Evaluation of trans sodium crocetinate on safety and exercise performance in patients with peripheral artery disease and intermittent claudication.

Trans sodium crocetinate (TSC) is a synthetic carotenoid that improves the diffusion of oxygen in animal models of ischemia/hypoxia. This study evaluated multiple doses of TSC in patients with peripheral artery disease (PAD) and hypothesized that a preliminary dose-response relationship could be identified on peak walking time (PWT). Forty-eight patients with symptomatic PAD and an ankle-brachial index < 0.90 were included, while critical limb ischemia, recent revascularization, and exercise limited by symptoms other than claudication were exclusionary. Patients were randomized to placebo or eight dosing levels of TSC ranging from 0.25 mg/kg to 2.0 mg/kg given intravenously once daily for 5 days. Subjects were tested on a graded treadmill protocol to claudication-limited PWT with the change to Day 5 as primary. A cubic regression was fit to detect a pre-specified inverted U-shaped dose-response relationship (65% power). Patient-reported walking distance from the Walking Impairment Questionnaire was a secondary endpoint. Adverse events were not predominant on any drug dose relative to placebo. Changes in PWT demonstrated a cubic trend for dose (p = 0.07, r = 0.39, r (2) = 0.15) with morphologic signals of benefit at doses above 1.00 mg/kg after both the first and fifth dosing days. Similar improvements occurred with the walking distance score at doses above 1.00 mg/kg. In conclusion, TSC was safe and well tolerated at all doses. Notable signals of benefit were observed at higher doses for both PWT and patient-perceived walking distance. These results support a phase II study to define the optimal dose for longer-term therapy with TSC. Clinical Trial Registration - URL:http://www.clinicaltrials.gov. Unique identifier: NCT00725881.