k-134-compound and Peripheral-Arterial-Disease

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Chi-Square Distribution; Cilostazol; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Female; Humans; Intermittent Claudication; Male; Middle Aged; Peripheral Arterial Disease; Phosphodiesterase Inhibitors; Predictive Value of Tests; Quinolines; Recovery of Function; Russia; Tetrazoles; Time Factors; Treatment Outcome; United States; Urea; Walking

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.. 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.. 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.. 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.. ClinicalTrials.gov: NCT00783081.

Topics: Ankle Brachial Index; Decision Support Techniques; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Humans; Intermittent Claudication; Maximum Tolerated Dose; Peripheral Arterial Disease; Phosphodiesterase 3 Inhibitors; Prospective Studies; Quinolines; Recovery of Function; Research Design; Russia; Time Factors; Treatment Outcome; United States; Urea; Walking

Cilostazol is a phosphodiesterase (PDE)3 inhibitor used to treat peripheral arterial disease with intermittent claudication, as there is clinical evidence that it improves treadmill exercise capacity. However, details of the mechanism underlying this enhanced walking capacity remain to be elucidated.. Based on the hypothesis that PDE3 inhibitors improve peripheral microcirculation in the hindlimbs via vascular smooth muscle relaxation and antiplatelet effects, we examined the effects of a more potent and selective PDE3 inhibitor, K-134, in rat models of peripheral arterial disease (PAD).. In a hindlimb ischemia model established by bilateral femoral artery occlusion, oral administration of K-134 for 27 days significantly increased blood flow in hindlimb skeletal muscle after exercise induced by electrical stimulation of the sciatic nerve. Moreover, K-134 enlarged the luminal area of intramuscular arteries and prevented rarefaction of capillary density in the gastrocnemius muscle. These effects were observed without pre-administration on the day following the last administration, suggesting that vasodilatory, antiplatelet and angiogenic activities of K-134 were indirectly responsible for the long-term beneficial effects. In fact, K-134 dose-dependently induced relaxation of rat femoral arteries in vitro, and inhibited rat platelet aggregation ex vivo. Interestingly, in a laurate-induced peripheral vascular injury model, oral administration of K-134 for 6 days prevented progression of hindlimb necrosis.. These findings suggest that the beneficial effects of PDE3 inhibitors on walking capacity are due to increased hindlimb skeletal muscle blood flow via intramuscular artery enlargement, and that K-134 is a promising drug for PAD associated with platelet hyperaggregability.

Topics: Administration, Oral; Animals; Blood Flow Velocity; Disease Models, Animal; Dose-Response Relationship, Drug; Hindlimb; Lauric Acids; Male; Muscle, Skeletal; Necrosis; Peripheral Arterial Disease; Phosphodiesterase 3 Inhibitors; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinolines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Time Factors; Urea; Vascular System Injuries; Vasodilation; Vasodilator Agents

K-134, a phosphodiesterase 3 (PDE3) inhibitor with anti-thrombotic and anti-hyperplastic activity, is being developed for the treatment of intermittent claudication. We assessed the efficacy of K-134 against gait disturbance in two rat experimental peripheral arterial disease (PAD) models: the bilateral laurate-induced PAD model and femoral artery ligation model. In the laurate-induced peripheral arterial disease model, 1 week of repeated oral administration of K-134 significantly improved gait disturbance. Cilostazol and clopidogrel did not significantly improve gait disturbance. Repeated oral administration of K-134 and cilostazol significantly improved gait disturbance in the femoral artery ligation model. We evaluated the effects of K-134 and cilostazol treatment on hindlimb blood flow pre- and post-treadmill exercise in this model by laser Doppler perfusion imaging. Both drugs increased hindlimb blood flow both pre- and post-treadmill exercise after 1 week of treatment. After 4 weeks of drug treatment, without preceding drug administration which is supposed to exert acute effects on vessel walls, both drugs significantly increased hindlimb blood flow after exercise. Moreover, K-134 at 30 mg/kg significantly prolonged walking distance. These results suggest that K-134 may be useful for treating intermittent claudication.

Topics: Animals; Disease Models, Animal; Hindlimb; Lameness, Animal; Male; Peripheral Arterial Disease; Phosphodiesterase 3 Inhibitors; Quinolines; Rats; Rats, Sprague-Dawley; Urea