Hypothesis / aims of study
LTX is an oral selective serotonin reuptake inhibitor and a multifunctional serotonin agonist antagonist. Serotonin plays an important role in centrally and peripherally modulating the reflexes of continence/micturition; 5-HT potentiates the guarding reflex which allows continence by increasing urethral pressure and inhibiting the micturition reflex. Animal studies (1,2) have confirmed that LTX increases urethral pressure, urethral sphincter activity and bladder capacity. These data support the therapeutic potential of LTX for the treatment of 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
The study is a double blind randomized placebo-controlled parallel group phase 2 dose ranging study to evaluate the efficacy, safety and tolerability of 3 doses of litoxetine versus placebo BID in women with mixed urinary incontinence (MUI), defined as having at least 7 incontinence episodes per week (at least 3 of which are stress incontinence episodes). The study design includes a 2-week Screening Period; a 2-week, single-blind (subject blind) Placebo Run-in Period and a 12-week double-blind Treatment Period which is followed by a 1-week Dose-tapering Period. The single- blind Placebo Run-In period serves to control for the placebo effect, which is expected to be relatively large in this type of studies. To reduce bias and to estimate more accurate baseline values for efficacy, the number of incontinence episodes at baseline is defined as the average number of episodes recorded in the last seven days of the placebo run-in period.
Efficacy is measured by an electronic diary. The primary efficacy is defined as percentage (%) change from end of the Placebo Run-in Period to Week 12 in the number of incontinence episodes/24 hours, and absolute change from baseline is the lead secondary endpoint. The % change is a traditional and informative measure for responses expected to be small counts, e.g the magnitude of a reduction of 1 episode depends on the baseline measure; a reduction from 5 to 4 episodes (20%) is not as meaningful a change as a reduction from 2 to 1 episodes (50%) although both are 1 absolute episodes.
Patients reported outcomes are measured as secondary variables. To assess the impact of the urinary incontinence status on quality of life the Kings Health Questionnaire is performed throughout the study. To provide additional clinical information on the subjects’ condition and change the Patient Perception of Bladder Condition (PPBC) and the Patient Global Impression of Improvement (PGI-I) are used throughout the study as global measures for bladder function and to assess patient perception of severity and symptom change.
Safety and tolerability are assessed throughout the study.
One-hundred and forty four female subjects aged 18-75 years of age, of 195 subjects estimated to be randomized, suffering from MUI for at least 3 months are included in this blinded review of baseline characteristics and safety information. Patient recruitment is greatest in Ukraine, followed by Georgia, Poland, Canada, UK and France.
The recruited population have the following baseline characteristics (mean ± SD):
Age 56±12 (years)
BMI 27.6±3.1 (kg/m2)
Number of all incontinence episodes over 7 days: 43.9±21.9
Number of urge episodes over 7 days: 31.8±19.8
Number of stress episodes over 7 days: 21.1±11.1
The blinded assessment of baseline characteristics does not suggest any differences in the patient population across sites or across the participating countries. The patients report a significant degree of incontinence at baseline. The data also suggest that the patient population is willing, capable and competent to use a hand held electronic device for recording of the patient reported outcomes.
A blinded safety review of treatment emergent adverse events (TEAE) revealed that 43 subjects reported 75 TEAEs. One of these events (somnolence) was reported as an SAE. Five subjects were discontinued from blinded study medication due to TEAEs: the serious event of somnolence reported above; events of vomiting, nausea, hyperhidrosis, rash and weakness in 1 subject; tachycardia in 1 subject; dizziness, asthenia, and hypoesthesia in 1 subject; and migraine and dyspepsia in 1 subject - all of the events resolved. The most frequently reported TEAEs were nausea (8 subjects, 5.9%), somnolence (5 subjects, 3.7%), diarrhoea (4 subjects, 2.9%), and asthenia/fatigue (4 subjects, 2.9%), followed by dry mouth, vomiting, urinary tract infection, headache and insomnia (3 subjects, 2.2% each).
Interpretation of results
The study started in Q1 2017. The baseline data reported correspond to almost 75% of the targeted study population to be recruited. These baseline assessments show a random variability, without a trend for site or country variability. Blinded review of adverse events suggest LTX treatment in the female patient population suffering from MUI seems safe and tolerated.
These are the first clinical data obtained with LTX in a development program for UI. The data from this study in women with MUI will be complemented by an ongoing US study in men and women suffering from UI. Taken together, the ongoing LTX development program will explore the optimal dose level and posology (fixed dose, dose titration), and will include data obtained in female and male subjects.
In order to adequately evaluate potential psychiatric effects of LTX, patients with current treatment of depression are excluded from the study. In France subjects with a history (past 6 months) of depression in the subject or in a close family member are also excluded, and the MINI neuropsychiatric interview is used to further determine in/exclusion into the study. In the US study, patients with a current diagnosis or history (past 6 months) of depression are excluded, and patient questionnaires are used to characterize psychiatric status over the duration of the study. FDA has also agreed on a set of adverse event of psychiatric interest to be monitored.
To date, the blinded data safety review from 144 randomized subjects in the phase 2 study does not suggest that litoxetine treatment is associated with development or worsening of depression or any other psychiatric disease in subjects with mixed urinary incontinence.
The authors are indebted to all participating patients and investigators.