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

Overview

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.

Interventions

• Device VERUM TTNS
  * 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
• Device SHAM TTNS
  * 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

Primary outcome measures

• The occurrence of neurogenic DO jeopardizing the upper urinary tract [Time frame: up to 12 months after SCI]

Secondary outcome measures (12)

• Volumetric changes during urodynamics and their relation to clinical outcomes [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Baseline; 3 months after SCI; 6 months after SCI; 12 months after SCI / study end]

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Prevention

Study locations

Switzerland · 4 centers

• Department of Neuro-Urology, Spinal Cord Injury Centre & Research, Balgrist University Hos — Zurich
• REHAB Basel — Basel
• Swiss Paraplegic Centre — Nottwil
• Spinal Cord Injury Department, Clinique romande de réadaption — Sion

Publications

• Birkhauser V, Liechti MD, Anderson CE, Bachmann LM, Baumann S, Baumberger M, Birder LA, Botter SM, Bueler S, Cruz CD, David G, Freund P, Friedl S, Gross O, Hund-Georgiadis M, Husmann K, Jordan X, Koschorke M, Leitner L, Luca E, Mehnert U, Mohr S, Mohammadzada F, Monastyrskaya K, Pfender N, Pohl D, Sadri H, Sartori AM, Schubert M, Sprengel K, Stalder SA, Stoyanov J, Stress C, Tatu A, Tawadros C, va PMID 32792454
• Liechti MD, van der Lely S, Stalder SA, Anderson CE, Birkhauser V, Bachmann LM, Brinkhof MWG, Curt A, Jordan X, Leitner L, Mehnert U, Mohr S, Pannek J, Schubert M, Kessler TM; TASCI Study Group. Update from TASCI, a Nationwide, Randomized, Sham-controlled, Double-blind Clinical Trial on Transcutaneous Tibial Nerve Stimulation in Patients with Acute Spinal Cord Injury to Prevent Neurogenic Detrusor PMID 31601539
• Anderson CE, Birkhauser V, Stalder SA, Bachmann LM, Curt A, Jordan X, Leitner L, Liechti MD, Mehnert U, Mohr S, Pannek J, Schubert M, van der Lely S, Kessler TM, Brinkhof MWG. Optimizing clinical trial design using prospective cohort study data: a case study in neuro-urology. Spinal Cord. 2021 Sep;59(9):1003-1012. doi: 10.1038/s41393-020-00588-z. Epub 2020 Nov 24. PMID 33235299
• Bueler S, Yiannakas MC, Damjanovski Z, Freund P, Liechti MD, David G. Optimized multi-echo gradient-echo magnetic resonance imaging for gray and white matter segmentation in the lumbosacral cord at 3 T. Sci Rep. 2022 Oct 3;12(1):16498. doi: 10.1038/s41598-022-20395-1. PMID 36192560
• Bueler S, Freund P, Kessler TM, Liechti MD, David G. Improved inter-subject alignment of the lumbosacral cord for group-level in vivo gray and white matter assessments: A scan-rescan MRI study at 3T. PLoS One. 2024 Apr 16;19(4):e0301449. doi: 10.1371/journal.pone.0301449. eCollection 2024. PMID 38626171
• Stalder SA, van der Lely S, Anderson CE, Birkhauser V, Curt A, Gross O, Leitner L, Mehnert U, Schubert M, Tornic J, Kessler TM, Liechti MD. Development of a Sham Protocol to Investigate Transcutaneous Tibial Nerve Stimulation in Randomised, Sham-Controlled, Double-Blind Clinical Trials. Biomedicines. 2023 Jul 7;11(7):1931. doi: 10.3390/biomedicines11071931. PMID 37509569
• Beghini L, Bueler S, Liechti MD, Jaffray A, David G, Vannesjo SJ. Optimized navigator-based correction of breathing-induced B0 field fluctuations in multi-echo gradient-echo imaging of the spinal cord. Magn Reson Med. 2025 Jul;94(1):215-230. doi: 10.1002/mrm.30475. Epub 2025 Mar 4. PMID 40034000
• Bueler S, Anderson CE, Birkhauser V, Freund P, Gross O, Kessler TM, Kundig CW, Leitner L, Mahnoor N, Mehnert U, Rothlisberger R, Stalder SA, van der Lely S, Zipser CM, David G, Liechti MD. Remote neurodegeneration in the lumbosacral cord one month after spinal cord injury: a cross-sectional MRI study. Ann Clin Transl Neurol. 2025 Mar;12(3):523-537. doi: 10.1002/acn3.52298. Epub 2025 Jan 27. PMID 39869509

Identifiers

NCT: NCT03965299 · 2019-00074

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗