title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00783081.
authors: Department of Emergency Medicine, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509, USA. roger@emedharbor.edu
authors: Roger J
authors: RJ
authors: Lewis
authors: Jason T
authors: JT
authors: Connor
authors: John R
authors: JR
authors: Teerlink
authors: James R
authors: JR
authors: Murphy
authors: Leslie T
authors: LT
authors: Cooper
authors: William R
authors: WR
authors: Hiatt
authors: Eric P
authors: EP
authors: Brass
references: Vasc Med. 2010 Jun;15(3):181-8
references: 20385711
references: N Engl J Med. 1991 Nov 21;325(21):1468-75
references: 1944425
references: J Am Coll Cardiol. 2008 Apr 22;51(16):1588-96
references: 18420103
references: J Am Coll Cardiol. 2006 Dec 19;48(12):2539-45
references: 17174195
references: J Am Coll Cardiol. 2006 Mar 21;47(6):1239-312
references: 16545667
references: JAMA. 2007 Mar 21;297(11):1197-206
references: 17374814
references: JAMA. 2001 Sep 19;286(11):1317-24
references: 11560536