Clinical trial NCT03965299: Transcutaneous Tibial Nerve Stimulation in Acute Spinal Cord Injury
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Spinal Cord Injury, Acute
Keywords: randomized, sham-controlled, double-blind trial
transcutaneous tibial nerve stimulation
spinal cord injury
neurogenic detrusor overactivity
neuromodulation
electrical stimulation
paraplegia; tetraplegia
urodynamics
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
name: Clinique Romande de Readaptation
name: Rehab Basel
name: Swiss Paraplegic Research, Nottwil
name: BioMedical Research Forschungslabor für Urologie, University of Bern
name: Translational Neuro-Urology Department of Biomedicine, University of Porto
name: Center for Lower Urinary Tract Research School of Medicine, University of Pittsburgh
First posted: 2019-05-29
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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)

Primary outcomes:
measure: The occurrence of neurogenic DO jeopardizing the upper urinary tract
timeFrame: up to 12 months after SCI
Secondary outcomes:
measure: Volumetric changes during urodynamics and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in bladder compliance [mL/cmH2O] during urodynamics and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Pressure changes during urodynamics and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in maximum flow rate [mL/s] as assessed by urodynamics and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in vesicoureterorenal reflux (VUR) as assessed by videography during urodynamics and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in pelvic floor activity as assessed by electromyography (EMG) during urodynamics and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in bladder storage and voiding parameters and their relation to clinical outcomes
timeFrame: Baseline; once every 2 weeks during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in bowel diary parameters and their relation to clinical outcomes
timeFrame: Baseline; once every 2 weeks during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in International Prostate Symptom (IPSS) questionnaire and their relation to clinical outcomes
timeFrame: Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in urinary symptoms as assessed by the Urinary Symptom Profile (USP) questionnaire and their relation to clinical outcomes
timeFrame: Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in Qualiveen questionnaire scores and their relation to clinical outcomes
timeFrame: Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in Female Sexual Function Index (FSFI) and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in International Index of Erectile Function (IIEF) and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in International Spinal Cord Society (ISCoS) Female / Male sexual function data sets and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in Neurogenic Bowel Dysfunction (NBD) score and their relation to clinical outcomes
timeFrame: Baseline; once per week during the TTNS intervention period; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Volumetric changes during rectal sensitivity testing and barostat assessment and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Pressure changes during anorectal manometry and barostat assessment and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in rectal compliance [mL/cmH2O] during anorectal manometry and barostat assessment and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in defecatory disorder [Rao's classification] identified during anorectal manometry and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in Lower Extremities Motor Scale (LEMS) from International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in Upper Extremities Motor Scale (UEMS) from International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in Spinal Cord Independence Measure III (SCIM-III) and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in spasticity in the knee and elbow flexors and extensors from the Modified Ashworth Scale (MAS) assessment and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: 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
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in neurophysiology measurements of evoked potentials (EPs) as well as nerve conduction measurements and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in lower urinary tract (LUT) neurophysiology: Current perception thresholds (CPTs) and LUT sensory evoked potentials (LUTSEPs) with their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in frequency power of surface electromyography (EMG) and electroencephalography (EEG) and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in EMG and EEG coherence measures and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in white and gray matter area in the lumbosacral enlargement (LSE) and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in white and gray matter area in upper cervical cord (at C2/C3) and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in white and gray matter volume of the conus medullaris (CM) and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in gray and white matter volume in the brain and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in fractional anisotropy (FA) in the brain and spinal cord and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in diffusivity in the brain and spinal cord and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in brain and spinal cord tissue microstructure and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Expression profile of microRNA (miRNA) in urine and blood as well as their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in inflammatory markers in bladder tissue, blood, and urine, as well as their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in levels of neurotransmitters (neurotrophins) in blood, and urine, as well as their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in the composition of urinary and stool microbiome and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
measure: Changes in bladder tissue and their relation to clinical outcomes
timeFrame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end
Other outcomes:
measure: Incidence of side effects as well as number and intensity/severity (mild/moderate/severe) of adverse events (AEs) and serious adverse events (SAEs) for the following categories:
timeFrame: During complete study period, up to 12 months
Locations:
city: Basel
country: Switzerland
facility: REHAB Basel
city: Nottwil
country: Switzerland
facility: Swiss Paraplegic Centre
city: Sion
country: Switzerland
facility: Spinal Cord Injury Department, Clinique romande de réadaption
city: Zürich
country: Switzerland
facility: Department of Neuro-Urology, Spinal Cord Injury Centre & Research, Balgrist University Hospital
Study officials:
affiliation: University of Zurich
name: Thomas M. Kessler, Prof. Dr. med.
role: STUDY_CHAIR
affiliation: Balgrist University Hospital
name: Thomas M. Kessler, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Balgrist University Hospital
name: Armin Curt, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Swiss Paraplegic Research, Nottwil
name: Martin Brinkhof, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Swiss Paraplegic Centre
name: Jürgen Pannek, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
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