Phosphodiesterase-5 Inhibitor PF-03049423 Effect on Stroke Recovery: A Double-Blind, Placebo-Controlled Randomized Clinical Trial.

BACKGROUND: The therapeutic potential of phosphodiesterase-5 inhibitor PF-03049423 was evaluated in a phase 2, multicenter, randomized, double-blind, placebo-controlled study of subjects with acute ischemic stroke ( CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov, unique identifier: NCT01208233; http://www.clinicaltrialsregister.eu, EudraCT number: 2010-021414-32). MATERIALS AND METHODS: Subjects (N = 70) received PF-03049423 6 mg (or placebo, N = 67) once daily, orally, commencing between 24 and 78 hours of stroke onset, and continuing for 90 days. Postbaseline efficacy assessments were performed on Days 7, 14, 30, 60, and 90. Modified Rankin Scale (mRS), Barthel Index, National Institutes of Health Stroke Scale, Box and Blocks Test, Hand-Grip Strength Test, 10-Meter Walk Test, Repeatable Battery Assessment of Neuropsychological Status Naming and Coding Subtests, Line Cancellation Test, and Recognition Memory Test were administered to evaluate poststroke recovery. The primary endpoint was the mRS responder rate (score 0-2 at Day 90). The study included a planned interim analysis of efficacy data. RESULTS: The primary efficacy analysis using logistic regression showed no statistically significant difference between PF-03049423 6 mg and placebo (responder rate of 42.6% and 46.2%, respectively). Although PF-03049423 showed a satisfactory safety and tolerability profile, no signal of efficacy emerged from any of the outcome measures. CONCLUSIONS: PF-03049423 showed no therapeutic potential for acute ischemic stroke.

Advantages of a wholly Bayesian approach to assessing efficacy in early drug development: a case study.

This paper illustrates how the design and statistical analysis of the primary endpoint of a proof-of-concept study can be formulated within a Bayesian framework and is motivated by and illustrated with a Pfizer case study in chronic kidney disease. It is shown how decision criteria for success can be formulated, and how the study design can be assessed in relation to these, both using the traditional approach of probability of success conditional on the true treatment difference and also using Bayesian assurance and pre-posterior probabilities. The case study illustrates how an informative prior on placebo response can have a dramatic effect in reducing sample size, saving time and resource, and we argue that in some cases, it can be considered unethical not to include relevant literature data in this way.

Minimizing Patient Burden Through the Use of Historical Subject-Level Data in Innovative Confirmatory Clinical Trials: Review of Methods and Opportunities.

The goal of clinical trial research is to deliver safe and efficacious new treatments to patients in need in a timely and cost-effective manner. There is precedent in using historical control data to reduce the number of concurrent control subjects required in developing medicines for rare diseases and other areas of unmet need. The purpose of this paper is to provide a review for a regulatory and industry audience of the current state of relevant statistical methods, and of the uptake of these approaches and the opportunities for broader use of historical data in confirmatory clinical trials. General principles to consider when incorporating historical control data in a new trial are presented. Bayesian and frequentist approaches are outlined including how the operating characteristics for such a trial can be obtained. Finally, examples of approved new treatments that incorporated historical controls in their confirmatory trials are presented.