Hypothesis / aims of study
Serotonin plays an important role in modulating continence/micturition, 5-HT potentiates the guarding reflex which allows continence by increasing urethral sphincter pressure and inhibiting the micturition reflex. Animal studies1,2 showed that LTX, an oral selective serotonin reuptake inhibitor and multifunctional serotonin agonist and antagonist, increases urethral pressure, urethral sphincter activity and bladder capacity. The serotonin selectivity of litoxetine, and the weaker affinity for epinephrine, norepinephrine and dopamine transporters, have the potential to provide a good cardiovascular safety profile and reduce the risk of nausea which is the most frequent side effect following treatment with serotonin reuptake inhibitors.
Taken together, these data suggest a useful therapeutic potential for LTX in subjects with urinary incontinence (UI) and specifically mixed urinary incontinence (MUI). Approximately 35% of women affected by UI suffers from the subtype MUI. As there is currently no medical treatment available for MUI, this represents a significant unmet medical need.
Study design, materials and methods
An RCT phase 2 study was conducted to evaluate efficacy, safety and tolerability of 3 doses of LTX (LTX40, LTX20, LTX10 mg) versus placebo (PBO) BID in women with Mixed Urinary Incontinence (MUI). MUI was defined as at least 7 incontinence episodes (IE) per week, at least 3 of which were stress IEs. The design comprised a 2-week screening period followed by a 2-week single (subject)-blind PBO run-in period, with the purpose to mitigate any placebo effect. Subjects who remained incontinent (having at least 7 events/ week 3 of which were stress IEs) after the placebo run in period were randomized to the 12-week double-blind Treatment Period (LTX40, 20, 10 mg or placebo BID) followed by a 1-week dose-tapering period3. Efficacy was measured by an electronic diary over 7 days and was measured as percentage change in number of IE from end of the PBO run-in period to week 12. Patient‘s perception of treatment was measured by Patient Perception of Bladder Condition (PPBC) at week 4, 8 and 12 while Kings Health Questionnaire (KHQ), and Patient Global Impression of Improvement (PGI-I) were evaluated at week 12. A responder analysis was also conducted for the patient reported outcomes. Safety and tolerability were assessed throughout the study.
198 subjects (57±12 years of age with an average 44±21 IEs/week) were randomized. All subjects in the study experienced a statistically significant improvement in their UI condition over 12 weeks of treatment. Based on adjusted means, LTX40 numerically reduced IE 23% more effectively than PBO in the overall study population and reduced IE 45% more effectively than PBO in a patient population with more severe UI after 12 weeks of treatment.3
Improvement in PPBC was noted in all study groups at week 4, when changes in the PBO seems to plateau while the improvement for the litoxetine treated groups continue to improve through the duration of the study. At the end of the study (week 12), the reduction in PPBC from baseline was most pronounced in the 40 mg BID treatment group (p=0.012 vs PBO) (Fig 1).
To determine whether the effect of litoxetine was clinically meaningful in terms of patient’s perception of treatment effect, a “responder” analysis was conducted. “Clinically meaningful” was defined as an improvement by 2 units (PPBC, PGI-I) or 15% (KHQ), These patient-reported impressions of improvement are summarized in Table 1.
Treatment with litoxetine was safe and well tolerated: 10 subjects terminated the study prior to completing the 12week study period due to adverse events (AE). One of these AEs (somnolence) was reported as an SAE and occurred in the LTX40 group. Treatment-emergent AEs which were observed in at least 2% of all litoxetine-treated subjects and had at least 2 times greater incidence than in the placebo group included nausea, headache, asthenia/fatigue, hypertension, vomiting, diarrhoea and rash. These TEAEs could be considered as adverse drug reactions (ADRs) for litoxetine treatment in female subjects with urinary incontinence. The most frequently reported AE in LTX treated subjects was nausea, which was reported in 12%, 10%, 6% and 2% of subjects in the LTX40, 20, 10 and PBO groups respectively.
Interpretation of results
This RCT has demonstrated a clinically meaningful treatment effect of litoxetine in women with MUI. The effect was more pronounced (up to 45% beyond PBO, p<0.05) in patients with more severe UI. The improvement in incontinence frequency was accompanied by improvement in Patient Reported Outcomes. This improvement, observed already after 4 weeks of treatment, continued to improve throughout the 12-week treatment period in LTX treated subjects. After 12 weeks of treatment a large proportion of patients report improvements of a magnitude considered clinically meaningful across 3 different questionnaire tools. LTX appears to be well tolerated.