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 [26] 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 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 [27];
(2) aged 25-60 years old;
(3) an Expanded Disability Status Scale score ≥6 [28];
(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) [29].
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 [30] 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 [31]. 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 [32]. 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 [32-34].
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 a sitting or prone position, 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.