocol has been approved by the UIC Institutional Review Boards (STUDY2022–1282), and the trial was successfully registered on ClinicalTrials.gov (NCT05930821). All participants will provide written informed consent.

2.2. Recruitment and enrollment

We will recruit 50 participants with MS residing in the greater Chicago-land and surrounding areas through flyers, e-mail distributions, advertisements, medical centers and neurology clinics, local community and support groups, and social media. To ensure a diverse participant sample, we will further establish relationships with MS support groups predominately representing specific racial/ethnic communities (e.g., African-Americans, Hispanics/Latinos). In addition, we will collaborate with the National MS Society (NMSS) and leverage their local and regional registries for widespread dissemination of the study information. Individuals interested in participating will be contacted by the research team, who will explain study procedures, address any questions, and conduct a screening for eligibility criteria. Eligible individuals will be scheduled for an in-person visit to the UIC research laboratory for completing informed consent process and baseline assessment. Participant recruitment and enrollment, including barriers, refusal rates and reasons, will be documented to provide information for optimal recruitment and improve generalizability of future Stage-II trials.

Participants will be randomly assigned into either exercise (GEMS) or control (FLEX-MS) conditions, and will receive intervention materials via certified postal mail and schedule the first one-on-one session with the assigned behavioral coach. Participants will be enrolled in 5 waves of 10–12 participants per wave across 2 years; each wave involves the 16-week period of the condition with a 16-week follow-up period. Participant recruitment for the first wave will begin in August 2023, with the interventions starting in September 2023. Subsequent waves will be recruited on an ongoing basis, with the final wave of enrollment completing by July 2024. The timeline of adjacent waves may overlap to ensure manageable sizes for each wave and effectively conduct study protocols to meet recruitment targets on time.

2.3. Participant eligibility

Participants will be considered eligible if they meet all of the following inclusion criteria: a) age ≥ 50 years [28], b) diagnosis of MS, c) relapse-free for the past 30 days, d) speak and read English as primary language, e) internet and e-mail access, ability to travel to the laboratory (for testing only), and willingness to complete the assessments, f) ambulatory with or without a single-point assistive device (e.g., cane, but not walker), g) asymptomatic (i.e., one or fewer affirmatives on the Physical Activity Readiness Questionnaire) or physician approval for undertaking exercise training [29], h) moderate level of mobility disability (scores of 2–4 on the Patient-Determined Disease Steps [PDDS] and 25–50 on the Multiple Sclerosis Walking Scale-12) [30,31], and i) without severe cognitive impairment (scores ≥18 on the Modified Telephone Interview for Cognitive Status [TICS-M]) [32,33]. The application of TICS-M for making eligibility decisions is critical for ensuring that participants do not have severe cognitive impairment that might preclude the ability to adhere to the conditions (e.g., able to successfully navigate and understand study materials, interact with behavior coach). Individuals who need bilateral assistive devices to walk, or who are diagnosed with other neurological conditions (e.g., dementia) or cardiovascular diseases (e.g., ischemic heart disease) will be excluded from participation.

2.4. Sample size and power

There is a lack of preliminary data on the effect of exercise training intervention in older adults with MS that were available for an a priori power analysis for the current study. We based the sample size on sample size guidelines for pilot RCTs [34,35] and feasibility research in MS [36]. The guidelines recommended a sample size of 24 (12 per condition) as sufficient for pilot studies based on rationale about feasibility, precision about the mean and variance, and regulatory considerations [34,35]. We further note that researchers have suggested a sample size of 40 (20 per condition) for a pilot study will have 80% power for the subsequent Stage-II studies seeking an effect size of 0.2 using an independent samples t-test with a 5% two-sided significance level [35]. Thus, our goal is to recruit 50 participants (25 per condition) for this Stage-I RCT, and we believe this will provide adequate experience and power for informing a future Stage-II RCT.

2.5. Outcomes

The primary outcomes include feasibility metrics and measures of the effect of the intervention on self-reported exercise behavior and accelerometer-measured PA. Feasibility will be evaluated based on process, resource, management, and scientific outcomes following the metrics in a feasibility study of Project GEMS [21]; detailed descriptions of feasibility metrics, proposed methodology, and importance to future research in MS are presented in Table 1. Self-reported exercise behavior will be assessed using the Godin Leisure-Time Exercise Questionnaire (GLTEQ) [37]. Free-living PA will be measured using ActiGraph model GT3X+ accelerometers (ActiGraph Corporation, Pensacola, FL, USA).

Table 1.

Feasibility metrics, proposed methodology, and importance to future research in multiple sclerosis [21].

Metric	What will be monitored and assessed?	How this will be monitored and assessed?	Importance to future Stage-II/III studies
Process: assesses participant recruitment and retention.	a. Recruitment and refusal rates b. Retention, attrition and adherence rates	a. We will use USPS, phone and electronic mail recruitment and record all contact with potential participants and refusal reasons (through an online refusal feedback form, email and over the phone). b. We will record all participants' flow through the recruitment, enrollment and intervention sections of the study. We will record adherence with the intervention via logbooks and video chats, and time spent in physical activity as measured during followup assessment.	a. To provide information on optimal recruitment method expected recruitment, and refusal reasons. b. To provide target areas for optimizing participant retention and intervention adherence.
Resources: assesses communication and monetary requirements of the study.	c. Communication with participants. d. Communication needs of participants and staff. e. Monetary costs of research	c. We will utilize a password protected database to monitor contact with all potential and enrolled participants. d. We will establish and record all problems and communication alterations. e. We will establish and record all monetary costs for the study; for both the intervention and waitlist control participants.	c. To establish communication frequency, quality and highlight communication problems. d. To establish communication needs and anticipated communication problems. e. To establish monetary cost to conduct the research and establish areas for cost saving.
Management: assesses data management and safety reporting during the study	f. IRB approval procedures. g. Staff preparation and report time for participant communication. h. Time and accuracy in data collection/entry. i. Reporting and handling of adverse events (AE), serious adverse events (SAE) and clinical emergencies	f. We will document communications between University IRB and staff, and time from submission of IRB application to approval. g. We will document all preparation, call time, attempted call time and report-taking time for each participant during the intervention. h. We will check for data completeness, and record time to collect, enter and check data. i. We will record our use and handling of standard university protocol for reporting of all AEs, SAEs and clinical emergencies.	f. To detail staff time requirements. g. To detail staff time requirements and highlight considerations for alterations. h. To detail what safety procedures should be implemented.
Scientific: assesses the safety, burden and treatment effect of the study.	j. AEs, SAEs and clinical emergencies. k. Participants' experience, burden, and compliance during the intervention. l. Treatment effect.	j. We will follow standard university protocol to record all AEs, SAEs and clinical emergencies, and ask participants to report and record all medical concerns via logbooks and video chats. k. We will record participant feedback on the intervention during the video chats, a feedback interview and a feedback survey. We will use participant self-reporting of exercise time and exertion during each exercise session, reported via logbooks and video chats. l. We will determine effect size and clinical meaningfulness of any change in health-related outcomes proposed in the study.	i. To determine the safety and feasibility of the intervention and highlight considerations for alterations. j. To determine acceptability and highlight considerations for alterations. Determining compliance will further allow correct conclusions to be drawn from the results. k. To determine data for power calculations and anticipated clinical impact.

The secondary outcomes involve the effects of the exercise training programs on physical and cognitive functions. Physical function will be assessed using a set of objective measures, including the Short Physical Performance Battery, 30-Second Sit to Stand, Timed up and Go, Timed 25-ft Walking Test, and Six-Minute Walk [24,38–44]. Cognitive function will be measured using the Brief International Cognitive Assessment for MS (BICAMS) and the NIH Toolbox Cognition Battery to facilitate cross-comparisons with other clinical research or populations.

The tertiary outcomes include MS symptoms, QOL, and vascular function (as a possible mechanism of changes in cognitive and mobility outcomes [25]). MS symptoms of fatigue, depression, anxiety, pain, and sleep quality will be measured by the Fatigue Severity Scale, Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale, short-form McGill Pain Questionnaire, and Pittsburgh Sleep Quality Index, respectively [45–49]. We will measure QOL using the Multiple Sclerosis Impact Scale and 36-Item Short Form Health Survey [50,51]. Vascular function will be non-invasively measured using the SphygmoCor^® XCEL System (AtCor Medical, Sydney, Australia) [52] for obtaining central blood pressure and arterial stiffness biomarkers. Details of study outcomes are provided in Table 2.

Table 2.

Summary of study outcomes.

Study Outcomes	Assessment	Procedures
Exercise behavior	Godin Leisure-Time Exercise Questionnaire (GLTEQ)	Participants report the frequency of engagement in mild, moderate, or strenuous PA for 15+ minutes during the previous week. The frequencies of mild, moderate, and strenuous bouts will be multiplied by 3, 5, and 9 METs, respectively; the resulting products are summed into a measure of overall PA, ranging from 0 to 119 [63].
Physical activity	ActiGraph model GT3X+ accelerometer	The accelerometer will be placed on an elastic belt worn around the waist over the nondominant hip during the waking hours of a 7-day period. A wear log and instruction sheet will be provided for participants to track their wear time and daily activities (e.g., bed and wake time). The accelerometer will be returned through the United States Postal Service using a prestamped, pre-addressed envelope. Data will be downloaded into one-minute epochs using ActiLife software and PA outcomes will be generated and averaged across all valid days (i.e., wear time ≥ 600 min/day) for each participant [64]. Data will be downloaded into one-minute epochs using ActiLife software and PA outcomes will be generated and averaged across all valid days (i.e., wear time ≥ 600 min/day) [64] for each participant, including time (min/day) spent in intensity levels (light intensity PA, MVPA, and sedentary behavior) and daily step count (steps/day).
Cognitive function	• Brief International Cognitive Assessment for MS (BICAMS); • NIH Toolbox Cognition Battery	• The BICAMS is a standard battery for cognitive evaluation in people with MS [65], and it includes the Symbol Digits Modalities Test, California Verbal Learning Test, and the Brief Visuospatial Memory Test-Revised as measures of cognitive processing speed, verbal learning and memory, and visuospatial learning and memory, respectively [65,66]. The primary outcomes are the raw score and age-, sex-, and education-adjusted z-score per assessment using regression-based norms [62]. • The NIH Toolbox is a validated measurement tool for assessing neurological and behavioral function [67]. We will includes the Pattern Comparison Processing Speed Test, List Sorting Working Memory Test, Flanker Inhibitory Control and Attention Test, Dimensional Change Card Sort Test as measures of processing speed, working memory, attention and executive function [68]; raw score, computed score, and age-corrected standard scores will be calculated and exported from the software. • All cognitive measures will be administered by trained personnel within the research team and in accordance with the administrator's manuals. Alternative versions of the cognitive tests will be used, when available, during the three assessment occasions (Weeks 0, 16, and 32) to mitigate potential learning effects.
Physical function	• Overall physical function via Short Physical Performance Battery (SPPB); • Lower-extremity function via 30-Second Sit to Stand (30STS); • Functional mobility via Timed up and Go (TUG); • Walking speed via Timed 25-ft Walking Test (T25FW); • Walking endurance via Six-Minute Walk (6 MW)	• The SPPB is an objective measure of physical function and has been validated in persons with MS [38]. This battery uses a 3-part assessment, including standing balance, gait speed, and lower-extremity strength [39,40]; performance scores for each assessment range from 0 (inability to complete assessment) to 4 (high level of performance), and then will be summed for a total score ranging from 0 to 12; higher scores indicates better physical function. • During the 30STS test, participants will be instructed to sit on a standard height (17-in.) chair, and perform sit-to-stand transitions with arms crossed over their chest as quickly and safely as they felt comfortable within 30 s. The number of complete repetitions performed in will be recorded [69,70]. • The TUG and T25FW tests will be used to measure functional mobility and walking speed, respectively [41,42]. For TUG, participants will perform the test as safely and quickly as possible by standing up from an armless chair without the use of hands, walking toward and around a cone located 3 m in front of the chair, walking back to the chair, and then sitting back down. For T25FW, participants will be instructed to walk as quickly and safely as possible across a 25-ft distance from a static start position. The average time of two trials will be recorded in seconds for both tests; a shorter duration for the TUG or faster speed for the T25FW represents better performance. • The 6 MW represents an objective measure of walking endurance [43,44]. Participants will walk as fast and as far as possible within the limits of safety and stability in a large, open space free of obstacles for 6 min. The total distance walked over the 6-min period will be recorded by assessors using a distance-measuring wheel; a longer distance indicates better walking endurance. All physical performance tests will be administered following standard instructions, and participants will be allowed to take rests as necessary.
MS symptoms	• Fatigue via Fatigue Severity Scale (FSS); • Depression via Modified Fatigue Impact Scale (MFIS); • Anxiety via Hospital Anxiety and Depression Scale (HADS); • Pain via Short-form McGill Pain Questionnaire (SF-MPQ); • Sleep quality via Pittsburgh Sleep Quality Index (PSQI)	• The FSS is a 9-item unidimensional measure of fatigue and its disabling consequences over the past week in medical populations including MS [45]. • The MFIS is a 21-item measure of physical, cognitive, and psychosocial impact of fatigue on daily life over the past four weeks [46]. • The HADS contains 14 items that measure the frequency of anxiety and depressive symptoms over the past week [47]. • The SF-MPQ has a 15-item adjective checklist that captures sensory and affective dimensions of pain experienced over the past week [48]. • The PSQI is a 19-item, self-rated questionnaire that yields a global score of sleep quality over the past month [49].
Quality of life	• Multiple Sclerosis Impact Scale (MSIS-29); • The 36-Item Short Form Health Survey (SF-36)	• The MSIS-29 a self-reported measure of physical and mental domains of QOL over the past 4 weeks for persons with MS [50]. • The SF-36 will be used to assess health-related quality of life including domains of physical functioning, role limitations due to physical problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health [51].
Vascular function	Central blood pressure and arterial stiffness indices via SphygmoCor® XCEL System (AtCor Medical, Sydney, Australia)	Participants will lie down in a supine position and rest for 5 min before the measurement, and then will be instrumented with a brachial cuff on the upper arm and initiate pulse wave analysis to obtain central blood pressure (systolic and diastolic blood pressure, mean arterial pressure, and pulse pressure) and aortic augmentation index. With participants still in the supine position, carotid to femoral pulse wave velocity will be measured using a carotid tonometer simultaneously with a leg cuff to capture pressure waveforms at the carotid and femoral sites. Each measurement will be performed three times separated by 1-min intervals, and the average value will be recorded as the final result.

2.6. Intervention condition – GEMS program

The GEMS program will be delivered through the UIC ENRL and undertaken within a participant’s home/community. The GEMS intervention consists of an aerobic and resistance exercise prescription, appropriate exercise equipment (training manuals with instruction videos, pedometer, and resistance bands), one-on-one coaching, action-planning via calendars, logbooks for self-monitoring, and social cognitive theory (SCT)-based newsletters [21,22].

The GEMS exercise prescription is based on current PA guidelines for adults with MS who have mild-to-moderate disability [23]. Participants will perform exercise training for 3 times per week; each session includes (a) aerobic exercise – 30+ minutes of moderate-intensity walking (≥100 steps/min) [53] monitored by a waist-worn pedometer, and (b) resistance training – 1–2 sets, 10–15 repetitions of 5–10 exercises targeting lower (chair squat, calf raise, glute bridge, leg extension, hamstring curl, and glute kickback) and upper body (back row, bicep curl, shoulder raise, triceps extension, overhead press, chest press, lateral raise, and reverse fly), and core muscle groups (abdominal crunch, standing ab twist, and modified plank) using resistance bands. The majority of resistance exercises can be performed with more challenges (e.g., higher level resistance bands), or modifications (e.g., completing while seated, or holding on to a sturdy chair or wall for balance) to ensure safety. Aerobic and resistance exercises can occur on the same day of the week, but an individual should have one day of rest between these combined training days for appropriate recovery. The progression of the 16-week exercise will follow three different trajectories for individualization; participants start with the same amount or intensity for the first 2 weeks (accommodation period), and then select a trajectory for the remaining 14 weeks whereby the exercise guidelines will be achieved by 6, 8, or 10 weeks. The selection of appropriate progression trajectory is based on personal training experience and guided by the behavioral coach. Detailed progression plans are provided in the supplementary material.

The GEMS program involves one-on-one semi-structured sessions with an MS exercise specialist (behavioral coach) that focus on guidance and oversight of exercise training, discussion of behavioral strategies for action planning and self-monitoring, and demonstration of newsletters based on SCT for optimizing exercise compliance [21,22,54]. There will be 8 coaching sessions throughout the 16 weeks conducted via Zoom (a HIPAA-compliant teleconferencing system) or replaced with phone calls if no access to the Internet. The content of the behavioral change sessions is provided in the supplementary material.

Action planning and self-monitoring are important to ensure the long-term success of the intervention program in maximizing behavioral change and compliance. This involves providing participants with calendars that serve as schedules or plans for exercise training sessions or other life events. Self-monitoring is achieved by using exercise logbooks for tracking the completion of exercise sessions throughout the 16-week intervention. This allows to record the completion status (steps, repetitions, sets of exercises), missed sessions with reasons, training experiences, and rating of perceived exertion. Throughout the program, participants will receive newsletters aligned with coaching sessions. Each newsletter covers a topic based on SCT, involving outcome expectations, self-monitoring, goal-setting, self-efficacy, barriers, and facilitators, and contain corresponding instructional materials, websites for additional information, personal testimonials of success with exercise behavior change, and practical recommendations.

2.7. Active control condition – FLEX-MS program

The FLEX-MS program is identical with GEMS but focusing on stretching as the mode of training for improving flexibility and range of motion in MS. The FLEX-MS program represents an active control based on Stretching for People with MS: An Illustrated Manual from the NMSS. Participants will be provided with flexibility exercise prescription, appropriate exercise equipment (training manuals and a yoga mat), one-on-one coaching, action-planning via calendars, logbooks for self-monitoring, and SCT-based newsletters. The training will involve the same frequency, duration, timeline, behavior change content, and interactions with behavioral coach as the GEMS program, and account for activity, social-contact, and attention [19]. This represents a major advancement over waitlist control and standard of care conditions in RCTs of exercise training in MS.

2.8. Safety protocols

The current study places a strong emphasis on participant safety, considering the age range and disability level of participants, as well as the non-directly supervised, home-based intervention. To safeguard against potential risks (e.g., exercise-related injury), the following procedures will be implemented. Participants will be informed potential risks associated with initiating an exercise training program in the informed consent. We will attempt to reduce risks of injury and harm by promoting gradual changes in exercise behavior across time during the one-on-one video coaching sessions. The levels of disability (PDDS scores) will be provided to the behavioral coach for planning purpose and safety consideration. Additionally, participants will be provided with an NMSS educational packet “Minimizing your risk for falls: A guide for people with MS” and a study-specific instruction sheet on fall prevention. Participants will be instructed to inform the behavioral coach should any safety concerns arise and to document any concerns or adverse events in their exercise adherence log. We will review the exercise adherence log information on an ongoing basis; adverse events will be documented and reported to the UIC Institutional Review Board and Data Safety Monitoring Committee. We will maintain effective communication with participants, record any potential MS relapses or other events that might influence exercise training, and provide appropriate guidance on exercise training modifications. However, if suspensions or terminations of training are required, it will be discussed with the research team and managed according to the specifics of each situation and documented with the IRB and for reporting purposes in the main outcome paper.

2.9. Data analysis plan

Data will be checked for accuracy, errors, and outliers before analyses and generate basic descriptive statistics and information for completing a CONSORT diagram. Process, resource, management and scientific feasibility metrics will initially be examined via percentage and frequency analysis and descriptive statistics. Additionally, we will analyze the potential demographic or clinical predictors of adoption and retention using logistic regression for binary outcomes (e.g., adopted vs. not adopted) and survival analysis for time-to-event data (e.g., time to dropout). The data analyses for efficacy outcomes will involve intent-to-treat principles and linear mixed-effects models to examine the effect of the exercise training intervention on cognition, physical function, exercise behavior, PA, vascular function, MS symptoms, and QOL in comparison with the control condition. The linear mixed-effects model will include Condition (2 levels: intervention vs. control) and Time (3 levels: 0, 16, & 32 weeks) as fixed effects, and individual as a random effect using unbounded variance components and the REML method. Overall effect sizes will be expressed as partial eta-squared, and small, medium, and large effects will be interpreted as values of 0.01, 0.06, and 0.14, respectively. We will further examine and compare the changes in efficacy outcomes using the criterion of a half standard deviation threshold, which is considered meaningful for detecting changes in health-related outcomes in chronic diseases [55,56]. We will further estimate Pearson correlation coefficients (r) among study outcomes (e.g., cognition and vascular biomarkers) at baseline and change scores following the intervention. The analyses will account for potential confounders, such as MS duration, age, sex, or other factors that differ between groups. Statistical analyses will be performed in R with the α level set at 0.05.

3. Discussion

The current study adopts an innovative intervention approach (via telerehabilitation) with rigorous design for evaluating the feasibility and initial efficacy of a home-based exercise training program in older adults with MS who have moderate mobility disability without severe cognitive impairment. The current literature indicates that face-to-face or supervised exercise training interventions have enhanced mobility, symptoms, and QOL in MS [12]. However, people living with MS tend to engage in significantly less PA and higher rates of sedentary behavior compared to the general population [57,58]. There is an urgent need for more effective intervention strategies for promoting daily PA, especially in the older age group who are experiencing challenges from both MS and aging. Traditional face-to-face delivery of exercise training may have limited accessibility and efficacy, making it difficult to increase everyday PA among individuals who have significant barriers in accessing healthcare, transportation, and exercise facilities [59]. In contrast, telerehabilitation and Internet-based interventions provide a promising alternative for delivering behavioral interventions that enhance PA and health outcomes, especially given the growing usage of digital devices within the MS community [60]. Moreover, this 16-week theory-based, remotely-delivered exercise training program involves a combination of aerobic cadence-controlled walking and resistance training, and is low-cost, convenient, and accessible for older adults with MS. This Stage-I RCT will assess the feasibility of such intervention for older adults with MS, such as the rate of enrollment, adherence, and retention. Our findings will establish a foundation for future development of large-scale intervention trials.

The secondary outcomes of this study focus on physical function, mobility, and cognitive function that are particularly compromised in older adults with MS. Previous research indicated a potential co-occurring effect of aging with MS progression, resulting in greater cognitive and motor disability and further reduced PA [7–9]. To date, there is insufficient evidence regarding exercise training and changes in outcomes among older adults with MS, especially with higher levels of mobility disability. One previous pilot trial used DVD-delivered exercise intervention targeting flexibility, strength, and balance, and demonstrated improved PA and QOL in older adults with MS [61]. However, that study did not include an aerobic exercise component, which has been shown participially beneficial for cognition in MS as well as delaying age-related declines in the general population [12]. Thus, the current project represents the first RCT that examines the feasibility and efficacy of combined aerobic and resistance exercise training based on prescriptive guidelines for MS on walking and cognition in older adults with MS. Indeed, the intervention protocol is aligned with exercise guidelines for MS and integrated with SCT-based behavior change techniques necessary for increasing adherence and supporting sustainability. This research may have clinical implications for improving PA levels among older adults with MS through alleviating travel concerns and reducing environmental and social barriers thereby increasing compliance and improving fitness and QOL.

There are several limitations of the proposed Stage-I RCT. One limitation is that we are measuring outcomes during in-person laboratory visits rather than online data collection. This was decided based on several considerations, including the lack of feasible, valid, and reliable remote assessments of physical function outcomes in MS, and potential technical issues due to online collection that may influence the properties of neuropsychological measures. Another limitation is that we are not collecting fitness data for aerobic power (e.g., maximal exercise testing) that could demonstrate improvements from the exercise intervention. This is to minimize the participant burden during the in-person laboratory visits, especially given the moderate mobility disability level and walking impairment of the target population. We further are already utilizing appropriate, comprehensive physical function assessments that have been applied in previous MS research. Additionally, despite utilizing reliable regression-based norms for the BICAMS, there might be potential limitations concerning age adjustments, given that normative data were mostly derived from samples below advanced age (e.g., ≤65 years) [62]. We will include both raw and corrected scores as primary outcomes and carefully consider the potential impact of higher age on our analysis and result interpretation. One final limitation is that of an inflated error rate with multiple, exploratory outcomes for the initial efficacy outcomes. We considered an adjusted alpha, but opted for caution in interpreting the significant outcomes based on an adjusted alpha value and any significant effects must be conformed in subsequent, fully-powered Stage-II efficacy trials.

Collectively, the proposed NIH Stage-I trial will examine the feasibility and initial efficacy of a 16-week home-based, combined exercise training intervention in older adults with MS who have moderate disability without severe cognitive impairment. This RCT will determine the feasibility and preliminary effect of the exercise training intervention on exercise behavior, PA, cognitive and physical function, MS symptoms, QOL, and vascular function compared with a social contact, attention control condition. If successful, the study will provide foundations for implementing larger, well-informed Stage-II/III trials using remotely-delivered exercise intervention for managing the consequences of aging with MS and other conditions with cognitive and motor declines (e.g., Parkinson’s disease).

Data availability

No data was used for the research described in the article.