Transcutaneous Tibial Nerve Stimulation in Acute Spinal Cord Injury

Study Overview
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Brief Summary
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Most patients with spinal cord injury (SCI) develop neurogenic lower urinary tract dysfunction (NLUTD), one of the most devastating sequelae of SCI which ultimately can lead to renal failure. We urgently need an intervention that prevents NLUTD before irreversible damage occurs. Neuromodulation procedures are a promising avenue so that we investigate the effect of transcutaneous tibial nerve stimulation (TTNS) in patients with acute SCI. This nationwide randomized, sham-controlled, double-blind multicentre clinical trial includes all SCI centres in Switzerland (Basel, Nottwil, Sion, Zürich). Patients are randomly assigned to VERUM TTNS (active stimulation, n=57) and SHAM stimulation (n=57) groups in a 1:1 allocation using computer-generated permuted block randomisation lists stratified on study centre and lower extremity motor score. Daily 30-minute sessions are performed five times a week during an intervention period of 6-9 weeks. The primary outcome of this study is the success of TTNS to prevent neurogenic DO jeopardizing the upper urinary tract, assessed by urodynamics at 1 year after SCI or any earlier time point if DO treatment is necessary (study end). Secondary outcome measures are bladder diary parameters, clinical symptom scores assessed by standardized and validated questionnaires. Furthermore, neurophysiological and neuroimaging outcome measures are assessed as well as, biochemical and molecular changes. Tertiary outcome measure is the safety of TTNS. Before the actual start of the TASCI RCT, start-up activities will include a piloting phase on groups of healthy volunteers and patients. The goal during this phase is to evaluate the feasibility of the experimental setup, in particular for the TTNS and SHAM intervention, but also to test the setup of the different pre and post assessments (e.g. neurophysiology and neuroimaging tests). Groups of up to 15 participants each will be enrolled in a few consecutive pilot studies allowing for fine tuning and small adaptations in between, if appropriate.

Official Title
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Transcutaneous Tibial Nerve Stimulation in Patients With Acute Spinal Cord Injury to Prevent Neurogenic Detrusor Overactivity: A Nationwide Randomised, Sham-controlled, Double-blind Clinical Trial

Conditions
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Spinal Cord Injury, Acute

Intervention / Treatment
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* Device: VERUM TTNS
* Device: SHAM TTNS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Patients with acute SCI (traumatic SCI and sudden onset (<7 days) non-traumatic SCI) within 40 days after injury Patients with acute SCI at cervical or thoracic level Willing to take part and follow the requirements of the TASCI protocol (up to one year after SCI) no percutaneous tibial nerve stimulation (PTNS) no functional electrical stimulation (FES), apart from upper limb FES no electrical muscle stimulation (EMS) Informed Consent Exclusion Criteria: Contraindications to the investigational product DO with contractions greater than 40 cmH2O at a bladder filling volume of less than 500mL at baseline visit Treatment with antimuscarinics or with mirabegron Known or suspected non-adherence, drug or alcohol abuse Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant Participation in another study with investigational drug or product within the 30 days preceding and during the present study Neuromodulation treatment for urological or bowel indication in the last six months or ongoing Botulinum toxin injections in the detrusor and/or urethral sphincter in the last six months Bilaterally absent tibial nerve compound muscle action potential (cMAP, amplitude < 1mV) Women who are pregnant or breast feeding Intention to become pregnant during the course of the study Individuals especially in need of protection (according to Research with Human Subjects published by the Swiss Academy of Medical Sciences [www.samw.ch/en/News/News.html]) Enrolment of the investigator, his/her family members, employees and other dependent persons Pre-existing or concomitant medical condition apart from SCI that might pose a safety issue or would interfere with interpretation of study results or study conduct (e.g. Parkinson's disease, neurodegenerative disorders including multiple sclerosis and amyotrophic lateral sclerosis, urological malignancies)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VERUM transcutaneous tibial nerve stimulation (TTNS)<br> | Device: VERUM TTNS<br>* Daily 30-minute TTNS intervention is performed 5 days a week during a treatment period of 6-9 weeks, until 3-month post assessments During a preparation phase of several minutes, sensory and motor thresholds are assessed and stimulation intensities are adjusted for the following 30-minute treatment phase<br>|
| Sham Comparator: SHAM transcutaneous tibial nerve stimulation (TTNS)<br> | Device: SHAM TTNS<br>* Daily 30-minute SHAM intervention is performed 5 days a week during a treatment period of 6-9 weeks, until 3-month post assessments During a preparation phase of several minutes, sensory and motor thresholds are assessed and stimulation intensities are adjusted for the following 30-minute treatment phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of neurogenic DO jeopardizing the upper urinary tract | Defined as composite measure: Urodynamic assessment establishing DO amplitude ≥40 cmH2O; or else initiation of DO treatment (with antimuscarinics and/or intradetrusor onabotulinumtoxinA injections) | up to 12 months after SCI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Volumetric changes during urodynamics and their relation to clinical outcomes | Cystometric capacity [mL], volume at first DO [mL], voided volume [mL] and post void residual [mL] as assessed by urodynamic measurement | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in bladder compliance [mL/cmH2O] during urodynamics and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Pressure changes during urodynamics and their relation to clinical outcomes | Maximum DO amplitude [cmH2O], detrusor leak-point pressure [cmH2O], maximum detrusor pressure [cmH2O] during storage phase, maximum detrusor pressure [cmH2O] during voiding phase, detrusor pressure at maximum flow rate [cmH2O] as assessed by urodynamic measurement | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in maximum flow rate [mL/s] as assessed by urodynamics and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in vesicoureterorenal reflux (VUR) as assessed by videography during urodynamics and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in pelvic floor activity as assessed by electromyography (EMG) during urodynamics and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in bladder storage and voiding parameters and their relation to clinical outcomes | Assessed by a bladder diary | Baseline; once every 2 weeks during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in bowel diary parameters and their relation to clinical outcomes | Assessed by a bowel diary | Baseline; once every 2 weeks during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in International Prostate Symptom (IPSS) questionnaire and their relation to clinical outcomes | The IPSS (International Prostate Symptom Questionnaire) score is based on questions concerning urinary symptoms and quality of life (QoL). It consists of 8 items covering 7 urinary symptoms related dimensions (subscales) and 1 additional item assessing quality of life. Each item is rated on a 6-point scale (0=not at all; 5=almost always). The lowest possible score in the total IPSS score is 0 (asymptomatic); the highest possible score is 35 (symptomatic). The QoL index is rated on a 7-point scale, with 0 indicating delighted and 6 terrible. | Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in urinary symptoms as assessed by the Urinary Symptom Profile (USP) questionnaire and their relation to clinical outcomes | The USP (Urinary Symptom Profile) score is based on questions concerning urinary symptoms and their severity in males and females. It consists of 13 items covering 3 dimensions (subscales) with 7 overactive bladder (OAB), 3 stress urinary incontinence (SUI), and 3 low stream (LS) related items. Each item is rated on a 4-point scale. The lowest score is 0 (asymptomatic); the highest score is 3 (symptomatic). | Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in Qualiveen questionnaire scores and their relation to clinical outcomes | Qualiveen-30 assesses the Specific Impact of Urinary Problems (SIUP) on Quality of Life. It consists of 30 items covering 4 domains, namely inconvenience (9 questions), restrictions (8 questions), fears (8 questions), and impact on daily life (5 questions). Each item is rated on a 5-point ordinal scale (0=asymptomatic; 4=symptomatic). The index of the SIUP on Quality of Life is the mean of the four individual scores. The lowest possible overall score in the Qualiveen-30 is 0 (Urinary problems have no specific impact on QoL); the highest possible score is 30 (Urinary problems have a huge specific impact on QoL). | Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in Female Sexual Function Index (FSFI) and their relation to clinical outcomes | The FSFI (Female Sexual Function Index) is based on questions concerning female sexual functions. It consists of 19 items covering 6 domains, namely sexual desire, arousal (both subjective and physiologic), lubrication, orgasm, satisfaction, and pain. The lowest possible score in the total FSFI is 2 (asymptomatic); the highest possible score is 36 (symptomatic). | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in International Index of Erectile Function (IIEF) and their relation to clinical outcomes | The IIEF (International Index of Erectile Function) is based on questions concerning erectile dysfunction. It consists of 15 items covering 5 domains, namely erectile functioning, orgasmic functioning, sexual desire, and intercourse satisfaction along with a fifth component which encompasses the concept of overall sexual satisfaction. While items 1-10 are rated on a 6-point Likert-type scale from 0 to 5, items 11-15 are rated on a 5-point Likert-type scale from 1 to 5. Higher scores are reflecting less dysfunction. Domain scores are computed by summing the sores for individual items in each domain. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in International Spinal Cord Society (ISCoS) Female / Male sexual function data sets and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in Neurogenic Bowel Dysfunction (NBD) score and their relation to clinical outcomes | The NBD (Neurogenic Bowel Dysfunction) score is based on questions concerning constipation and fecal incontinence and was developed for and validated in the spinal cord injury population. It consists of 10 items. The lowest possible score in the total NBD is 0 (asymptomatic); the highest possible score is 47 (symptomatic). The interpretation of the total NBD score is very minor NBD (0-6), minor NBD (7-9), moderate NBD (10-13), and severe NBD (≥14).The NBD score is assessed by using the international spinal cord injury (ISCoS) bowel function basic data set. | Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Volumetric changes during rectal sensitivity testing and barostat assessment and their relation to clinical outcomes | Initial sensation [mL], volume at urge to defecate [mL], maximum tolerated volume [mL] as assessed by rectal sensitivity testing; rectal capacity [mL] assessed by barostat assessment | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Pressure changes during anorectal manometry and barostat assessment and their relation to clinical outcomes | Basal internal anal sphincter pressure [mmHg], squeeze external anal sphincter pressure [mmHg], relaxation internal anal sphincter pressure during defecation [%, mmHg], intraabdominal pressure during defecation [mmHg] | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in rectal compliance [mL/cmH2O] during anorectal manometry and barostat assessment and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in defecatory disorder [Rao's classification] identified during anorectal manometry and their relation to clinical outcomes | Anorectal manometry is the preferable test for defecatory disorder. Rao's classification describes the four types of manometric patterns (I-IV) that are identified through manometric assessments | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) assessment to quantify the severity of the spinal cord injury | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in Lower Extremities Motor Scale (LEMS) from International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | LEMS is based on assessments of ISNCSCI and composed from the sum of muscle function grading of the five key muscles of the lower limbs. It consists of a 6-point scale (0=no; 5=normal activity) for each muscle and body site. The lowest possible score in the total LEMS score for one body site is 0 (symptomatic); the highest possible score is 50 (asymptomatic). | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in Upper Extremities Motor Scale (UEMS) from International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | UEMS is based on assessments of ISNCSCI and composed from the sum of muscle function grading of the five key muscles of the upper limbs. It consists of a 6-point scale (0=no; 5=normal activity) for each muscle and body site. The lowest possible score in the total LEMS score for one body site is 0 (symptomatic); the highest possible score is 50 (asymptomatic). | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in Spinal Cord Independence Measure III (SCIM-III) and their relation to clinical outcomes | The SCIM-III (Spinal Cord Independence Measure III) score is based on questions concerning independence of persons with a spinal cord injured. It consists of 19 items covering 3 domains, self-care, respiration and sphincter management, and mobility. The self-care subscale ranges from 0 to 20. The respiration and sphincter management subscale ranges from 0 to 40. The mobility subscale ranges from 0 to 40. Total score ranges from 0 (symptomatic) to 100 (asymptomatic). Higher scores reflect higher levels of independence. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in spasticity in the knee and elbow flexors and extensors from the Modified Ashworth Scale (MAS) assessment and their relation to clinical outcomes | The MAS is a 5-point nominal scale that uses subjective clinical assessments of muscle tone ranging from 0 - 'No increases in tone' to 4 - 'Limb rigid in flexion or extension'. A grade of (1+) indicates resistance in the movement. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in spasticity in daily life as assessed by the Spinal Cord Injury Spasticity Evaluation Tool (SCI-SET) questionnaire and their relation to clinical outcomes | The SCI-SET (Spinal Cord Injury Spasticity Evaluation Tool ) score is based on questions concerning the positive and negative effects of spasticity on different areas of daily life. Each of the 35 items are rated on a 7-point scale (-3=extremely problematic; 0=no effect; 3=extremely helpful). Calculations include counts and sum scores of areas of daily life where spasticity is problematic (count range: 0 to 35, sum score range: 35 to 0) or helpful (counts range: 0 to 35, sum score range: 0 to +35) as well as a mean score of all applicable items (range: -3 to +3) | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in neurophysiology measurements of evoked potentials (EPs) as well as nerve conduction measurements and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in lower urinary tract (LUT) neurophysiology: Current perception thresholds (CPTs) and LUT sensory evoked potentials (LUTSEPs) with their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in frequency power of surface electromyography (EMG) and electroencephalography (EEG) and their relation to clinical outcomes | Fast Fourier Transformation analysis for delta, theta, alpha, beta, and gamma band power as assessed via EEG of the cortex and EMG of the muscle | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in EMG and EEG coherence measures and their relation to clinical outcomes | Coherence for EEG and EMG signals computed as cortico-muscular, inter- and intra-muscular coherence for typical EEG/EMG frequency bands (delta, theta, alpha, beta, and gamma). | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in white and gray matter area in the lumbosacral enlargement (LSE) and their relation to clinical outcomes | White and gray matter areas are obtained by segmenting the T2*-weighted MRI images for white and gray matter at the level of LSE | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in white and gray matter area in upper cervical cord (at C2/C3) and their relation to clinical outcomes | Obtained by segmenting the T2*-weighted MRI images for white and gray matter at the vertebral level C2/C3. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in white and gray matter volume of the conus medullaris (CM) and their relation to clinical outcomes | White and gray matter volume are obtained by segmenting the T2*-weighted MRI images for white and gray matter in the CM | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in gray and white matter volume in the brain and their relation to clinical outcomes | Gray and white matter volume in the brain are computed by feeding the whole-brain T1-weighted MRI images into a voxel-based morphometry algorithm. Changes in the gray and white matter volume will be evaluated in urologically relevant brain areas. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in fractional anisotropy (FA) in the brain and spinal cord and their relation to clinical outcomes | FA is a common dimensionless measure used in Diffusion Tensor Imaging (DTI) studies and ranges from 0, isotropic movement of water molecules (e.g., cerebrospinal fluid), to 1, fully anisotropic movement of water molecules (e.g., fiber bundles). | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in diffusivity in the brain and spinal cord and their relation to clinical outcomes | Mean, axial, and radial diffusivity (MD, AD, RD) are common measures used in DTI studies providing information about the integrity of the underlying tissue. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in brain and spinal cord tissue microstructure and their relation to clinical outcomes | Quantitative tissue parameters assessed using MRI Multi-Parameter Mapping. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Expression profile of microRNA (miRNA) in urine and blood as well as their relation to clinical outcomes | MicroRNA (miRNA) sequencing is used to identify regulated miRNAs specific to TTNS intervention in urine and blood. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in inflammatory markers in bladder tissue, blood, and urine, as well as their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in levels of neurotransmitters (neurotrophins) in blood, and urine, as well as their relation to clinical outcomes | Analysis will be performed using ELISA to detect molecules likely to be involved in the underlying molecular mechanisms of neuromodulation. | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in the composition of urinary and stool microbiome and their relation to clinical outcomes | Gut and bladder microbial patterns are determined from stool and urine samples | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 
| Changes in bladder tissue and their relation to clinical outcomes |  | Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized, sham-controlled, double-blind trial, transcutaneous tibial nerve stimulation, spinal cord injury, neurogenic detrusor overactivity, neuromodulation, electrical stimulation, paraplegia; tetraplegia, urodynamics