Efficacy of sacral neuromodulation versus placebo in patients with multiple sclerosis with neurogenic lower urinary tract, bowel, and sexual dysfunction: study protocol for a multicenter randomized placebo-controlled trial

Background Multiple sclerosis (MS) is frequently accompanied by neurogenic lower urinary tract dysfunction (NLUTD). Sacral neuromodulation (SNM) is a guideline-endorsed therapy for refractory urinary symptoms, but evidence in NLUTD remains limited. We aim to provide robust efficacy data. Methods Since August 2023, this multicenter, placebo-controlled, double-blind, superiority, randomized trial has enrolled adults with MS and NLUTD refractory to guideline-endorsed therapies. All participants undergo a 1-month test phase with a tined lead and external stimulator, and responders (≥ 50% improvement in at least one group-specific bladder diary variable) receive an implantable pulse generator (IPG). After a 1-month optimization period, participants are randomized 1:1 to active (IPG ON) or placebo (IPG OFF) treatment for 4 months. Blinding is maintained through subsensory stimulation. Bladder diaries and questionnaires are collected at baseline, post-test phase, after optimization, midterm, and study end (total duration 6 months). Urodynamics are performed at baseline and at study end. The primary objective is to determine whether continuous SNM is more effective than placebo in sustaining symptom improvement over time. The primary outcome is the proportion of participants with a confirmed response at randomization (C) who, 4 months after randomization (E), still show ≥ 50% improvement from baseline in at least one group-specific bladder diary variable. The proportions maintaining this response are compared between the IPG ON and IPG OFF groups. Secondary outcomes include changes in bladder, bowel, and sexual function (ICIQ), health-related quality of life (EQ-5D-5L), treatment satisfaction (Global Assessment Score, GAS), urodynamic measures, safety monitoring, and effective stimulation parameters. The primary outcome will be analyzed by logistic regression and continuous secondary outcomes by linear mixed models; subgroup analyses are exploratory. Assuming success rates of 0.5 (SNM) versus 0.15 (control), 27 patients per group are required (power 0.8, α = 0.05); 30 per group will be randomized (approximately 86 enrolled) to allow for dropouts. Discussion This trial will provide high-quality evidence on SNM in a well-defined MS cohort and may help refine patient selection and define the role of SNM in the management of lower urinary tract dysfunction. Trial registration ClinicalTrials.gov NCT05380856. Registered on 19 May 2022.