Abstract 9800: Clinical Effects of the Phosphodiesterase Inhibitor K-134 in Peripheral Artery Disease and Claudication

Background: In peripheral artery disease (PAD), claudication limits exercise performance, functional status and quality of life. Phosphodiesterase III inhibitors improve claudication-limited exercise performance in patients with PAD. K-134, a novel phosphodiesterase III inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess safety, quality of life and peak walking time (PWT) on a graded treadmill with cilostazol as an active comparator.

Design: Patients with PAD were randomized to receive placebo (N = 87), K-134 at a dose of 25 mg (N = 42), 50 mg (N = 85) or 100 mg (N = 84), or cilostazol at a dose of 100 mg (N = 89), each given twice daily for 26 weeks. A Data Safety Monitoring Board (DSMB) implemented adaptive design was used to allow early discontinuation of unsafe or minimally informative K-134 arms. Interim safety assessments at 2 weeks included dosing of study medication at the study site followed by measurements of postural vital signs and symptoms, and at 4 weeks with a treadmill test at peak drug concentration to evaluate for ischemia or arrhythmias.

Results: Based on prospectively defined adaptive criteria, the 25 mg K-134 arm was discontinued as the 50 mg and 100 mg doses were adequately tolerated, had no unanticipated safety signals, and were thus most likely to be informative concerning K-134 in the target population. In the intention-to-treat cohorts at 26 weeks PWT increased by 37% in the 100 mg K-134 arm and 23% on placebo (primary analysis p = 0.089). Using a mixed effects analysis in the entire population, 100 mg K-134 and cilostazol were each superior to placebo in improving PWT. In the per protocol population both K-134 100 mg and cilostazol 100 mg increased PWT as compared with placebo at 14 and 26 weeks. K-134 had tolerability and adverse effect profiles similar to that of cilostazol, with gastrointestinal adverse events, headache and dizziness the most common. Both drugs were associated with an increase in withdrawals prior to study completion due to adverse events as compared with placebo.

Conclusions: K-134 was generally well tolerated, and at a dose of 100 mg twice daily had a safety profile and effect on treadmill walking performance that was similar to that of cilostazol.