Abstract 14430: The Novel Phosphodiesterase 3 Inhibitor K-134 Improves Walking Performance in Japanese Patients with Intermittent Claudication
Background: Patients with intermittent claudication (IC) associated with Peripheral Arterial Disease (PAD) are restricted in their walking performance by misbalance between oxygen supply and metabolic demand of the muscles in the lower extremities during exercise. K-134, a novel phosphodiesterase 3 inhibitor, was evaluated in a phase II trial to assess safety, treadmill performance and quality of life in Japanese patients with IC.
Design: Japanese patients with IC were randomized to receive placebo (N=42), or K-134 at doses of 25 mg (N=43), 50 mg (N=43), or 100 mg (N=44) each given twice daily for 24 weeks in a multi-center, double-blinded, parallel-group study. Peak walking time (PWT) and claudication onset time (COT) were measured by exercise treadmill test utilizing a modified Gardner protocol. Medical Outcomes Trust Health Survey Short Form (SF-36v2), Walking Impairment Questionnaire (WIQ), ankle-brachial index (ABI), asymmetric dimethylarginine (ADMA), intimal-medial thickness (IMT) and MRI/MRA brain scan were measured.
Results: After 24 weeks of treatment, 100 mg K-134 demonstrated a positive trend in PWT improvement compared with placebo. It was increased by 12.3% in the placebo arm, 31.0% in the 25 mg arm, 26.5% in the 50 mg arm, and 28.2% in the 100 mg arm. However, no dose-response relationship was found. A similar trend was observed in COT. In addition, ADMA and IMT which are considered to correlate with cardiovascular risk were decreased in a dose-dependent manner. The incidence of adverse events (AEs) considered as related to study medication increased in a dose-dependent manner. The most common AEs were palpitation and tachycardia which were assessed as mild except for one moderate palpitation. There was no difference in incidence of serious adverse events across the arms. Although the incidence of AEs leading to withdrawal was the highest in the 50 mg arm, the 100 mg arm had a lower AE withdrawal rate than the placebo arm. K-134 was well-tolerated up to the 100 mg bid dose for 24 weeks.
Conclusions: K-134 demonstrated a positive trend for improvement in PWT in patients with IC over a range of doses from 25 mg to 100 mg. Moreover, K-134 was generally well tolerated up to the 100 mg bid dose. K-134 may offer a new therapeutic option for treatment of IC.
- © 2011 by American Heart Association, Inc.