The study is a single-center nonrandomized pilot and feasibility trial to explore the feasibility of an outpatient rehabilitation intervention for children 6 months to 3 years of age with SMA treated with genetic-based therapies. Participation in the study will occur over a 25-week period, with a baseline assessment visit followed by a 12-week intervention period and a 12-week nonintervention period. The trial site will be a pediatric rehabilitation hospital in Toronto, Canada.

A convenience sample of 5-10 participants (children and parent or guardian dyads) will be enrolled. Current standards of practice deem formal sample size calculations unnecessary for feasibility trials since findings obtained from the small sample size in this study will allow for generalization to a larger definitive trial. Thus, a pragmatic approach will be undertaken, justifying the sample size used in this study [34]. This also supports the practicality of this study design, as the participant pool does not need to be exhausted to deliver the intervention.

The inclusion criteria are as follows: (1) SMA (type I, II, or III) diagnosis; (2) received or receiving a genetic-based therapy; (3) age 6 months to 3 years; (4) able to participate in twice-weekly therapy at the study site; (5) able to bring appropriate respiratory equipment to weekly therapy sessions, if required; (6) parent or guardian must be able to speak and read English; (7) child participant must be able to understand and follow directions in English, as age appropriate; and (8) parent or guardian must consent to participate on behalf of their child.

The exclusion criteria are as follows: (1) live outside of Ontario, and (2) tracheostomy or use of daytime ventilation (excluding ventilation used during naps).

Inclusion and exclusion criteria will be assessed during the recruitment process. Respiratory safety screening will be conducted by the principal investigator if the use of respiratory equipment is identified.

Participants will be recruited from across Ontario, Canada. A multipronged recruitment strategy will be implemented using active (clinical referrals and an institutional research client database) and passive (self-referral through web posts) approaches. Posts include institutional internet posts (social media and the institution’s website) as well as social media sharing on websites commonly accessed by families with children with SMA. Figure 1 describes potential recruitment pathways and participant flow.

Parents will consent on behalf of their child before study visits are conducted by trained research staff. The intervention comprises a 12-week intervention period (OT and PT sessions plus a home exercise program) followed by a 12-week nonintervention period (home exercise program only). The 12-week intervention period was based on previous exercise therapy studies on pediatric neurological conditions such as cerebral palsy [29-31], and a small number of SMA exercise studies [23,32,35,36]. The on-off block structure is what is typically offered at the institution.

Participants will not be required to stop any additional private therapies during the study. However, participants will be asked not to start any new treatments or therapy during the study. All additional activities should be recorded in the home exercise diary.

In week 0, therapy goals will be set using the Canadian Occupational Performance Measure (COPM) and Goal Attainment Scaling (GAS) goals created with the participant’s parents, and baseline functional assessments will be completed. OT and PT goals will be individual to each participant. With that, the therapy sessions are created and personalized to the participant and their goals.

During the intervention period, active therapy will be delivered in person through weeks 1-11. A total of 2 therapy sessions (one 45-minute PT and one 45-minute OT session) per week in addition to a home exercise program will be completed. It will be recommended that participants complete the home exercise program 5 days per week in addition to the 2 therapy sessions (OT and PT). During the nonintervention period, the home exercise program will be continued. Functional assessments will be reevaluated at week 12 and then again at week 24 to determine whether functional gains were maintained. See Figure 1 for a detailed participant flow. A total of 3 weeks of sessions will be permitted to be missed or conducted through video conferencing software over the intervention period.

During the nonintervention period, the participant will receive an updated home exercise program to be completed 5 days per week. A research team member will contact the participant every 2 weeks to review the home exercise diary and other activities in which the participant is participating and to reiterate the importance of the home exercise program.

All on-site therapy and assessment sessions will be completed in a private therapy room; however, sessions could occur in a group therapy room if needed.

Assessments will be administered at prescribed time points, as described in Table 1.

The intervention uses 2 types of providers: assessment therapists and treatment therapists. Assessment therapists will complete the listed outcome measures at week 0, end of intervention or early withdrawal (week 12), and follow-up (week 24). Treatment therapists will plan and conduct the therapy sessions based on the COPM and GAS goals created by the assessment therapists. For a participant, the assessment and treatment therapists will be different to avoid bias.

The assessment and treatment therapists will be OTs and PTs with previous experience and training working with young children with SMA. Assessment therapists will complete the standardized training for the respective assessments. Assessment OTs will complete the Bayley Scale (all sections except the gross motor function), COPM, and GAS. Assessment PTs will complete the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) or Hammersmith Functional Motor Scale-Expanded (HFMSE), gross motor section of the Bayley Scale, COPM, and GAS.

All assessment measures except the participant-facing measures (ie, demographics survey, ITQOL, AIM, IAM, and FIM) will be completed in hard copy. A trained research team member will input the data into Research Electronic Data Capture (REDCap) [45,46] forms for secure retention and ease of exportation and analysis. Participant-facing measures will be completed by parents or guardians electronically on REDCap.

The trial’s feasibility will be evaluated using process, resource, management, and scientific domains [33]. Specific feasibility indicators within the domains, their data management plan, and success criteria are described in Table 2.

Process indicators will examine key items to ensure the success of the trial. Recruitment rate, eligibility criteria, adherence rate, and retention rate data will be collected from recruitment logs. Results for these indicators will be reported as ratios, means, and frequencies. Questionnaire completion times and completion correctness will be reported as means and frequencies. Item scores for acceptability measures (AIM, FIM, and IAM) will be summed by each participant and reported as averages for each measure. Resource indicators will assess time and resource issues that could occur when running a definitive trial. Therapists will record session and documentation durations for all visits. These results will be presented as a ratio and compared to the success criteria. With the same data, session and documentation times will be compared to similar values in the literature as well as clinician reports. Last, protocol deviations will be reviewed by deductive content analysis to determine if protocol revisions are required. Management indicators will assess potential human and data management issues when running the trial and will be evaluated through deductive content analysis of completed measures and data analysis notes. Adverse events will be analyzed by deductive content analysis. Feasibility indicators will be compared to the success criteria, as appropriate.

From a scientific standpoint, a preliminary examination of the intervention’s effectiveness will be assessed through safety and efficacy. Participant demographics and medical history collected from the demographics survey will be summarized descriptively. Preliminary efficacy will be evaluated through descriptive statistics and within-subject change scores of intervention assessment measures (ie, ITQOL, CHOP-INTEND or HFMSE, Bayley, COPM, and GAS goals). No between-subject analysis will be completed due to the small sample size. Change scores will measure functional gains and losses during the intervention period (t₁₂-t₀), nonintervention period (t₂₄-t₁₂), and the entire trial (t₂₄-t₀) for each participant separately.

The sample size for a larger equivalence trial will be calculated [50]. Specifically, the trial will test whether the intervention (genetic-based therapy and the intervention) and standard treatment (genetic-based therapy only) are equally effective. With that, there are 2 null hypotheses: and , where T=intervention, S=standard treatment, and δ=clinically admissible margin of equivalence. Using the information gained from the completed outcome measures, a primary end point will be confirmed. Calculations for continuous outcome measures by Zhong will be used:

Where N=size per group; z_x=standard normal deviation for 1- or 2-sided and ; δ₀=clinically acceptable margin; and s²=polled SD of both comparison groups. As per convention, α will be set at .05 and β will be set at .80. δ₀ will be calculated as the difference between the mean changes in the chosen primary end point for the current intervention (taken from this feasibility study) and typical change scores for the age-matched populations from the literature minus one.

A data safety monitoring board (DSMB) will be established to review and evaluate the accumulated study data for participant safety. The DSMB will function independently from the study investigators and have no direct involvement with study conduct. Any recommendations regarding the continuation, modification, or termination of the trial will be made to the study investigators based on the received reviews. A DSMB term of reference was prepared and is available upon request.

Adverse events or serious adverse events will be collected and reported by therapists and research personnel. The study doctors will assess the seriousness of adverse events or other unintended effects and will propose a management plan as required. Serious adverse events will be reported to the DSMB.

This study has been approved by the Research Ethics Board at Holland Bloorview Kids Rehabilitation Hospital in Toronto, Canada (REB#0550). All participants, through a substitute decision-maker, will partake in an informed consent discussion and sign an informed consent form before being enrolled in this study.