Project 170961

Coronary arteries that have been totally blocked for 6 weeks or longer, are called chronic total occlusions (CTO). CTO are found in 30% of all coronary angiograms and frequently cause significant cardiac symptoms (such as chest pain and shortness of breath), and likely contribute to decreased survival. Because angioplasty success rates are low in CTO,approximately 50% or worse, patients are usually referred for more invasive bypass surgery, or treated with medications and forced to live a restricted lifestyle. The major problem for angioplasty in a CTO is to successfully advance a small guidewire through the CTO into the distal artery beyond the occlusion. This difficulty is due to very hard plaque containing densely packed collagen in the CTO and the absence of a discrete channel for the guidewire to cross the CTO. For the past several years, we have been researching a new therapy to improve angioplasty success rates in these blocked arteries. We have shown in animal models that direct injection of an enzyme, called collagenase, into the occlusion softens the collagen in the plaque that is blocking the artery, allowing a guidewire to successfully cross the CTO, without damaging the normal layers of the blood vessel. More recently, we have developed a collagenase formulation that is suitable for human use. In this application, we propose the first human trial with collagenase in 20 patients with totally blocked arteries (occlusion age ranges from 6 weeks to 18 months of age). Since it is a first-in-man study, we intend to gradually increase the dose of the drug with careful assessment in each patient for significant side effects (cardiac or other organs), and for effects on guidewire crossing. A total of 4 doses will be tested. We expect the highest dose will be most effective for guidewire crossing, with acceptable side effect profile. These results will be used to determine the most appropriate dose for a large- scale clinical trial.

first-in-human trial of intracoronary collagenase therapy for chronic total occlusions