Study design and settings
The study is a prospective, assessor blinded, parallel group pilot RCT. Figure 1 illustrates the study schedule. The implemented study design will adhere to the CONSORT guidelines [27] and will be conducted at two established MS centers:
(1) The Regional Center for Diagnosis and Treatment of Multiple Sclerosis, Binaghi Hospital, Cagliari, Italy and
(2) The Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel.
Methodology and work plan
Approval will be obtained from each Institutional Review Board Committee (IRB) prior to commencement. All participants will sign an informed consent form and will be randomly assigned to one of the two intervention groups:
(1) Telerehab VR training;
(2) Conventional therapy
A block randomization procedure will be performed by the study coordinator who will place numbered tickets in sealed opaque envelopes. The sealed envelopes will be opened sequentially by the investigator only after the participant’s name and other details will be written on the appropriate envelope. The participants will be informed as to the resulting group allocation before the pre-intervention tests. The assessor will then assign the participants to an intervention program. The two interventions will be comparable in length (8-weeks), frequency (twice weekly) and session duration (50-60 min). The 8-week intervention period is in accordance with other studies investigating upper limb physical rehabilitation in PwMS [2].
Pre-intervention tests (T0) characterizing groups and obtaining baseline values of primary and secondary outcome measures will be performed one-week±3 days prior to the intervention program. Within one-week±3 days after completion of the intervention, post-intervention tests will be performed (T1). The same tests will be conducted at a 1-month±3 days follow-up, (T2) after completion of the intervention. During the follow-up period (T1-T2), patients will be instructed to continue their regular activities. All assessments and interventions will be performed at the two MS centers. Due to the nature of the intervention, therapists and participants will not be blinded to the group allocation; however, the assessor will be blinded. Figure 2 illustrates the procedures that participants will undergo at T0, T1, and T2.
Participants
In total, 24 individuals with MS will be recruited from the two participating MS centers (12 from each center). Recruitment of participants will be handled by advertisement and awareness of the trial through the medical staff of each participating center.
Inclusion criteria
(1) diagnosis of MS according to the revised McDonald Criteria 2017 [28];
(2) aged 25-60 years old;
(3) an Expanded Disability Status Scale score ≥6 [29];
(4) an ability to understand and execute simple instructions;
(5) a cut-off score of >0.5 pegs/s (=18s) on the nine-hole peg test (NHPT) (selected due to its high discriminative and predictive ability in distinguishing ADL independence in PwMS) [30].
Exclusion criteria:
(1) orthopedic and other neurological disorders affecting upper limb movements (e.g., epileptic seizures);
(2) contra-indication to physical activity (e.g., heart failure, severe osteoporosis);
(3) moderate or severe cognitive impairments as indicated by the Mini-Mental State Examination [31] score <21;
(4) pregnancy (self-reported);
(5) severe uncorrected visual deficits;
(6) MS clinical relapse or treatment with corticosteroid therapy within 90 days prior to enrollment;
(7) started or stopped a disease-modifying therapy for MS within 90 days prior to enrollment;
(8) patients who received a course of physical or occupational therapy (home, outpatient or inpatient) within the past 30 days;
(9) other treatments that could influence the effects of the interventions. PwMS eligible for participation will be informed of the study by their rehabilitation specialist, both orally and in writing. All participants will provide written informed consent.
Sample size
The sample size is based on Julious’s (2005) recommendation that the rule of thumb for a pilot study is a sample size of 12 subjects per group [32]. The justifications for this sample size are based on rationale relating to feasibility, mean and variance precision, regulatory considerations and the expected change in the study's primary outcome measure (NHPT). According to the literature, a 20% change in the NHPT demonstrates a clinically meaningful worsening in PwMS [33]. In our study, power will be set at 80% and alpha at 5%. Therefore, 24 subjects (12 in each group) will be required in order to detect differences between the two treatment groups (assuming non-inferiority with moderate correlations among covariates, r-squared = 0.50).
Interventions
Both interventions will focus specifically on functional upper limb exercise training and be administered by experienced physiotherapists or occupational therapists with at least 2 years of professional experience in the field of neurorehabilitation. Therapists at each site will receive training protocols to ensure homogeneity of treatment between sites.
Telerehab VR intervention
The telerehab VR intervention consists of a custom-made software program, that will run on a personal computer (or tablet), developed under Unity (Unity Technologies Inc., San Francisco, USA). Unity is a cross-platform game engine worldwide adopted to create three-dimensional, two-dimensional, virtual reality, and augmented reality games, as well as simulations and other experiences. PwMS will be requested to perform several ADLs from the three main areas of self-care, dressing and meal preparation. Taking place in a realistic home scenario, the PwMS will pick up objects and move them to a predefined target clearly indicated on the screen. By controlling the object’s trajectory within the virtual scenario through the vision of their hands and forearms provided by a low-cost non-contact infrared controller (Leap Motion). This instrument was proven successful in upper limb rehabilitation of individuals with neurologic and orthopedic conditions [34-36].
During the exercise, the hand coordinates will be continuously recorded, thus, data kinematic data calculated on the basis of the 3D trajectory like speed, accuracy on target placement and movement smoothness will be accessible. This data will be stored in the PC/tablet and will also be sent remotely to the clinical center for further analysis/processing. Both target position and task complexity will define the exercise difficulty, which can be modified (i.e. increased or decreased) automatically on the basis of the previous performance or manually modified by the user. A suitable period of familiarization with the installation/management of the hardware and software will be carried out under the supervision of engineers and therapists to ensure that the exercises are being correctly performed. A schematic representation of the system is shown in Figure 2.
Conventional therapy
Conventional therapy will focus on task-related upper-limb treatments while in sitting denoting the standard care for PwMS [2]. Several manual techniques, therapy tools and objects of ADL will be allowed during treatment. Use of additional electrical or mechanical therapy devices (ie, support arm systems, splints) will be avoided. The interventions will be conducted on a one-on-one basis in the physiotherapy or occupational therapy department of each participating center. Training and therapy content will be tailored to each participant's preferences, the agreed movement aims and their motor function level.
Safety considerations and adverse events
Adverse events occurring during and between treatments will be recorded and compared between groups (without statistical comparisons). Training and all measurements are non-invasive and place the subject at no risk other than those that normally may occur during functional upper limb activities. Nevertheless, the patient will be free to withdraw from the study at any time. The investigator has the right to withdraw a patient from the study due to any reason concerning the health or well-being of the patient, or in case of lack of cooperation. The reason for any withdrawal will be noted in the patient’s hospital file.
Outcomes
Primary outcomes (collected at T0, T1, T2)
NHPT
The NHPT was selected based on the widespread adoption and extensive data available. Furthermore, the NHPT is recommended as a gold standard for measuring manual dexterity in PwMS [33]. The NHPT has excellent psychometric properties as to reliability, discriminant, concurrent and ecological validity, can detect progression over time, is sensitive to treatment and as such, is recommended for inclusion in clinical trials. Briefly explained, the NHPT requires participants to repeatedly place nine pegs into nine holes, one at a time, as quickly as possible and then remove them from the holes. The total time needed to complete the task is then recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand [4,8].
Secondary outcomes (collected at T0, T1, T2)
Action Research Arm Test (ARAT)
The ARAT is a 19 item observational measure used by physical therapists and healthcare professionals to assess upper extremity performance in terms of coordination, dexterity and functioning in several neurologic conditions, including MS [37]. Items comprising the ARAT are categorized into four subscales (grasp, grip, pinch and gross movement) and arranged in order of decreasing difficulty, with the most difficult task examined first, followed by the least difficult task. Task performance is rated on a 4-point scale, ranging from 0 (no movement) to 3 (movement performed normally).
Manual Ability Measure-36 (MAM-36)
The MAM-36 is a questionnaire based on perceived ease or difficulty that a person may experience when performing unilateral and bilateral ADL tasks. During a semi-structured interview, the subject is asked to rate 36 unilateral and bilateral ADL tasks using a 4-point scale. The score of the different tasks are summed up and transformed using a Rasch-derived conversion table. The MAM-36 has adequate psychometric properties and is recommended as an outcome measure for upper limb function in PwMS [38].
Health status questionnaire (SF-36)
The Short Form-36 is one of the most widely used generic measures of health-related quality of life and has been shown to discriminate between subjects with different chronic conditions and between subjects with different severity levels of the same disease. The instrument addresses health concepts relevant to MS patients from the patient's perspective. Availability of normative data makes the SF-36 beneficial for comparative purposes. There is considerable evidence of the validity of the SF-36 in PwMS [39].
Adherence and user satisfaction
Adherence to exercise will be evaluated at the end of the intervention phase by examining the patient’s exercise diaries. The User Satisfaction Evaluation Questionnaire (USEQ) will be used to assess the participants’ satisfaction with the training program [40]. The USEQ is a reliable questionnaire with internal consistency designed to evaluate the satisfaction of the user in virtual rehabilitation systems.
Impression of change (collected only at post-intervention T1)
A 7-point Likert-type global rating scale from both the patient and therapist’s perspective will be applied. The question that will be asked will be: “Compared to before treatment, at present, how would you rate your/the participant’s functional upper limb activities?” The responses will be rated as: 1= worse than ever, 2 = much worse, 3 = slightly worse, 4 = unchanged, 5 = slightly improved, 6 = much improved, 7= greatly improved.
Brief Repeatable Battery of Neuropsychological Tests (BRB-N) (collected only at baseline T0)
The BRB-N are sensitive measurement tools aiding in identifying cognitive impairment in PwMS. This battery of tests includes the Selective Reminding Test, the 10/36 Spatial Recall Test, the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Test and the Word List Generation Test [41]. Cognitive status will be collected only at baseline.
Statistical analysis
Data analysis will be performed by the SPSS 25.0 program. The data will be initially examined for normality violations, outliers, errors and patterns of missing values; missing data will be replaced by multiple imputation techniques found in the SPSS. In the event of exacerbations, the analysis will be conducted with and without the individuals who had relapsed in order to identify any untoward effects on the outcomes. The data analysis itself will follow intent-to-treat principles. The effect of the intervention on the NHPT (Aim 1), ARAT (Aim 1), MAM-36 (Aim 1), SF-36 (Aim 2), adherence and user satisfaction (Aim 3), will be examined using the Condition × Time mixed model multivariate analysis of variance (MANOVA) followed by an inspection of the univariate F-ratios. Conditions will be a between-subjects factor and time and a within-subjects factor. Interactions and main effects will be further calculated using post-hoc analyses with a correction of alpha. Effect sizes associated with univariate F-statistics will be expressed as eta-squared (η2) and effect sizes based on a difference in mean scores will be expressed as Cohen’s d. We will include cognitive scores (BRB-N) as covariates in all final statistical analyses.
Roles and mode of integration between the teams.
Data will be shared throughout the project by personal meetings, Skype™ video calls, conference calls and e-mail correspondence. Specifically, the Italian group will be responsible for designing and implementing three new VR scenarios relating to functional activities of the upper limb. The new VR scenarios will be planned in conjunction with the Israel group who will also play an active role in the quality assessment procedures of the developed elements. Both groups will participate equally in the pilot RCT. Roles include: recruitment and guidance of patients and therapists, implementing the telerehab VR system in the patient's home with multi-layer security, end-to-end encryption, assessment of outcome measures and data collection. Both sites will contribute to the analysis and interpretation of data and dissemination of the findings. An additional role of the Israel team will be to prepare a user manual detailing how to use the system and providing clinical guidelines/recommendations for both the therapist and patient. Both groups will be responsible for data entry, coding, security and storage. No anticipated harm is expected, therefore, a data monitoring committee is not required. However, an independent biostatistician will be involved in the data analysis. Periodic reports on progress of the trial will be provided to the funding bodies. There is no intended use of professional writers.