Objective:  To compare change in urgency urinary incontinence episodes (UUIEs) in women undergoing posterior tibial nerve stimulation (PTNS) plus mirabegron to PTNS plus placebo for treatment of refractory urgency urinary incontinence (UUI) and OAB-wet symptoms.
Hypothesis:  Combination therapy of PTNS and mirabegron, a beta-3 agonist, will contribute to a greater
decrease in the number of urgency urinary incontinence episodes as measured by a 3-day bladder diary
compared to PTNS plus placebo in women.
Primary Aim: The primary aim of this study is to compare the efficacy of combined treatment of PTNS and
mirabegron versus PTNS plus placebo on change in the number of UUI episodes at 12 weeks.
Secondary Aims:
- Comparing urinary symptom specific distress and quality of life over a 12-week course of PTNS.
- Comparing the side effect/adverse event profile of combined treatment of PTNS and mirabegron
versus PTNS plus placebo over a 12-week course of PTNS

Methods:   A randomized controlled clinical trial was performed in individuals identifying as female > 18 years old with UUI and OAB-wet symptoms refractory to second-line treatment or who could not tolerate anticholinergic medications. Institutional Review Board approval was obtained.  Participants provided written informed consent, and both participants and providers were blinded to treatment allocation. Participants were randomized (1:1) to either PTNS plus mirabegron or PTNS plus placebo. Participants completed a 3-day bladder diary (baseline) prior to and post 12-week treatment of PTNS. Additionally, validated subjective symptom distress and impact questionnaires were also obtained pre- and post-treatment.  The primary outcome was change in number of UUIEs over a 3-day bladder diary pre- vs. post-treatment. Secondary outcomes included urinary frequency, SUIEs, nocturia, and total pad use on the 3-day bladder diary in addition to subjective outcomes measured by the Urogenital Distress Inventory (UDI-6), Overactive Bladder Questionnaire-Short Form (OAB-q SF), Incontinence Impact Questionnaire Short Form (IIQ-7) questionnaires, as well as adverse events. The primary outcome was analyzed via sample t tests; Chi-square tests or Fisher’s exact tests for categorical variables, and paired t-tests (intra-arm) for continuous variables were used as appropriate.  Analysis was per protocol including all women providing 12-week outcome data. A significance level was set at 0.05.

Results:  Fifty-four subjects were randomized with mean±SD baseline age 56.2 ± 15.6 and baseline BMI 35.0 ± 9.4 (kg/m2). There were no differences between arms in any clinical-demographic variables noted (Table 1). Eight patients (7 mirabegron, 1 placebo) did not complete the study due to non-compliance with the 12 week PTNS treatment.  There was a significant difference between the mirabegron arm and the placebo arm in changes pre-to post-treatment UUIEs (mirabegron arm 9.4 ± 3.9 versus placebo arm 5.3 ± 5.4, p=0.007).  Significant differences were found pre-to post-treatment between arms in urinary frequency (mirabegron arm 11.2 ± 6.8, placebo arm 6.1 ± 6.1, p=0.012), change in the OABq SF Symptom Bother score (mirabegron arm 53.6 ± 30.0, placebo arm 33.3 ± 35.7, p=0.048), and change in OABq SF Symptom HRQL score (mirabegron arm -32.7 ± 20.5, placebo arm -15.1 ± 19.6, p=0.005).  No significant differences were noted for other secondary outcomes (Table 2).  Significant differences were noted in all within-arm outcomes (Table 3). 90.0% of subjects in the mirabegron arm had > 50% reduction in UUI episodes compared to 23.1% in the placebo arm (p<0.001).  Adverse events included 3 patients in each arm who experienced UTIs which resolved with treatment.  Additionally, 3 patients in each arm reported transient leg swelling from PTNS treatments which resolved.  All patients who reported adverse events completed the full 12 week PTNS treatment protocol.

The results reveal that the mirabegron arm produced statistically significant improvement in both objective and subjective outcomes compared to the placebo arm.

Conclusion:  In subjects undergoing PTNS treatment for refractory UUI and OAB-wet symptoms, the addition of the β-3 agonist mirabegron produced significant improvement in both objective and subjective irritative bladder outcomes compared to PTNS plus placebo. These data should be considered and discussed with patients presenting to providers with refractory UUI bladder symptoms considering PTNS therapy.

Continence 7S1 (2023) 100749
DOI: 10.1016/j.cont.2023.100749