Wireless, Implantable Tibial Nerve Stimulator System for the Treatment of Refractory Lower Urinary Tract Symptoms in Patients With Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
Prevalence of lower urinary tract symptoms (LUTS) in patients with multiple sclerosis (MS) increases with disease duration. Current management of urinary clinical symptoms in MS is mainly conservative. Its long-term outcome is often poor because of the progressive disease course and the treatment related side effects. Alternative therapeutic options are botulinum toxin injections, electrical stimulation of dorsal penile/clitoral nerve, and sacral nerve modulation. Posterior tibial nerve stimulation (PTNS) is a second minimally invasive method of electrical stimulation. Multiple benefits may derive from the development and validation of a dedicated protocol of a new self-activated neuromodulation therapy, which may improve therapy compliance/effectiveness, quality of life and social life in MS patients with refractory LUTS. Furthermore, it may contribute to reduce outpatient visits, health costs and work absenteeism.

Official Title
-----------------
Prospective Single Centre Trial of Percutaneous Tibial Nerve Stimulation With the Implantable StimRouter Neuromodulation System for the Treatment of Refractory Lower Urinary Tract Symptoms in Patients With Multiple Sclerosis

Conditions
-----------------
Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
-----------------
* Device: StimRouter®, Self-activated and self-controlled neuromodulation device (Bioness Inc, CE0086).


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female aged 18 - 80; Diagnosis of multiple sclerosis according to McDonald [20]; Clinical stability over the past 6 months (no relapses and no disability progression, defined as worsening of ≥1 point in the EDSS score if reference EDSS is ≤5.5, and ≥0.5 points if reference EDSS is>5.5); One or more of: urinary frequency greater than 8 times/24 hours, urinary urge incontinence at least 2 episodes in 24 hours on 3-day voiding diary; Urodynamic diagnosis of detrusor over-activity (DOA)and / or detrusor-sphincter dyssynergia (DSD); Previous failure of conservative treatments (challenge over ≥6 months) i.e. lifestyle modification-fluid consumption, behavioral modification, and pharmacological therapy and stable OAB medications for at least 30 days; No pharmacological treatment of overactive bladder (antimuscarinics and beta-3 agonists) for 2 weeks prior to screening; Positive response to ongoing PTNS treatment defined as ≥50% reduction in urinary frequency, and/or ≥50% fewer incontinence episodes, or a return to normal voiding frequency (<8 voids/day), based on retrospective diary review (treatment compliant and non-compliant patients) or PTNS treatment naïve able to sense tibial nerve stimulation (to be tested with TENS exam). Competent sphincter mechanism and normally functioning upper urinary tract; Leg circumference in the range of 20-30 cm at implantation site; No contraindications for surgical intervention (e.g. being immunocompetent, no anticoagulant treatment, no current infection); For female patients: using effective contraceptive methods; Ability to comply with study requirements; Having provided written informed consent. Exclusion Criteria: Previous participation in another study with any investigational drug or device within the past 90 days; Any metal implant in the area of StimRouter lead implantation site; Anatomical defects that preclude use of the device; Treatment with botulinum toxin injections, urinary incontinence surgery or implantation of artificial graft material, spinal or genitourinary surgery, abdominoperineal resection of the rectum or radical hysterectomy (female)/ prostatectomy (male) within the last 6 months; Previous treatment with sacral neuromodulation; Diagnosis of pelvic pain disorders, stress incontinence, current urinary tract infection, urinary stone and/or urinary tract malignancy; cystocele, enterocele or rectocele of grade 3 or 4; Critical limb ischemia; Previous or current pelvic radiotherapy and/or chemotherapy; Severe uncontrolled diabetes; Being prone to excessive bleeding; Having a pacemaker or implantable defibrillator or other neural stimulation systems; Exposure to diathermy or electrocautery; Clinically significant peripheral neuropathy; Neutropenic or immune compromised; Pelvic radio- and/or chemotherapy; Morbid obesity (BMI >40); Pregnant or lactating women, or women planning a pregnancy during the study, <9 months post-partum; Male: alpha-blocker for benign prostatic hyperplasia; Allergy to local anesthetic or adhesive; Life expectancy <1 year.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective, interventional, single center
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: With stimulation<br>Implantation of device electrodes subcutaneous in lower tibia area; stimulation of posterior tibial nerves. | Device: StimRouter®, Self-activated and self-controlled neuromodulation device (Bioness Inc, CE0086).<br>* Regimen 1 (weeks 0-12): one stimulation every 2 days, for a duration of 30 minutes each. Regimen 2 (weeks 12-24): Three stimulation treatments per week, for a duration of 30 minutes each.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in bladder volume | filling volume at the time of the first uninhibited detrusor contraction during cystometry | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cystometric capacity (mL) | Video-urodynamic parameter | 6 months | 
| Compliance (ml/cmH20) | Video-urodynamic parameter | 6 months | 
| Maximum detrusor pressure (cmH20) during storage phase | Video-urodynamic parameter | 6 months | 
| Maximum detrusor pressure (cmH20) during voiding phase | Video-urodynamic parameter | 6 months | 
| Voided volume (mL) | Video-urodynamic parameter | 6 months | 
| Maximum flow rate (mL/s) | Video-urodynamic parameter | 6 months | 
| Post void residual | Video-urodynamic parameter | 6 months | 
| Pelvic floor electromyographic activity (normal/detrusor sphincter dyssynergia/non-relaxing pelvic floor) | Video-urodynamic parameter | 6 months | 
| Number of voids/day | 3-day voiding diary | 3, 4.5, 6 months | 
| Volume voided/void | 3-day voiding diary | 3, 4.5, 6 months | 
| Number of leaks per day | 3-day voiding diary | 3, 4.5, 6 months | 
| Degree of urgency prior to void | 3-day voiding diary | 3, 4.5, 6 months | 
| Number of CISC through the day | 3-day voiding diary | 3, 4.5, 6 months | 
| Residual urine volume | 3-day voiding diary | 3, 4.5, 6 months | 
| Multiple Sclerosis Quality of Life-54 (MSQOL-54) | 54 items, two summary scores: physical health and mental health, range 0-100, a higher score indicates a better quality of life | 3, 4.5, 6 months | 
| Over active bladder questionnaire (OAB) | Symptom severity of OAB range 6-36, higher score values indicate greater symptom severity or bother, lower scores indicate minimal symptom severity. Health related quality of life (HRQL) subscales (coping, sleep, and social), range 13-78, Higher scores indicate better HRQL. | 3, 4.5, 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
overactive bladder, posterior tibial nerve stimulation, lower urinary tract symptoms