Randomized trial of AT-1015 for treatment of intermittent claudication. A novel 5-hydroxytryptamine antagonist with no evidence of efficacy.
AT-1015 is a novel selective 5-HT2A serotonin receptor antagonist that is known to impair platelet aggregation and vasoconstriction. Serotonin has been hypothesized to contribute to claudication symptoms in individuals with peripheral arterial disease (PAD) via microvascular vasoconstrictor and thrombotic effects. AT-1015 was thus evaluated in 439 patients with claudication who were randomized in a double-blind, placebo-controlled trial comparing 10 mg, 20 mg, and 40 mg BID versus placebo for 24 weeks. Treadmill walking performance was assessed by peak walking time (PWT) and pain-free walking time (PFWT). Quality of life (QoL) was measured by the Walking Impairment Questionnaire (WIQ) and the Health Status Survey SF-36. Limb hemodynamics was assessed with the ankle-brachial index (ABI). The 40 mg arm was terminated prematurely by recommendation of the Data Safety Monitoring Committee due to an excess number of non-fatal myocardial infarctions. At study conclusion, there were no statistically significant differences in the mean change of PWT, PFWT, ABI and QoL between the 10 mg and 20 mg BID treatment groups compared with placebo. The proportion of patients who experienced an adverse event (AE) was similar across all treatment groups. Antimuscarinic and gastrointestinal AEs were more common in the AT-1015 treatment groups. Two deaths occurred: one in the placebo group and the other in the AT-1015 20 mg group. Although a prolongation of the QTc interval was observed in all groups, this was not clinically significant (QTc > 500 ms). Mean supine pulse rates were significantly increased in all AT-1015 treatment groups, consistent with predicted antimuscarinic effects. Population pharmacokinetic analysis fit a one-compartment model with first-order absorption and elimination. These data indicate that selective serotonin receptor blockade does not improve exercise tolerance or quality of life in individuals with claudication.
Hiatt
William R
WR
Department of Medicine, University of Colorado School of Medicine, Section of Vascular Medicine, and the Colorado Prevention Center, Denver, CO 80203, USA. Will.Hiatt@uchsc.edu
Hirsch
Alan T
AT
Cooke
John P
JP
Olin
Jeffrey W
JW
Brater
D Craig
DC
Creager
Mark A
MA
D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D007383:Intermittent Claudication / Q000188:drug therapy*; D007540:Isonipecotic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D058830:Serotonin 5-HT2 Receptor Antagonists; D016138:Walking
D007540:Isonipecotic Acids; C411870:N-(2-(4-(5H-dibenzo(a,d)cyclohepten-5-yliden)piperidino)ethyl)-1-formyl-4-piperidinecarboxamide; D058830:Serotonin 5-HT2 Receptor Antagonists