FES: Effect on Walking in the Real World and Participation in Daily Life in People With Multiple Sclerosis.

OVERARCHING PLAN. To evaluate the utility of FES for improving function and real-world outcomes in PwMS with gait impairments. Study design: a 4-month (4M) parallel 1:1 RCT in 70 PwMS. Epoch A: Group 1, 4M of FES. Group 2, 4M of sham stimulation. Epoch B; Groups 1 and 2, 4M of FES - followed by 1-month no-FES follow-up to evaluate carryover. Outcomes: We will examine gait quality, muscle function, physical activity, and factors influencing long-term FES adoption. Covariates: age, sex, clinical (MS severity, symptoms) and biomechanical (i.e. orthotic effects) factors, and wear time /stimulation levels. Interprofessional team: expertise in biomechanics, remote monitoring of PwMS, clinical trials, biostatistics and implementation science.

STUDY DESIGN. This study is a 4-month parallel 1:1 randomized controlled trial (RCT) involving 70 PwMS, designed to evaluate the impact of FES on mobility and long-term adoption. Participants will be randomized into two groups. Group 1: will receive FES during EPOCH A (4 months) and EPOCH B (4 months). Group 2 (delayed start): will receive 4 months of Sham stimulation during EPOCH A, and FES during EPOCH B. Follow-up: After Epoch B, all participants will be followed for 1 month with no FES sleeve or stimulation to assess carryover. Randomization. Participants will be stratified and randomized via a computer-generated sequence, with allocation concealed by an independent researcher. Blinding. Study coordinators and assessors will be blinded to group assignment to minimize bias. Setting. The UCSF Center for MS and Neuroinflammation provides state-of-the-art care to over 6,000 adults with MS annually. We have extensive experience with research studies enrolling patients including pivotal trials for MS,66 67 gathering patient generated data (PGD; i.e., remote physical activity)68, 69 and deploying digital technologies for health70 (see Facilities). Recruitment. Our goal is to enroll 70 adults (for 58 approximately 35 in each group, conservatively allowing for up to 20% attrition) with relapsing or progressive MS71 and some previously identified gait impairment who meet full inclusion/exclusion criteria. The study coordinator will pre-screen potential participants for disability level (EDSS) in the electronic health record (EHR).72 Some enrollment criteria require in-person assessment. Within each Group: We will include between 2:1 and 3:1 women to men, since MS affects 2-3 times more women than men. We will cap enrollment of non-Hispanic White patients at 65% to ensure that our participants reflect composition of our diverse clinic population (30-35% of whom identify as Black, Hispanic, Asian, or "Other") and that our data are generalizable to the experience of diverse PwMS. Patients will be contacted by IRB-approved means (telephone or email) or during a regular clinic visit (by the study team). Informed Consent. The study coordinator will obtain informed consent from eligible patients as detailed in the Human Subject's form prior to enrollment. Enrollment and screening. An eHEALS survey will assess participants' ability to use electronic health information. Patients who have given written informed consent will be formally enrolled into the study. We will block enroll (approximately 9 per disability group) across the EDSS disability spectrum based on preliminary data40, 43, 44, 49, 53, 54, 57: "mild - mild gait" (2.0-4.0), "moderate gait" (4.5-5.5), "unilateral support-" (6.0), and "bilateral support-" (6.5) for gait. This stratification enables evaluation of FES effects across diverse disability levels.

STUDY PROCEDURES. Overview. Participants will complete baseline assessments over 2-3 visits (within 1-2 weeks) to minimize fatigue, a common MS symptom. Baseline (Pre-Epoch A). They will undergo an in-clinic visit aligned with routine neurological care, including a detailed neurological exam and patient-reported outcomes (PROs, Table 2) available as paper or digital versions via REDCap74. Demographic/socioeconomic data will be obtained from the EHR. Based on inclusion criteria, participants will receive a standard-of-care referral to a neuro-PT. Participants will receive a Fitbit (Inspire 3 or newer), for continuous activity monitoring, with training and setup using anonymous credentials. One week of baseline activity data will be collected at home before initiating Epoch A (Group 1: FES, Group 2: Sham). At 4M (end of Epoch A) & 8M (end of Epoch B). Standardized assessments will include walking endurance, mobility, speed, fall risk (monthly surveys), balance, and participation-based measures (all detailed in Table 2), recommended by the MS Evidence Database to Guide Effectiveness task force for both clinical and research use.75 A trained PT will be present for all tests (for safety). Participants will rate effort (Rate of Perceived Exertion, scale: 0-10) and fatigue (0-10 scale) pre/post walking tests; if effort exceeds 4-5 or increases by ≥20%, they may rest longer or return another day. 1M Follow-up. Outcomes will be repeated per Table 2. A validated electronic patient-reported EDSS (ePR-EDSS76) will be collected to confirm no unexpected disability progression, which is not anticipated in this timeframe.

Intervention: Functional electrical stimulation via neural sleeve. The Cionic Neural Sleeve ("FES") is an FDA-cleared Class 2 medical device designed to aid mobility by stimulating leg muscles through metal electrodes embedded in a Nylon/Lycra garment (Fig 2).42 The interior of the sleeve has small metal electrodes which are covered by reusable 1.75"x1.75" gel sensor pads that adhere to the skin's surface. The electrodes connect to a handheld Control Unit, which powers the device and can be controlled via a smartphone application using Bluetooth Low Energy. The sleeve features gel sensor pads for skin contact and Velcro flaps for secure placement. Originally approved on February 14, 2022 [K213622], its compatibility was extended to include Android systems on July 21, 2022 [K221823]. Please see Preliminary Data (PD) below. Each participant will receive a neural sleeve and be asked to use it on their weaker limb (Group 1: 8M FES; Group 2: 4M Sham then 4M FES). Following manufacturer and FDA approved guidelines, a Cionic team member will fit the participant's affected leg with the appropriate Cionic sleeve size (XS - L). In a seated position, test stimulation is applied to muscle groups (dorsiflexors, plantarflexors, knee extensors/ flexors).

FES SETTINGS: FES Stimulation. Using a tailored electrode settings at an initial frequency of 35Hz and pulse width of 300µs, which has been shown in Cionic prior work (unpublished) to activate a visible motor contraction of the dorsiflexors. Stimulation intensity will start at 0mA, increasing in 10mA increments (range: 25-30mA) based on participant feedback (comfort/effectiveness) and gait effects. Sham Stimulation. Our own pilot data (Cionic; 12 PwMS) as well as literature propose a high-frequency (50-100 Hz), low-intensity (paresthesia, not painful), small pulse width (50-200μs) for stimulation that can be felt, but does not promote motor muscle contractions for sham stimulation/control,.77, 78

Cionic setup protocol details: Placement. Using the Neural Sleeve, electrodes will be positioned over four key gait muscles (see Figure 2): (1) quadriceps (vastus lateralis and rectus femoris at mid-thigh) for knee extension; (2) tibialis anterior (proximal third of the anterior-lateral tibia) for dorsiflexion; (3) gastrocnemius (medial/lateral heads at the proximal calf) for plantarflexion; and (4) hamstrings (biceps femoris along the posterior thigh) for knee flexion. Stimulation: the intensity of stimulation (mA) per day will be recorded and saved in the FES dashboard for each participant (initial group levels described above). The stimulation level per week will be used as a covariate in the analysis. Progression of FES: Figure 3 describes how FES will be progressed over the study. Minute-by-minute wear time will be recorded by the device and stored for analysis. Muscle selection: inclusion criteria require some lower extremity weakness (e.g. tibialis anterior, leading to foot drop). Activation of other muscle groups will be based on individual muscle weakness (<5/5 on manual muscle testing by the study PT) and recorded. The Cionic team will follow up with the participant (as per manufacturer guidelines) for virtual training, safety questions and all technical support throughout the study (see patient LOS). Risk mitigation for Cionic (set up and use): the study PT and Cionic team will assess participants' gait to note any visible impairments and ensure it is appropriate for device use. Individuals may use their assistive device (i.e. cane, walker) if applicable, assessing need to begin with AFO or other orthosis with sleeve for stability. The stimulation will never be raised to the point of discomfort or pain.

Details on Gait Metrics. Instrumented Walkway. Instrumented walkways (IWW) offer precise measurements of temporal-spatial parameters (i.e., gait speed, step length, support times, and base of support), which have been used to identify underlying causes of gait dysfunction in MS, as well as guiding treatment.96-98 A 16-foot ZenoTM IWW is permanently housed within our MS Clinic for clinical and research use (Bove), enrolling participants with variable neurological conditions, gait impairments and risk of falls. This reliable pressure IWW has been recognized (by the FDA) as the ground truth for gait measurements.99 Gait metrics. The ProtoKinetics software [PKMAS, LLC, Havertown, PA, USA) exports 679 gait variables from the IWW. From prior literature and our experience,99, 100 core variables capturing changes in gait in PwMS are: velocity (cm./sec - mean), cadence (steps/min - mean), step length (magnitude [increase] and symmetry - L/R ratio OR ASI [asymmetry index, aiming for =1]), variability (single support %, stride width: aiming for lower values). We will also include: total double support %, single support %, stride velocity, mean gait variability index, walk ratio, stride time, stride length. At baseline, 4M, 8M and follow/up: guided, and guarded by a study PT(safety), participants will walk over IWW at comfortable and fast gait speeds (2-4 passes per protocol)99 using their usual assistive device (cane, walker). Rationale for Timepoints: PwMS with disability will likely demonstrate slowing (~1-2s) of gait over time, the timepoints will account for natural progression. Ample rest breaks will be given between protocols.

Inclusion criteria

• Diagnosis of MS (relapsing or progressive) by 2017 McDonald Criteria79
• Ages 22-75 years old
• EDSS 2 - 6.5 (wide range of impairment, 6.5 = ambulation requires walker or 2 canes)
• ≥ 1/5 (and <5/5 on manual muscle test) of affected leg muscles
• Any MS therapy, or no disease modifying treatment.
• Technological criteria: availability of Wi-Fi in the home or workspace for connectivity.

Exclusion criteria

• Cognitive, dexterity or visual impairment that, in the opinion of the study neurologist (RB), would put the participant at risk or limit their ability to comply with the study protocol.
• Inability to provide informed consent
• FES use in the last 6 months
• Musculoskeletal / cardiovascular comorbidities that in the opinion of the study physical therapists (VB, JB), places the patient at risk.
• Recent (last 30 days) relapse affecting gait
• >2/4 on the Ashworth scale (3= passive movement difficult)