Idiopathic overactive bladder (OAB) symptoms have a profound impact on the quality of life of the affected individuals. Neuromodulation of peripheral nerves in the lower limbs is considered a standard treatment method in patients who have failed previous behavioral therapy, pelvic floor exercises, and pharmacotherapy. Percutaneous or transcutaneous tibial nerve stimulation is most frequently used. 
Peroneal electrical Transcutaneous NeuroModulation (peroneal eTNM®) is a new method based on highly selective transcutaneous neuromodulation of the peroneal nerve. Its main advantage is an excellent efficacy/safety ratio, ease of use, and the possibility of home self-treatment. Recently, the randomized, active-controlled study demonstrated significantly better safety and excellent tolerability of peroneal eTNM® compared to solifenacin [1].
Both the absolute and relative numbers of treatment related adverse events (TRAE) in the peroneal eTNM® group were lower compared with those in the group of solifenacin recipients. Although the study was not primarily designed to compare efficacy variables, peroneal eTNM® was shown to be similarly effective as solifenacin in all assessed efficacy endpoints.
At the individual level, the urgency urinary incontinence is considered the most bothersome lower urinary tract symptom for both genders [2]. Therefore, the aim of the present study was to evaluate the safety and efficacy of peroneal eTNM® compared to solifenacin in the subgroup of patients suffering from OAB wet or mixed urinary incontinence. We hypothesized that peroneal eTNM® would be better tolerated and show comparable efficacy to solifenacin in the treatment of incontinent OAB patients.

The primary study was designed as a prospective, randomized, multicenter, active-controlled trial (EudraCT reg. Nr. 2019-003321-14). The study design has been described in detail previously [1]. 
In brief, the study enrolled adult treatment-naïve female patients with a clinical diagnosis of idiopathic OAB or mixed incontinence with the predominance of OAB symptoms lasting for at least 6 months. The inclusion criteria at baseline included ≥ one urgency episode grade 3 or grade 4 according to Patients Perception of Intensity of Urgency Scale (PPIUS) in course of 24 hours and frequency ≥ 8 times/24 hours as documented using the 7-day bladder diary. The exclusion criteria included urinary tract infection, significant prolapse of the pelvic organs, history of previous malignant disease in the pelvic area and any neurological disease that may affect urinary bladder function. 
After signing the informed consent, eligible subjects were randomized in a 2:1 ratio to receive 12 weeks of daily at home treatment with peroneal eTNM® for 30 minutes, or solifenacin 5mg once daily. The primary endpoint of this subgroup analysis was safety and tolerability, secondary endpoint was proportion of subjects who became continent at the end of treatment (EoT). Additional efficacy assessments included change in number of voids, nocturia, severe urgency episodes, urinary incontinence episodes, urgency urinary incontinence episodes/24 h; change in level of urgency; change in voided volume; and change in OAB V8 questionnaire total score after 12 weeks of therapy.
Statistical methodology
Due to mainly non-normal data distribution, descriptive statistics are presented using median and 25% and 75% interquartile ranges (IQRs) of the median unless indicated otherwise. The changes between the baseline and study intervals are shown as relative changes to indicate trend. Descriptive statistical analyses were performed with GraphPad Prism 9.0.0 (GraphPad Software, Inc., San Diego, CA).

Patients
Overall, of the 120 patients screened for the primary study, 77 were randomized and 71 completed the study. The subgroup analysis was performed in study participants who presented with at least one incontinence episode in 24 hours at baseline and completed the study according to protocol (n = 26 in the peroneal eTNM® group and n = 16 in the solifenacin group). Patient demographic and baseline characteristics are summarized in Table 1.  
Safety and tolerability 
In the peroneal eTNM® group, 17 adverse events were recorded, three of them were considered TRAE. One patient had mild abdominal pain for two days, one patient reported erythema/discomfort at the stimulation point, while one patient experienced moderate headache for twelve days. All TRAE resolved without sequelae and all patient were able to complete the study protocol. 
In the solifenacin group, 22 adverse events were recorded, nine of them were considered TRAE. They included dry mouth (n=6), sore throat (n=1), rash (n=1) and dyspepsia (n=1).  
One TRAE was judged as of moderate severity (rash), while eight were considered mild.
Efficacy 
In the peroneal eTNM® group, 13 (50%), 16 (62%), and 18 (69%) of patients became continent at week 4, week 8, and week 12 (EoT). The proportion of patients who became dry with the solifenacin treatment was 9/16 (56%) at week 4. In contrast to the peroneal eTNM® group, no further improvement was observed at week 8 (50%) and EoT (56%). Also, both treatment methods showed a significant and similar level of improvement in all bladder diary derived variables. In addition, we observed comparable improvement]in symptom severity score as measured by OAB V8 (Table 2).

In present subgroup analysis, the peroneal eTNM® showed favorable safety profile compared to solifenacin. Despite the higher number of patients treated with peroneal eTNM® (2:1 randomization), both the absolute and relative numbers of TRAEs in the peroneal eTNM® group were lower compared to those in the solifenacin group. 
Although the study was not primarily designed to compare efficacy variables, peroneal eTNM® showed efficacy similar to solifenacin in all assessed efficacy variables.

The data collected in this study confirm that OAB treatment using peroneal eTNM® has better safety profile and comparable efficacy to solifenacin in the subgroup of incontinent OAB patients. Future adequately powered studies are needed to assess the position of peroneal eTNM® in the treatment algorithm of the OAB.

Krhut J, Rejchrt M, Slovak M, Dvorak RV, Peter L, Blok BFM, Zvara P. Prospective, Randomized, Multicenter Trial of Peroneal Electrical Transcutaneous Neuromodulation vs Solifenacin in Treatment-naïve Patients With Overactive Bladder. J Urol. 2023 Apr;209(4):734-741.
Agarwal A, Eryuzlu LN, Cartwright R, Thorlund K, Tammela TL, Guyatt GH, Auvinen A, Tikkinen KA. What is the most bothersome lower urinary tract symptom? Individual- and population-level perspectives for both men and women. Eur Urol. 2014 Jun;65(6):1211-1217.

Continence 7S1 (2023) 100953
DOI: 10.1016/j.cont.2023.100953