A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication

• Published in: Journal of vascular surgery 2012-02, Vol.55 (2), p.381-389.e1
• Main Authors: Brass, Eric P., MD, PhD, Cooper, Leslie T., MD, Morgan, Roger E., MD, Hiatt, William R., MD
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Analysis of Variance; Biological and medical sciences; Chi-Square Distribution; Cilostazol; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Female; General and cellular metabolism. Vitamins; Humans; Intermittent Claudication - drug therapy; Intermittent Claudication - enzymology; Intermittent Claudication - etiology; Intermittent Claudication - physiopathology; Male; Medical sciences; Middle Aged; Peripheral Arterial Disease - complications; Peripheral Arterial Disease - drug therapy; Peripheral Arterial Disease - enzymology; Peripheral Arterial Disease - physiopathology; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - adverse effects; Predictive Value of Tests; Quinolines - administration & dosage; Quinolines - adverse effects; Recovery of Function; Russia; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tetrazoles - administration & dosage; Time Factors; Treatment Outcome; United States; Urea - administration & dosage; Urea - adverse effects; Urea - analogs & derivatives; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels; Walking
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2011.09.004

Background Phosphodiesterase inhibitors have been shown to improve claudication-limited exercise performance in patients with peripheral artery disease. K-134, a novel phosphodiesterase inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess its safety, tolerability, and effect on treadmill walking time. Design Patients with peripheral artery disease 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 twice daily for 26 weeks. Peak walking time (PWT) was assessed using a graded treadmill protocol at baseline and after 14 and 26 weeks of treatment. A Data and Safety Monitoring Board–implemented adaptive design was used that allowed early discontinuation of unsafe or minimally informative K-134 arms. Results As determined by the prospectively defined adaptive criteria, the 25-mg K-134 arm was discontinued after 42 individuals had been randomized to the arm. During the 26-week treatment period, PWT increased by 23%, 33%, 37%, and 46% in the placebo, 50-mg K-134, 100-mg K-134, and cilostazol arms, respectively (primary analysis placebo vs 100-mg K-134 arm not statistically significant, P = .089). Secondary analyses showed that cilostazol significantly increased PWT after 14 weeks of treatment and that the 100-mg K-134 dose and cilostazol both increased PWT vs placebo after 14 and 26 weeks in those individuals who completed the 26-week trial and were compliant with the study drug, or when the data were analyzed using a mixed-effects model incorporating all time points. K-134 had tolerability and adverse effect profiles similar to that of cilostazol. Both drugs were associated with an increase in withdrawals before study completion due to adverse events compared with placebo. Conclusions K-134 was generally well tolerated. K-134 at a dose of 100 mg twice daily did not affect PWT according to the primary analysis, but K-134 and cilostazol both increased PWT when analyzed using a mixed-effects model and in the per-protocol population.