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The mainstay of pharmacologic treatment of overactive bladder is anticholinergic therapy. Cholinergic blockade is efficacious in decreasing the symptoms of urgency, frequency, and urge incontinence, but also is associated with undesirable side effects such as dry mouth, blurred vision, constipation, and central nervous system side effects. The property of anticholinergic agents that has been associated with increased efficacy and tolerability is receptor specificity. The safety of anticholinergic agents has been associated with the pharmacokinetics, metabolism, protein binding, and ability to penetrate the blood brain barrier. Trospium chloride, available in Europe for more than 20 years and under review by the US Food and Drug Administration for the treatment of overactive bladder, is a quaternary amine that is minimally metabolized, not highly protein-bound, and theoretically should not cross the blood brain barrier. Some of the characteristics of this unique anticholinergic agent are reviewed in this article and the relative contributions of these factors are discussed.

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Word count: 250/250Purpose: To evaluate long-term safety and durability of response to UGN-101, a mitomycincontaining reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma (UTUC). Materials and Methods:In this open-label, single-arm, multi-center, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade UTUC received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology, and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method.Treatment-emergent adverse events (TEAEs) were monitored. Results:Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term follow up; 23/41 patients (56%) remained in complete response after 12 months (95% CI: 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI: 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs.

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Background: Evidence-based clinical practice relies on unbiased reporting of negative results. Meta-analysis of drug safety and efficacy across many clinical trials is difficult given the unconstrained nature of reasons that are provided to ClinicalTrials.gov to explain clinical trial terminations. Methods and Findings:We scanned all trials in ClinicalTrials.gov marked with the "terminated" status (N=3122), meaning the trial had been stopped before the scheduled end date.Under the current reporting framework, any number of reasons may be given for termination, and these need not conform to a controlled vocabulary. Here we develop a controlled vocabulary for trial termination, and map each terminated trial to as many as three vocabulary terms.Mapping to this "ontology of termination" allows further analysis and conclusions. First, we identify the subset of terminated trials that ended citing safety concerns (6.2%) or failure to establish efficacy (10.8%), and were further able to stratify these rates across trials of different phases. Second, we examine termination reasons where a stricter data model could have preserved more evidentiary value, either because the data model was misused (7.6%) or because the given reason le unclear whether the decision to terminate was based on analysis of the data (74.9%, with 20.4% mentioning a decision-maker that may have had access to the data).ird, we show that imposing a controlled vocabulary of reasons for termination would avoid ambiguity and improve the evidentiary value of clinical trials. Conclusions:We encourage wider use of an "ontology of termination" and propose four questions that should be posed on trial termination. ese simple steps would promote transparency and enable ready access to negative trial results for meta-analysis.