Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication

Abstract

Background: Claudication secondary to peripheral artery disease (PAD) is associated with substantial functional impairment. Phosphodiesterase (PDE) inhibitors have been shown to increase walking performance in these patients. K-134 is a selective PDE 3 inhibitor being developed as a potential treatment for claudication. The use of K-134, as with other PDE 3 inhibitors, in patients with PAD raises important safety and tolerability concerns, including the induction of cardiac ischemia, tachycardia, and hypotension. We describe the design, oversight, and implementation of an adaptive, phase II, dose-finding trial evaluating K-134 for the treatment of stable, intermittent claudication.

Methods: The study design was a double-blind, multi-dose (25 mg, 50 mg, and 100 mg of K-134), randomized trial with both placebo and active comparator arms conducted in the United States and Russia. The primary objective of the study was to compare the highest tolerable dose of K-134 versus placebo using peak walking time after 26 weeks of therapy as the primary outcome. Study visits with intensive safety assessments were included early in the study period to provide data for adaptive decision making. The trial used an adaptive, dose-finding strategy to efficiently identify the highest dose(s) most likely to be safe and well tolerated, based on the side effect profiles observed within the trial, so that less promising doses could be abandoned. Protocol specified criteria for safety and tolerability endpoints were used and modeled prior to the adaptive decision making. The maximum target sample size was 85 subjects in each of the retained treatment arms.

Results: When 199 subjects had been randomized and 28-day data were available from 143, the Data Monitoring Committee (DMC) recommended termination of the lowest dose (25 mg) treatment arm. Safety evaluations performed during 14- and 28-day visits which included in-clinic dosing and assessments at peak drug concentrations provided core data for the DMC review. At the time of review, no subject in any of the five treatment arms (placebo, three K-134-containing arms, and cilostazol) had met pre-specified definitions for resting tachycardia or ischemic changes on exercise ECG. If, instead of dropping the 25-mg K-134 treatment arm, all arms had been continued to full enrollment, then approximately 43 additional research subjects would have been required to complete the trial.

Conclusions: In this phase II, dose-finding trial of K-134 in the treatment of stable intermittent claudication, no concerning safety signals were seen at interim analysis, allowing the discontinuation of the lowest-dose-containing arm and the retention of the two highest-dose-containing arms. The adaptive design facilitated safe and efficient evaluation of K-134 in this high-risk cardiovascular population.

Trial registration: ClinicalTrials.gov: NCT00783081.

Figures

Figure 1

Schematic of Adaptive Arm-dropping Strategy. This figure illustrates the adaptive arm-dropping strategy planned for the trial, based on the use of logistic dose-response models to integrate information from the placebo and all K-134 containing arms. Initially, the trial begins with equal randomization to the placebo, cilostazol, and the three K-134-containing arms. At each of two planned interim analyses, occurring when 28-day data are available from either 50 or 100 patients, logistic dose-response models are fit for each of the three safety and tolerability endpoints (resting tachycardia [denoted HR > 120], signs of ischemia on ECG, and medication discontinuation), using data from the placebo and K-134-contining arms. If the lower limit of the 80% confidence interval around the logistic model (the upper and lower limits are illustrated by dotted lines) exceeds the maximum tolerable limit of the safety or tolerability endpoint at a particular dose (excluding placebo), then that arm of the trial is to be discontinued. In the hypothetical scenario shown in the figure, the ischemia safety endpoint limit is exceeded (arrow) when N = 50 for the highest (100 mg) dose of K-134 so that arm is discontinued and the four remaining arms are continued until N = 100. At the second interim analysis, however, the maximum tolerable rate for resting tachycardia is exceeded by the lower limit of the 80% confidence interval at both the 50-mg and 100-mg doses (arrows). Since the 100-mg dose was already discontinued in this hypothetical example at the 50-patient review, the 50-mg dose arm would be discontinued at this point and new research subjects would be randomized in a balanced manner to one of the three remaining arms for the remaining duration of the trial.