Noninvasive Spinal Cord Stimulation for Early SCI

PURPOSE:

The purpose of this clinical study is to investigate the safety and effectiveness of non-surgical transcutaneous spinal cord stimulation (TSCS) in helping with recovery of bladder function in individuals with SCI. Assessments: The immediate effects of TSCS (i.e., effects with stimulation on), long-term effects of TSCS, and the persisting effects of TSCS (i.e., any changes in function that are still present with stimulation off, after several weeks of using the stimulation regularly -pre versus post study comparison). This is a Phase II study. A Phase II study is undertaken after preliminary safety testing for a treatment.

Investigational Study Device:

The SCONE™ (Spinal COrd NEuromodulation) class II investigational device is a non-invasive central nervous system (CNS) stimulator (electrical continence device) designed to provide TSCS for the improvement of symptoms of bladder dysfunction associated with centrally-mediated NLUTD.

The SCONE™ device's primary mechanism of action is electrical stimulation delivered to the spinal cord through the skin. The device consists of an electrode connected by an electrical cable to a battery-powered pulse source and uses advanced waveforms to deliver electrical stimulation directly to the spinal cord neural networks associated with pelvic floor function with the aim to activate and retrain the neural circuits responsible for urinary bladder control.

Primary Objective:

To assess the effect of non-invasive TSCS on LUT function in people with sub-acute and chronic SCI following eight weeks of therapy in comparison to inactive sham control.

Secondary and Ancillary Objectives:

To assess the effect of non-invasive TSCS on bowel dysfunction, sexual dysfunctions, cardiovascular function, spasticity, and quality of life.

Specific Aim 1 - TSCS Mapping: To establish function-specific TSCS parameters and electrode placement to activate spinal neural circuits controlling LUT function in individuals with sub-acute and chronic SCI.

Primary Outcomes: Motor threshold (TSCS parameters) based on surface EMG for skeletal muscles innervated by motor neurons localized in the same spinal cord segments as neural circuits controlling LUT function [surface EMG of the EAS (surrogate for EUS)].

Hypothesis: In light of recent findings on the efficacy of spinal cord stimulation to improve LUT function, the optimal parameters for EMG responses (i.e., mapping) will be revealed during TSCS.

Specific Aim 2 -Effect of Real-Time TSCS: To test the safety and efficacy of real-time TSCS in improving LUT function in individuals with sub-acute and chronic SCI.

Primary Outcomes: Voiding efficiency of the bladder [surface EMG of the EAS (surrogate EUS)]; continuous cardiovascular monitoring for TSCS-dependent changes in BP i.e., adverse cardiovascular events such as AD.

Hypothesis: The investigators hypothesize that acute TSCS will reproducibly and safely improve voiding and storage functions in LUT and elicit pelvic floor EMG without any cardiovascular adverse events.

Specific Aim 3 - Effect of Long-Term TSCS: To investigate the efficacy of long-term TSCS in mitigating the NLUTD in the sub-acute and chronic period following SCI.

Primary Outcomes: Neurogenic Bladder Symptom Score (NBSS). Secondary outcomes: UDI and TNFBM. Ancillary Outcomes: Neurogenic Bowel Dysfunction (NBD) Score, sexual function screening tool, Sexual Health Inventory for Men (SHIM) Questionnaire, IIEF, FSFI, FSDS, 24hr ABPM, International Standards for Neurological Classification of SCI (ISNCSCI), Patient Health Questionnaire -9 (PHQ-9), PTSD Checklist for DSM-5 (PCL-5), WHO Quality of Life-BREF (WHOQOL-BREF), and modified Ashworth Score (MAS). Outcomes will be performed at baseline, 8- and 16-weeks post TSCS. Follow-up assessments will be performed 8 weeks after cessation of treatment to assess the persisting effects of TCS.

Hypothesis: Long-term TSCS will promote bladder/bowel voiding and storage functions as well as improvements in sexual function.

Specific Aim 4 - Effect of Delayed Onset TSCS: To investigate the efficacy of delayed long-term TSCS in mitigating NLUTD in the sub-acute and chronic period following SCI.

Primary Outcomes: NBSS. Secondary Outcomes: UDI and TNFBM. Ancillary Outcomes: NBD Score, sexual function screening tool, SHIM Questionnaire, IIEF, FSFI, FSDS, 24hr ABPM, ISNCSCI, PHQ-9, PCL-5, WHOQOL-BREF, and MAS. Outcomes will be performed at baseline, 8 weeks (sham) and 16 weeks (after 8 weeks of TSCS therapy). Follow-up assessments will be performed after cessation of TCS to assess the persisting effects of TSCS.

Hypothesis: Based on our promising preliminary findings in chronic SCI, the investigators hypothesize that even with delayed onset, TSCS will promote bladder/bowel voiding and storage functions, as well as boost sexual function.

Primary Efficacy Endpoint: Reduction in NBSS score by 10 points at 8 weeks of therapy.

Secondary Efficacy Endpoint: Mean improvement in voiding efficiency by at least 50%. Mean reduction in TNFBM by at least 50%.

RESEARCH DESIGN:

Overall Research Design:

The study will include sixty adults (19 - 65 years, n=50 in Ukraine and n=10 in Canada) with a sub-acute (time since injury of 3-6 months) or chronic (time since injury 12+ months), motor-complete SCI [ASIA Impairment Scale (AIS) A or B] at spinal segments C5-T10, with documented impaired bladder function. The expected duration of study participation for each participant will be 33 weeks. Eligible Canadian participants enrolled into the study will attend 58 visits at ICORD.

Detailed Research Design:

The investigators propose a phase II, randomized, single-blinded, sham-controlled clinical trial to examine the effect of non-invasive TCS on LUT function in people with SCI. The investigators will include sixty adults (19 - 65 years, n=50 in Ukraine and n=10 in Canada) with a sub-acute (time since injury of 3-6 months, n=25 in Ukraine and n=5 in Canada) or chronic (time since injury 12+ months, n=25 in Ukraine and n=5 in Canada), motor-complete SCI [AIS A or B] at spinal cord segments C5-T10, with documented impaired LUT function. Individuals with SCI will be recruited at Rivne Regional War Veterans Hospital for the Ukrainian site, and at ICORD for the Canadian site. The rationale for including the Canadian cohort (n=10) is to control for the environmental impact such as potential differences in intensity of sub-acute and chronic rehabilitation and severity of war-related psychological impact on functional recovery. Furthermore, participants will be instructed to adhere to established bowel and LUT routines and refrain from initiation of new medications for bowel and LUT management without notifying the Principal Investigator of this study.

Secondary and ancillary outcomes will include assessments of bowel function, sexual functions, cardiovascular function and spasticity. Group 1 (G1; n=25 in Ukraine and n=5 in Canada) will receive therapeutic TSCS for 8 weeks (3 times per week; 1 hour per session) in conjunction with conventional rehabilitation (3-4 hours per day; 5 days per week). G2 (n=25 in Ukraine and n=5 in Canada) will receive 8 weeks of sham stimulation in conjunction with conventional rehabilitation. After 8 weeks, G2 will switch to therapeutic TSCS for 8 weeks (i.e., delayed onset of TSCS). G1 will continue to receive TSCS therapy for another 8 weeks for a total of 16 weeks.

STATISTICAL PLAN \& DATA ANALYSIS:

Short term changes in voiding efficiency and BP will be analyzed using paired t-tests (Aim 2). Primary and secondary outcome responder rates (i.e., proportion of participants realizing ≥10-point improvement from baseline in NBSS, 50% improvement in voiding efficiency, 50% reduction in TNFBM) will be analyzed using logistic regression (Aims 3 and 4). Primary, secondary, and ancillary outcomes will also be analyzed directly using mixed effects repeated measures models including fixed effects for treatment arm and country, and a random effect to account for nonindependence of repeated measurements within participants. Treatment-arm specific 95% confidence intervals will be constructed for all outcomes. Logistic, mixed effect models, and analysis of variance (ANOVA) (for short term changes in voiding efficiency and BP) will also incorporate interaction terms to examine differential effects associated with Ukraine-based vs Canada-based participants. Since the study is not powered for this assessment, interaction p<0.20 will be taken as evidence of possible differential effects and analyses limited to Ukraine-based participants only will be conducted separately. Interaction terms will also be included in mixed effects models to examine differential time trends between treatment arms (baseline to 8-week and 8-week to 16-week). Sham group 16-week outcomes will also be compared to experimental group 8-week outcomes (both having undergone 8 weeks of therapy to that point). Data transformations or nonparametric methods (e.g., Wilcoxon signed-rank test for paired data, Friedman test for nonparametric repeated measures) will be substituted in cases where distributional assumptions are not met. Analyses will include all participants completing each phase of the study; sensitivity analyses and multiple imputation will also be conducted as appropriate to examine the possible impact of attrition, which is expected to be low in this inpatient study. Analyses will not be corrected for multiple comparisons in view of the exploratory nature of many of the other outcomes.