The Efficacy and Safety of PSD503 (phenylephrine 20% w/w) for Topical Application in Women with Stress Urinary Incontinence: A Phase II, Multi-Centre, Double-Blind, Placebo-Controlled, Cross-Over Study

ABSTRACT

Introduction: Stress urinary incontinence (SUI) is the involuntary leakage of urine during periods of increased abdominal pressure (e.g., coughing, running or lifting). It is caused by an incompetent urethral sphincter which may arise as a consequence of damage to the pelvic floor muscles sustained during pregnancy and childbirth. Pharmacological therapy includes the off-label use of sympathomimetic medication (alpha-adrenergic agonists), to enhance urethral tone and alleviate symptoms, however their associated cardiovascular side effects (e.g. hypertension) limits their utility. PSD503 (Plethora Solutions Ltd, London, UK) is a controlled dose topical gel, which contains the alpha-adrenergic agonist phenylephrine (20% w/w). It has been developed as a locally administered treatment for SUI, to increase urethral tone and provide symptomatic relief, in the absence of systemic side effects.

Objectives: The primary objective of this trial was to evaluate efficacy of topical PSD503, in the treatment of SUI in female patients (n = 12), by measuring percentage change in pad weight gain following an exercise stress pad test, from pre-dose to post-dose. Secondary objectives included measurement of phenylephrine plasma concentrations, the evaluation of blood pressure and pulse rate and assessment of safety and tolerability as compared to placebo.

Materials & Methods: The trial was of a 2-treatment, 2-period crossover design, which enabled within-subject comparison of PSD503 and placebo. There was a 3-10 day washout period between treatment periods. Patients with SUI (positive urinary stress test and urodynamic assessment; incontinence episode frequency > 7 and < 21 per week, as determined by a frequency volume chart) underwent a pre-dose exercise stress pad test, blood pressure and pulse assessment. A blood sample was taken to determine baseline phenylephrine plasma concentration. A single application of 0.25 mL PSD503 or 0.25 mL placebo was administered to the anterior vaginal wall, over the site of the internal urethral sphincter and urethra. The exercise stress pad test was then repeated 2 hours post-dose administration and blood pressure and pulse rate measured at various time points over a minimum period of 3 hours. Phenylephrine plasma concentrations were quantified at one and three hours post-dose administration.

Results: Application of PSD503 resulted in a median 54% reduction in leakage (as measured by change in pad weight) compared with a median 38% reduction with placebo. The reduction in median absolute change for PSD503 was 22% and 10% for placebo. The median pre-dose, one hour and three hour post-dose phenylephrine plasma concentrations were 0.00 ng/mL, 4.22 ng/mL and 1.645 ng/mL respectively. This finding was consistent with the observation that PSD503 did not elevate blood pressure or pulse rate in any of the subjects. PSD503 appeared to be well tolerated.

Conclusions: The results presented indicate that PSD503 may be an effective localised treatment for the reduction of the involuntary leakage of urine associated with SUI, which avoids side effects associated with systemic administration of alpha-adrenergic agonists.

KEYWORDS: Stress Urinary Incontinence (SUI); phenylephrine; topical; PSD503; exercise stress pad test; pharmacokinetics.

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