Hypothesis / aims of study
Overactive Bladder (OAB) is a serious and prevalent condition, with symptoms affecting approximately 1 in 6 adults . OAB symptoms, especially urinary incontinence, have a profound negative impact on patients’ quality of life . Current oral therapies for OAB are hampered by high rates of adverse events, poor treatment compliance, and limited efficacy, especially in patients with more substantial disease burden. Advanced therapies demonstrate improved efficacy but require more invasive administration procedures and incur limiting adverse events as well. A substantial need exists for therapies with better efficacy, reduced adverse events, and improved patient convenience and compliance.
TAR-302 is a novel drug-device combination product that continuously delivers trospium chloride into the bladder urine for prolonged periods of time. Preclinical models have demonstrated that TAR-302 is well tolerated and produces local drug levels several fold higher than those that can be achieved with oral dosing, without appreciable systemic exposure. This therapy is being investigated for the management of OAB symptoms in patients not sufficiently controlled by oral therapies.
Study design, materials and methods
This open label Phase 1b study evaluated the safety, tolerability, and preliminary efficacy of TAR-302 in patients with idiopathic overactive bladder (iOAB) refractory or intolerant to oral therapy. Study subjects were required to have at least 4 incontinence episodes over 3 days at study entry. Subjects received a single administration of TAR-302 for 42 days of intravesical dwell time. TAR-302 was placed with an insertion catheter and removed via cystoscope. Pharmacokinetic (PK) analyses were conducted in blood and urine. Response to TAR-302 was assessed using 3-day voiding incontinence diaries and quality of life was assessed using the OAB-q Short Form (OAB-q SF).
11 subjects successfully completed the study. Baseline characteristics are presented in Table 1. TAR-302 was well tolerated throughout the study: AEs potentially related to TAR-302 were all mild, and included hematuria (n=4), bladder discomfort (n=2), and bladder pain (n=2). There was only 1 AE observed typical of antimuscarinic exposure: a single report of transient dry mouth on day 36, which resolved spontaneously. 2 subjects experienced UTIs, which were considered potentially related to insertion procedures.
PK analyses demonstrated urine that trospium levels averaged 3.27 µg/mL across the study, well above predicted urine levels achieved with oral trospium (0.5-1 µg/mL) . These intravesical concentrations produced negligible systemic exposure (average: 0.22 ng/mL).
Subjects experienced a mean reduction of 75% in daily urge incontinence (UI) episodes, from 5.57 events per day at baseline to 1.4 events at Day 42 (p<0.01). 3 of the 11 subjects were fully continent at Day 42. Subjects also experienced clinically and statistically significant improvements in both symptom bother and health-related quality of life, as measured by the OAB-q SF: mean scores on the symptom bother subscale decreased by 41 points (74 at baseline, 33 at day 42, p<0.01), and mean scores on the HRQOL subscale increased by 45 points (32 at baseline, 77 at day 42, p<0.001).
Surprisingly, subjects appeared to experience durable symptom benefit well after removal of TAR-302 at Day 42, despite no further therapeutic intervention during this period. Mean UI episodes remained significantly lower than baseline at Day 84 (2.67 UI episodes/day, -52%, p<0.05); additional measures of UI improvement are noted in Table 2. Further, clinical (though not statistical) improvements on both OABq-SF subscales were also observed at Day 84: symptom bother decreased by 19 points (74 at baseline vs. 55 at Day 84), and HRQOL increased by 18 points (32 at baseline vs. 50 at Day 84; minimum clinically meaningful change = 10 points).
Interpretation of results
TAR-302 demonstrated encouraging safety, tolerability, and preliminary efficacy in the management of symptoms for patients with urge urinary incontinence insufficiently controlled with oral therapies.