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‐worldoutcomes in PwMS with gait impairments. Study design: a 4‐month (4M) parallel 1:1 RCT in70 PwMS. Epoch A: Group 1, 4M of FES. Group 2, 4M of sham stimulation. Epoch B; Groups 1and 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 influencinglong‐term FES adoption. Covariates: age, sex, clinical (MS severity, symptoms) andbiomechanical (i.e. orthotic effects) factors, and wear time /stimulation levels.Interprofessional team: expertise in biomechanics, remote monitoring of PwMS, clinicaltrials, 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‐termadoption. Participants will be randomized into two groups. Group 1: will receive FESduring EPOCH A (4 months) and EPOCH B (4 months). Group 2 (delayed start): will receive 4months of Sham stimulation during EPOCH A, and FES during EPOCH B. Follow‐up: After EpochB, all participants will be followed for 1 month with no FES sleeve or stimulation toassess carryover. Randomization. Participants will be stratified and randomized via acomputer‐generated sequence, with allocation concealed by an independent researcher.Blinding. Study coordinators and assessors will be blinded to group assignment tominimize bias. Setting. The UCSF Center for MS and Neuroinflammation providesstate‐of‐the‐art care to over 6,000 adults with MS annually. We have extensive experiencewith research studies enrolling patients including pivotal trials for MS,66 67 gatheringpatient generated data (PGD; i.e., remote physical activity)68, 69 and deploying digitaltechnologies 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 whomeet full inclusion/exclusion criteria. The study coordinator will pre‐screen potentialparticipants for disability level (EDSS) in the electronic health record (EHR).72 Someenrollment criteria require in‐person assessment. Within each Group: We will includebetween 2:1 and 3:1 women to men, since MS affects 2‐3 times more women than men. We willcap enrollment of non‐Hispanic White patients at 65% to ensure that our participantsreflect 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 ofdiverse PwMS. Patients will be contacted by IRB‐approved means (telephone or email) orduring a regular clinic visit (by the study team). Informed Consent. The studycoordinator will obtain informed consent from eligible patients as detailed in the HumanSubject's form prior to enrollment. Enrollment and screening. An eHEALS survey willassess participants' ability to use electronic health information. Patients who havegiven written informed consent will be formally enrolled into the study. We will blockenroll (approximately 9 per disability group) across the EDSS disability spectrum basedon preliminary data40, 43, 44, 49, 53, 54, 57: "mild ‐ mild gait" (2.0‐4.0), "moderategait" (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 2‐3visits (within 1‐2 weeks) to minimize fatigue, a common MS symptom. Baseline (Pre‐EpochA). 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 willbe obtained from the EHR. Based on inclusion criteria, participants will receive astandard‐of‐care referral to a neuro‐PT. Participants will receive a Fitbit (Inspire 3 ornewer), for continuous activity monitoring, with training and setup using anonymouscredentials. One week of baseline activity data will be collected at home beforeinitiating Epoch A (Group 1: FES, Group 2: Sham). At 4M (end of Epoch A) & 8M (end ofEpoch B). Standardized assessments will include walking endurance, mobility, speed, fallrisk (monthly surveys), balance, and participation‐based measures (all detailed in Table2), recommended by the MS Evidence Database to Guide Effectiveness task force for bothclinical 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 (0‐10scale) pre/post walking tests; if effort exceeds 4‐5 or increases by ≥20%, they may restlonger or return another day. 1M Follow‐up. Outcomes will be repeated per Table 2. Avalidated electronic patient‐reported EDSS (ePR‐EDSS76) will be collected to confirm nounexpected disability progression, which is not anticipated in this timeframe.Intervention: Functional electrical stimulation via neural sleeve. The Cionic NeuralSleeve ("FES") is an FDA‐cleared Class 2 medical device designed to aid mobility bystimulating leg muscles through metal electrodes embedded in a Nylon/Lycra garment (Fig2).42 The interior of the sleeve has small metal electrodes which are covered by reusable1.75"x1.75" gel sensor pads that adhere to the skin's surface. The electrodes connect toa handheld Control Unit, which powers the device and can be controlled via a smartphoneapplication using Bluetooth Low Energy. The sleeve features gel sensor pads for skincontact 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 neuralsleeve and be asked to use it on their weaker limb (Group 1: 8M FES; Group 2: 4M Shamthen 4M FES). Following manufacturer and FDA approved guidelines, a Cionic team memberwill 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 initialfrequency 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. Stimulationintensity will start at 0mA, increasing in 10mA increments (range: 25‐30mA) based onparticipant feedback (comfort/effectiveness) and gait effects. Sham Stimulation. Our ownpilot 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 stimulationthat can be felt, but does not promote motor muscle contractions for shamstimulation/control,.77, 78Cionic setup protocol details: Placement. Using the Neural Sleeve, electrodes will bepositioned over four key gait muscles (see Figure 2): (1) quadriceps (vastus lateralisand rectus femoris at mid‐thigh) for knee extension; (2) tibialis anterior (proximalthird of the anterior‐lateral tibia) for dorsiflexion; (3) gastrocnemius (medial/lateralheads at the proximal calf) for plantarflexion; and (4) hamstrings (biceps femoris alongthe posterior thigh) for knee flexion. Stimulation: the intensity of stimulation (mA) perday will be recorded and saved in the FES dashboard for each participant (initial grouplevels described above). The stimulation level per week will be used as a covariate inthe analysis. Progression of FES: Figure 3 describes how FES will be progressed over thestudy. 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. tibialisanterior, leading to foot drop). Activation of other muscle groups will be based onindividual 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) forvirtual training, safety questions and all technical support throughout the study (seepatient LOS). Risk mitigation for Cionic (set up and use): the study PT and Cionic teamwill assess participants' gait to note any visible impairments and ensure it isappropriate 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 forstability. The stimulation will never be raised to the point of discomfort or pain.Details on Gait Metrics. Instrumented Walkway. Instrumented walkways (IWW) offer precisemeasurements of temporal‐spatial parameters (i.e., gait speed, step length, supporttimes, and base of support), which have been used to identify underlying causes of gaitdysfunction in MS, as well as guiding treatment.96‐98 A 16‐foot ZenoTM IWW is permanentlyhoused within our MS Clinic for clinical and research use (Bove), enrolling participantswith variable neurological conditions, gait impairments and risk of falls. This reliablepressure IWW has been recognized (by the FDA) as the ground truth for gaitmeasurements.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, 100core 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: aimingfor lower values). We will also include: total double support %, single support %, stridevelocity, mean gait variability index, walk ratio, stride time, stride length. Atbaseline, 4M, 8M and follow/up: guided, and guarded by a study PT(safety), participantswill walk over IWW at comfortable and fast gait speeds (2‐4 passes per protocol)99 usingtheir usual assistive device (cane, walker). Rationale for Timepoints: PwMS withdisability will likely demonstrate slowing ( 1‐2s) of gait over time, the timepoints willaccount for natural progression. Ample rest breaks will be given between protocols.