Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies.

BACKGROUND: Revefenacin (TD-4208) is a potent, lung-selective, long-acting muscarinic antagonist currently in development as a once-daily nebulized therapy for chronic obstructive pulmonary disease (COPD). We evaluated the pharmacodynamics (bronchodilator activity), pharmacokinetics (PK) and safety of single- and multiple-dose administrations of revefenacin in two clinical trials (Study 0059 and Study 0091) in patients with moderate to severe COPD. METHODS: In Study 0059, 32 patients were randomized to receive a single dose of revefenacin (350 or 700 µg), active control ipratropium (500 µg) or placebo inhalation solution administered via standard jet nebulizer in a double-blind, crossover fashion. In Study 0091, 59 patients were randomized to receive once-daily inhalations of revefenacin (22, 44, 88, 175, 350 or 700 µg) or placebo for 7 days in a double-blind, incomplete block, five-way crossover design. The primary efficacy endpoint was change from baseline in peak (0-6 h) forced expiratory volume in 1 s (FEV1) in Study 0059, and trough FEV1 after the final dose (Day 7) in Study 0091. In both studies, secondary endpoints included area under the FEV1-time curve (FEV1 AUC) values from time 12-24 h post dose and FEV1 AUC values from time zero to 24 h post dose. RESULTS: Revefenacin demonstrated a rapid onset and sustained duration of bronchodilator action in both studies. In Study 0059, mean peak FEV1 was significantly higher (p < 0.001) for revefenacin and ipratropium compared to placebo, with differences of 176.8 mL for 350 µg revefenacin, 162.2 mL for 700 µg revefenacin and 190.6 mL for ipratropium. In Study 0091, mean trough FEV1 on Day 7 was significantly higher (p < 0.006) for all revefenacin doses compared to placebo, with differences ranging from 53.5 mL (22 µg dose) to 114.2 mL (175 µg dose). The results for the other spirometry endpoints were consistent with the primary endpoint for each study, demonstrating that the bronchodilator effect of revefenacin lasted more than 24 h following nebulized administration. Revefenacin was rapidly absorbed and extensively metabolized, followed by a slow apparent terminal elimination and minimal accumulation with repeated dosing. In both studies, adverse events were generally mild and occurred with similar frequencies in all groups, with no indication of significant systemic anti-muscarinic activity at any dose. CONCLUSIONS: Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure.

Validity of self-reported smoking status among participants in a lung cancer screening trial.

Lung cancer remains a devastating disease associated with substantial morbidity and mortality. Recent research has suggested that lung cancer screening with spiral computed tomography scans might reduce lung cancer mortality. Studies of lung cancer screening have also suggested that significant numbers of participants quit smoking after screening. However, most have relied solely on self-reported smoking behavior, which may be less accurate among participants in lung cancer screening. To assess the validity of self-reported smoking status among participants in a lung cancer screening trial, this study compared self-reported smoking status against urinary cotinine levels. The sample included 55 consecutive participants enrolled in a randomized clinical trial comparing annual spiral computed tomography and chest X-ray for lung cancer screening. Participants were a mean of 59 years of age and predominantly Caucasian (96%) and male (55%). Self-reported smoking status was assessed before and after participants learned of the purpose of the biochemical verification study. Using urinary cotinine as the "gold standard," the sensitivity and specificity of self-reported smoking status were 91% and 95%, respectively (kappa = 0.85, P < 0.001, 95% confidence interval = 0.71-0.99). Total misclassification rate was 7%. However, three of the four misclassified participants reported concurrent use of nicotine replacement strategies. Eliminating these cases from the analysis revealed sensitivity of 100% and specificity of 95% (kappa = 0.96, P < 0.001, 95% confidence interval = 0.88-1.00). In conclusion, self-reported smoking status among participants in a lung cancer screening trial was highly consistent with urinary cotinine test results.

An exact method for link parameter estimation in error benchmarking: an application to Phase II two-stage single arm oncology trials.

Bayesian trial designs rely on the specification of a vague data prior to the determination of trial outcome. Phase II two-stage single arm oncology trials have a generally small sample size which may not provide the necessary amount of data to outweigh a misspecified or overly optimistic prior. To account for this issue, clinicians may wish to benchmark Bayesian errors with frequentist measures of trial validity, Type I and Type II errors. A confidence prior, reflecting the clinician's confidence in the efficacy of the treatment before data accrual, is used to equate the errors across design strategies. An exact method, modelling both the inherent small sample size and multi-stage decision process of Phase II single arm trials, is presented for constructing the confidence prior.

The impact of health insurance coverage on pediatric diabetes management.

AIMS: To examine the association between health insurance coverage, insulin management plans, and their impact on diabetes control in a pediatric type 1 diabetes mellitus clinic population. METHODS: Retrospective cohort design drawn from the medical records of the Pediatric Endocrinology Clinic at the University of Louisville, Kentucky. RESULTS: Out of 701 patients, 223 had public insurance, and 478 had private insurance. 77% of publically insured used two or three injections per day vs. 40% private. Conversely, 58% of privately insured used a multiple daily injection (MDI) plan or insulin pump (vs. 21%). 84% of MDI patients had private insurance with 93% using insulin pens compared with 38% of publically insured. Mean HbA1c was 8.6% for privately insured vs. 9.8% public, p<0.0001. Privately insured MDI and pump patients had the lowest HbA1cs. CONCLUSIONS: Insurance type had a significant effect on the insulin management plan used and was the most significant factor in overall diabetes control. Limitations on insulin pen use and number of glucose test strips may play a role in the decreased use of MDI/insulin pumps by publicly insured patients. Addressing factors related to insurance type, including availability of resources, could substantially improve diabetes control in those with public insurance.