A First-in-Patient, Multicenter, Double-Blind, 2-Arm, Placebo-Controlled, Randomized Safety and Tolerability Study of a Novel Oral Drug Candidate, CTP-499, in Chronic Kidney Disease.

The prevalence of chronic kidney disease (CKD) related to type 2 diabetes is increasing worldwide. In addition to standard of care, treatment with anti-inflammatory and antifibrotic agents such as CTP-499, a novel oral, multisubtype selective inhibitor of phosphodiesterases, may be important in CKD treatment. A phase 1b randomized, double-blind, placebo-controlled clinical trial of CTP-499 in CKD patients (25 active, 8 placebo) with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m(2) was conducted to assess safety and tolerability. Secondary outcomes included pharmacokinetics and exploratory effects on inflammatory and hematology markers. Patients received 600 mg CTP-499 or matching placebo tablets orally once daily for 2 weeks, then twice daily for 2 additional weeks. CTP-499 was well tolerated with no serious or severe adverse events, or adverse events leading to discontinuation. CTP-499 was rapidly absorbed and produced acceptable interpatient variability. Of the 5 metabolites (M1-M5), M5 was the most abundant in plasma and urine. Exposure to CTP-499 and metabolites was higher in CKD patients than previously reported in healthy volunteers. No statistically significant differences were detected between the CTP-499- and placebo-treated groups for any of the biomarkers tested. This study provides data supporting further evaluation of CTP-499 in CKD patients.

A Randomized Phase I Evaluation of CTP-499, a Novel Deuterium-Containing Drug Candidate for Diabetic Nephropathy.

To determine maximum tolerated dose and food effect for CTP-499, a novel agent being studied for the treatment of diabetic kidney disease. CTP-499 has demonstrated anti-inflammatory, anti-fibrotic and anti-oxidative activities in vitro as well as anti-inflammatory and renoprotective effects in a diabetic nephropathy (DN) model. Two studies were performed. Study 1 was a single-dose escalation study with 600, 1200, 1800, and 2400 mg doses of controlled-release (CR) CTP-499 and a 400 mg immediate release dose to aid in the development of prototype formulations of CTP-499. Study 2 was a food-effect study. Plasma concentrations of CTP-499 and its metabolites were measured to determine pharmacokinetic parameters in each study. Safety was assessed to determine tolerability. Doses up to and including 1800 mg were well tolerated. Cmax was either equivalent (CTP-499) or slightly lower (metabolites) for the fed condition, while overall exposure was equivalent (CTP-499) or slightly higher (metabolites) for the fed condition. The range of tolerated doses of CTP-499 and the effects of food on exposure were identified, contributing to selection of the dose for Phase II development.

Pharmacokinetics of once-daily trospium chloride 60 mg extended release and twice-daily trospium chloride 20 mg in healthy adults.

The objective of this study is to characterize the steady-state pharmacokinetics and compare the relative bioavailability of the extended-release capsule formulation of the antimuscarinic trospium chloride, developed for once-daily administration, and trospium chloride immediate-release tablets. This is a single-center, multidose, randomized, open-label, 2-period, 2-arm crossover, bioavailability study in healthy adult male and female subjects who are within 20% of their ideal body weight. Subjects receive trospium 60-mg extended-release capsules once daily and trospium 20-mg tablets twice daily for 10 days, each in a crossover manner. Twenty-four subjects are enrolled in the study. With multiple dosing of trospium 60 mg extended-release once daily versus 20 mg twice daily, lower geometric least squares mean area under the concentration-time curve from 0 to 24 hours (17 360 vs 28 590 pg.h/mL; ratio 61%; 90% confidence interval, 51-72) and maximum plasma concentration (1517 vs 2502 pg/mL; 61%; 90% confidence interval, 49-75) are observed. Furthermore, with trospium 60 mg extended-release versus 20 mg, median time to maximum plasma concentration is later (5.0 vs 4.5 hours) and half-life is longer (35.8 vs 27.2 hours). Trospium exposure is lower with multiple dosing of trospium 60 mg extended-release compared with trospium 20 mg twice daily. Thus, with the extended-release formulation, trospium concentrations are less likely to reach the threshold where adverse events may sometimes occur.

A validated patient reported measure of urinary urgency severity in overactive bladder for use in clinical trials.

PURPOSE: Overactive bladder (OAB) is a syndrome consisting of urinary urgency with or without urge incontinence, usually with increased urinary frequency and nocturia. In response to current limitations in OAB clinical research a new patient reported measure of urgency severity associated with OAB has been developed, namely the Indevus Urgency Severity Scale (IUSS). We report the measurement properties of the IUSS. MATERIALS AND METHODS: Validation study data were collected alongside a phase III clinical trial of 20 mg trospium chloride twice daily vs placebo in patients with OAB associated with urge incontinence. We evaluated IUSS item variability, known group, content, criterion and construct validity, test-retest reliability, responsiveness and respondent burden. RESULTS: A total of 658 patients were evaluated at baseline and 579 were reevaluated at week 12. IUSS demonstrated good item variability. Greater urgency severity was associated with increased symptom bother and worse health related quality of life, as measured by the OAB QOL questionnaire. IUSS had a significant positive association with essential clinical and quality of life outcomes, demonstrating content validity. IUSS was highly responsive to a decrease in the average number of patient toilet voids per 24 hours to 7 or fewer toilet voids and average urge incontinence episodes per 24 hours to zero. It discriminated between patients who had above and below the median number of toilet voids and urge incontinence episodes per 24 hours. IUSS also had good test-retest reliability and content validity, and it created minimal respondent burden. CONCLUSIONS: IUSS is a validated patient reported measure of urgency severity for collecting event specific information in the context of a clinical trial.

The overactive bladder-symptom composite score: a composite symptom score of toilet voids, urgency severity and urge urinary incontinence in patients with overactive bladder.

PURPOSE: To our knowledge there is no index in urology that yields a single, quantifiable and clinically interpretable measure of overactive bladder (OAB) symptoms, including urgency, 24-hour voiding frequency and urge urinary incontinence (UUI). Urgency is the most difficult of these symptoms to measure. The Indevus Urgency Severity Scale (Indevus Pharmaceuticals, Lexington, Massachusetts) was recently developed and validated to capture urgency severity per toilet void. The scale has been combined with 24-hour frequency and UUI episodes to create the OAB Symptom Composite Score (OAB-SCS). We present this composite score. MATERIALS AND METHODS: Two multicenter trials were performed to determine the effects of trospium chloride given as 20 mg tablets vs placebo. A total of 1,157 patients, including 581 who received placebo and 576 who received trospium, were randomly assigned to treatment. Daily OAB-SCS totals were obtained for each patient for each day during the 7-day diary collection period for every visit. RESULTS: The average baseline OAB-SCS value was 36. The mean change from baseline in the trospium and placebo groups was 5 and 1 OAB-SCS points in patients with mild OAB, 10 and 5 in patients with moderate OAB, and 13 and 9 in patients with severe OAB, respectively. CONCLUSIONS: The OAB-SCS discriminated between placebo and pharmacologically treated (trospium chloride) patients with OAB in this study. The OAB-SCS is an improvement over individual symptoms alone. It is easy to implement and interpret and it will prove to be a clinically relevant tool in clinical trials in which patient diary data are captured.

Shortening the NIH Stroke scale for use in the prehospital setting.

BACKGROUND AND PURPOSE: Prehospital stroke scales should identify stroke patients and measure stroke severity. The goal of this study was to identify a subset of the 15 items in the National Institutes of Health Stroke Scale (NIHSS-15) that measures stroke severity and predicts outcomes. METHODS: Using 2 distinct data sets from acute stroke clinical trials, we derived and validated shortened versions of the NIHSS (sNIHSS). Stepwise logistic regression and bootstrap techniques were used in selection of NIHSS-15 items. Areas under the receiver operator characteristic curve (C statistics) were used to compare predictive performance of logistic models incorporating differing versions of the NIHSS. RESULTS: The derivation analyses suggested the 8 NIHSS-15 items that were most predictive of "good outcome" 3 months after stroke, in order of decreasing importance: right leg item, left leg, gaze, visual fields, language, level of consciousness, facial palsy, and dysarthria. The sNIHSS-8 comprises all 8 and the sNIHSS-5, the first 5. In the validation models, C statistics were NIHSS-15=0.80, sNIHSS-8=0.77, and sNIHSS-5=0.76. Statistical comparisons suggested that the NIHSS-15 had better predictive performance than the sNIHSS-8 or the sNIHSS-5; the absolute difference in C statistics was small. There was no significant difference between the sNIHSS-8 and the sNIHSS-5. CONCLUSIONS: Much of the predictive performance of the full NIHSS-15 was retained with a shortened scale, the sNIHSS-5. Shortening the NIHSS-15 will facilitate its use during prehospital evaluations. The sNIHSS severity information may be useful to triage acute stroke patients in communities and to provide a baseline stroke severity for prehospital acute stroke trials.