We are conducting a multicenter 2-arm, superiority randomized controlled trial (RCT) with 3 assessment points (baseline, T0; postintervention at 12 weeks, T1; and follow-up at 6 weeks, T2). Participants will be allocated to the intervention (MS-FIT) or control group in a 1:1 ratio by simple randomization.

Participants in the MS-FIT group will have access to the MS-FIT exergame for at-home self-administration [28] (Multimedia Appendix 1) in addition to their leisure-time physical activities. Participants in the control group will have the possibility to perform only their leisure-time physical activities. Exercise will not be allowed and rehabilitation treatments, except for speech therapy, sphincter rehabilitation, and psychological support, must be suspended. The study design is illustrated in Figure 1.

Participants will be recruited among those followed by 14 Italian neurorehabilitation centers; specifically, at the Italian Multiple Sclerosis Society Rehabilitation Services of Genoa and Padua, the Multiple Sclerosis Center of IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Foundation “Carlo Besta” Neurological Institute (Milan), the Vita-Salute San Raffaele University (Milan), the Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) of the University of Genoa, the Neurology Unit of IRCCS Neuromed (Pozzilli), the Department of Medical Science and Public health of the University of Cagliari, Department of Translational Biomedicine and Neurosciences (DiBraiN) of the University A. Moro (Bari), the IRCCS Fondazione Don Carlo Gnocchi ONLUS (Milan), the Uosi Multiple Sclerosis Rehabilitation of the IRCCS Istituto delle Scienze Neurologiche of Bologna, Department of Advanced Medical and Surgical Sciences (DAMSS) of the University of Campania Luigi Vanvitelli (Naples), the Department of Neurosciences of the S. Camillo-Forlanini Hospital (Rome), the Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia” (DGFI) of the University of Catania, and the IRCCS Centro Neurolesi “Bonino-Pulejo” (Messina).

The assessments will be carried out in person at the several centers. The intervention with MS-FIT will be performed at home.

People with MS along with mild disability, low risk of falling, preserved cognitive functions, and low anxiety and depression as reported in medical records are potential eligible participants. They will be contacted by telephone by the study manager of the related center (Multimedia Appendix 1), who will explain the study process in detail to ensure that patients understand the entire clinical trial; they will receive detailed information, including the purpose, procedures, follow-up content, data storage, benefits, and risks of the study, and will be given adequate time to consider participation. They will be informed that for the entire period of participation in the study, only leisure-time physical activities will be allowed, but not exercise and rehabilitation. They will also be informed verbally that their participation is voluntary and that they can withdraw their consent at any time without giving reasons and without depriving themselves of any treatment and care or other disadvantages.

Patients who agree to participate will be scheduled for a screening visit with a therapist (Multimedia Appendix 1). First, they will be asked to sign the written informed consent (Multimedia Appendix 2) after carefully reading and understanding the information about the study procedures and data security measures (including information on how to contact the study team in case of questions) provided to them. This approach is compliant with the General Data Protection Regulation and has been approved by the ethics committees.

After consent, recruited patients will proceed to the screening evaluation, where inclusion and exclusion criteria are assessed, and they will immediately receive feedback on whether or not they can participate in the study. Enrolled patients will be randomized by the study manager through the electronic case record form (eCRF) (Multimedia Appendix 1) into one of the 2 groups (ie, MS-FIT and control) and informed of the result of the assignment.

Eligibility criteria were selected to ensure optimal fitness of the study sample with respect to the subsequent implementation of the MS-FIT intervention in the health care setting, to minimize the impact of confounding variables (eg, rehabilitation outcomes), and to ensure comparability with other studies on similar interventions.

All participants will be allowed to continue their leisure-time physical activities.

Participants in the MS-FIT group will receive the MS-FIT exergame [28]. They will be required to train at home with MS-FIT for 12 weeks by performing the exercises for a total of 30 minutes/day for at least 3 days/week.

While gaming, participants will choose their favorite and most useful exercises; the difficulty of the exercise will increase based on the user’s performance. In this way, the exercise selection and the reward structure will ensure the personalization of the intervention.

Before starting the intervention, each participant will be trained in the use of the tool by the study manager.

Participants in the control group will not receive MS-FIT; however, as a reward for their participation, we will offer them the MS-FIT intervention at the end of their study involvement.

All participants will be assessed at T0, T1, and T2.

The assessment will consist of clinical tests measuring the domains most relevant to MS. The primary outcome will always be administered first; the order of the secondary outcomes will be randomized across participants; however, the same order will be maintained for the individual participant. We assume that the administration of all tests will take, on average, about 60 minutes.

Multimedia Appendix 3 summarizes when the different outcome measures should be collected.

In addition to withdrawal of consent at any time, the study manager at each site may also consider as criteria for premature withdrawal any medical conditions that could jeopardize the safety of the patient if she or he continues the study, changes in the disease treatment during the study, and noncompliance of the participants to the study procedures.

The sample size was calculated by referring to the TUG change after a Pilates intervention found by Kalron et al [30] in a group of people with MS. The authors found no difference between the group receiving the Pilates intervention and the control group receiving an intervention of physical therapy. The Pilates group improved the TUG performance by about 1.8 seconds, which is clinically relevant for people with MS. Considering a variability of about 3.4 seconds, a power of 80%, a significance level (2-sided) of 5%, and a potential loss of 15% of patients at follow-up, the estimation of the necessary sample size consists of approximately 63 participants for the experimental group (a total of 126).

Data entry, including quality checks and double entry validation, will be performed through eCRF (Multimedia Appendix 1). Missing data from the unit record will be compared with the corresponding handwriting case record form and corrected accordingly.

Descriptive statistics will be used to evaluate differences between the 2 groups of participants. The study hypotheses will be tested using an intention-to-treat analysis, where all consenting patients who were randomized during the accrual period will be included in the analysis.

Continuous data will be summarized using count, mean, median, SD, and IQRs, whereas categorical measures will be described using frequencies. The assumption of normality will be tested with the Shapiro-Wilk test. Pre-post effects within groups will be investigated using the paired t test or the Wilcoxon matched-pairs signed-rank test. Between-group proportions will be compared by chi-square or Fisher exact test, while between-group comparisons for continuous variables will be done using either the unpaired 2-sided t test or the 2-sided Wilcoxon 2-sample test for nonnormal data. Correlations will be computed using Pearson or Spearman coefficients.

The primary analysis will be performed by comparing mean changes from T0 to T1 in the primary and secondary study outcomes. In particular, the MS-FIT group will be compared with the control group with analyses of covariance. The model includes change as the dependent variable, with the intervention group as the main effect and baseline and number of sessions as additional covariates. Finally, generalized estimating equation models will be performed to assess the persistence of the intervention effect; here the mean effect of the intervention at the time points T0, T1, and T2 on all outcomes, adjusted for the baseline value, will be evaluated between the 2 groups.

Differences in the outcome measures between subgroups defined by different polymorphisms will be analyzed using the analysis of variance or the Kruskal-Wallis test, as appropriate.

Statistical analysis will be performed using STATISTICA 7.1 software (StatSoft GmbH). Significance will be recognized for P<.05.

This trial is conducted in accordance with the protocol (version 1, July 27, 2018), the Declaration of Helsinki, and good clinical practice. It has been approved by the Ethics Committee of San Martino Hospital (134/2018) and registered before patient enrollment at ClinicalTrials.gov (NCT04011579).

Any change to this protocol must be agreed upon by all the study investigators. Each amendment must be signed by the principal investigator at each site, and amendment forms will be submitted to the local Ethics Committee for approval. The amendment will be updated in the clinical trial registry.

Participants will be asked to sign the written informed consent, and their data will be deidentified. Participants will not receive any compensation for participating in the study.

A formal audit process at the end of the study is proposed for this trial.

Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of our research, although patient feedback was an important source for the development and improvement of the MS-FIT tool investigated in this trial [28]. Published results will be disseminated to study participants upon request.

The results of this RCT study will be disseminated. Dissemination includes communication and promotion of the project activities and results to participants, people with MS, and their stakeholders (eg, caregivers, health care professionals, and the scientific community). Dissemination activities will begin at launch and will continue throughout the duration of the study. Specific activities include dissemination through materials such as flyers and videos to be distributed through the internet, social networks, forums, or at local, national, and international events, and specific meetings with end users; dissemination through presentation of results in national and international peer-reviewed scientific journals; dissemination through presentation of research results at major national and international health care conferences and annual meetings; and dissemination through the ClinicalTrials website registry.

Cumulative data suggest that the Pilates method has proven beneficial in several neurological diseases and may be a PA tool for people with MS. A recent review [22] in MS showed that Pilates improves balance, gait, physical-functional conditions (muscle strength, core stability, aerobic capacity, and body composition), and cognitive functions; in contrast, fatigue, QoL, and psychological function did not show a clear improvement. Furthermore, high adherence (average adherence ≥80%) and few adverse effects were reported. For these reasons, future research is needed to develop clinical protocols that can maximize the therapeutic effects of Pilates for people with MS. In this context, novel devices and technologies for home-based interventions could provide solutions to overcome limitations due to urban barriers (eg, transportation), daily activities (eg, working time), and clinical conditions (eg, level of disability) and to ensure continuity of care. Therefore, practicing Pilates at home through eHealth tools could help people with MS to regularly engage in PA and to successfully maintain their physical, cognitive, and emotional status.

Here, we describe the RCT protocol designed to test the efficacy of a home-based PA intervention delivered through the MS-FIT exergame on balance and gait. In addition, we will also assess the effects on cognition, QoL, and well-being.

The present RCT protocol was designed taking into account previous studies in the MS scientific literature in terms of the number of weeks of intervention, weekly frequency, session duration, outcomes, setting, and control group [22]. Because only one study evaluated long-term monitoring after the intervention [58] and it is unclear whether the obtained results are maintained, as an additional element of novelty, we propose to schedule a follow-up assessment in order to define whether the effects of Pilates persist.

The first limitation of this study is that we will only have evidence of the effectiveness of a Pilates exergame for people with MS with mild disability. However, even people with MS at more advanced disease stages benefit from regular PA to maintain fitness, prevent pain and secondary complications of inactivity, and treat or reduce symptoms. Thus, as specific prescriptions should be tailored to clinical conditions, a dedicated trial for patients with a higher level of disability should be considered. Second, due to the discontinuation of the Kinect Sensor V2 adopted in MS-FIT, for the successful translation of the exergame into clinical practice, a new compatible commercial sensor will be identified, and the app will be adapted; Microsoft Azure Kinect and Mentor Age (Wita Società a responabilità limitata) are valid and comparable systems already taken into account by other researchers [28,59,60]. Third, although the MS-FIT tool was not developed to pursue rehabilitation purposes, it would be helpful to analyze the MS-FIT intervention as a complement to the work of health care professionals and evaluate if it is able to potentiate the effect of a rehabilitation intervention, possibly also in people with MS with a higher level of disability. Finally, direct evidence, such as MRI acquisition, will not be considered to reveal which microstructural changes are due to the MS-FIT intervention.

MS-FIT is a usable and accepted digital health tool for telerehabilitation implementing Pilates exercises and aims at supporting the self-administration of Pilates training at home. This study will provide evidence for the use of the MS-FIT tool in clinical practice as a complement to rehabilitation and for the continuity of care of people with MS. However, a feasibility protocol involving patients with moderate disability (EDSS between 4 and 6) should be designed and tested, followed by a multicenter trial that assesses the effectiveness of the tool and paves the way for more extensive use in MS.