Treatment with litoxetine, an investigational oral selective serotonin reuptake inhibitor, led to nearly 22% of patients becoming continent.
Litoxetine, an investigational oral selective serotonin reuptake inhibitor and multifunctional serotonin agonist and antagonist, significantly reduced the rate of incontinence events and was safe and well tolerated in a placebo-controlled randomized phase 1/2 study of patients with urinary incontinence.
After 8 weeks of treatment, litoxetine at a dosage of 30 mg twice daily reduced the number of incontinence events by 1.96/day compared with a reduction of 0.76 events/day in patients randomized to placebo, for a treatment difference of 1.19 events/day (P = .017). In addition, 21.6% of subjects in the litoxetine arm versus 0% in the placebo arm became continent following treatment (P = .043), reported Roger Dmochowski, MD, at the 2020 European Association of Urology Virtual Congress.
“Overall, there was significant reduction in incontinence episodes in the active arm versus the placebo arm,” said Dmochowski, professor, Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville. “This particular serotonin reuptake inhibitor was safe and well tolerated with twice daily administration in the study population as defined. Tolerability was further improved by a dose escalation regimen and a fixed dose overall period for exposure. Litoxetine also significantly decreased incontinence episode frequency as compared to placebo.”
The therapeutic potential of litoxetine given twice daily was assessed in 84 patients aged 18 to 70 years old with urinary incontinence, defined as ≥7 incontinence episodes per week. Study subjects were entered into a 2-week screening placebo run-in period followed by 8 weeks of double-blind treatment during which they were randomized 2:1 to a dose-titration schema of litoxetine (n = 53) or placebo (n = 29). Patients randomized to litoxetine received 10 mg twice daily for 1 week followed by 20 mg twice daily for 1 week, and subsequently 30 mg twice daily for 6 weeks. Treatment was followed by a 1-week dose tapering period and 4 weeks of safety follow-up. Two patients were not treated due to randomization error. Incontinence events were measured by patient bladder diary.
Patients’ median age was 58.5 years, their median body mass index was 29.8 kg/m2, and median incontinence episode frequency was 17.5 events/week at baseline. About one-fourth (26%) were men.
In the randomized phase 1 portion of the study, in the overall study population, the decrease in the rate of incontinence events per week by dosage was 1.97 with 40 mg twice daily litoxetine, 1.94 with 20 mg twice daily, and 1.59 with 10 mg twice daily, compared with 1.37 in the placebo arm.
In patients with more severe urinary incontinence, the rate of incontinence events was reduced by 3.72/week with 40 mg twice daily of litoxetine (P <.05 vs placebo), 3.53/week with 20 mg twice daily of litoxetine (P <.05 vs placebo), 2.60/week with 10 mg twice daily of litoxetine, and 2.02/week in the placebo recipients.
The effect of litoxetine on incontinence episodes was found to be similar between men and women.
Scores on the Patient’s Perception of Bladder Condition (PPBC) showed gradual improvement from baseline to assessments made at weeks 4, 8, and 12. Following the treatment period, 56% of patients who receive 40 mg twice daily of litoxetine and 32% of patients assigned to placebo reported “no/very minor/some minor problems” on the PPBC.
Up to 71% of patients treated with 40 mg twice daily of litoxetine had a clinically significant improvement of ≥15% in the King’s Health Questionnaire (KHQ). More than 70% of the litoxetine group, irrespective of dosage, had an improvement of ≥10 units on the general health domain of the KHQ, versus 54% of the placebo group; 64% to 82% of litoxetine recipients had a ≥10-unit improvement on the physical limitations domain, versus 63% of the placebo group; 72% to 79% of those assigned to one of the litoxetine groups had a ≥10-unit improvement on the emotions domain, compared with 63% of the placebo group; and 59% to 74% of the litoxetine group had a ≥10-unit improvement on the sleep/energy domain versus 59% of the placebo arm.
Litoxetine was well tolerated: 3.8% of the patients on litoxetine discontinued the study due to a treatment-emergent adverse event (TEAE) compared with 3.4% of the placebo recipients. Some 37.7% of patients assigned to litoxetine and 34.5% assigned to placebo reported a TEAE. On logistic regression analysis, there was no statistical difference in TEAEs between study arms. Psychiatric evaluations did not show any difference between study groups. There were no serious adverse events in either arm.
Dmochowski is a scientific advisor to Ixaltis SA.
Dmochowski R. Litoxetine (LTX) shows significant treatment effect in urinary incontinence (UI). 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract 358.