Collagenase Total Occlusion-1 (CTO-1) Trial

Abstract

Background— Percutaneous interventions for chronic total occlusions have low success rates, primarily because of failure of guide wire crossing. Collagen-rich matrix constitutes the main barrier to chronic total occlusion crossing. In preclinical studies, local delivery of a bacterial collagenase formulation improved guide wire crossing. The Collagenase Total Occlusion-1 (CTO-1) Trial is a phase I, dose-escalation trial to assess the safety and efficacy of collagenase therapy to facilitate guide wire crossing in coronary artery chronic occlusions. Methods and Results— Twenty subjects with ≥1 previous failure of chronic total occlusion guide wire crossing were enrolled at 2 sites. Subjects were treated in 4 distinct cohorts of 5 patients, with escalation of collagenase dose in each cohort from 300 to 1200 μg. Collagenase was locally delivered into the occlusions with either an over-the-wire balloon system (n=8) or a fine-cross microcatheter (n=12) for a period of 30 minutes. Subjects were brought back to the catheterization laboratory for guide wire crossing and angioplasty the next day. Guide wire crossing was successfully achieved in 15 subjects (75%). A soft-tip guide wire (Whisper, Pilot-50, Fielder XT) was either the sole or predominant guide wire used in 75% of successful crossings. Non–ST-segment–elevation myocardial infarctions occurred in 3 patients as a result of side-branch ischemia during stenting. Computed tomographic angiography at 3 months showed no late complications and patent stents in successfully treated chronic total occlusion. Anginal improvement occurred with a reduction in Canadian Cardiovascular Society class from baseline to 3 months (2.5±0.6 versus 0.9±0.9; P <0.001). Conclusion— Local delivery of collagenase into coronary chronic total occlusion is feasible and safe with encouraging guide wire crossing results in previously failed cases. Larger clinical trials are required to determine efficacy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01271335.

Functionalized Graphene Oxide with Chitosan for Protein Nanocarriers to Protect against Enzymatic Cleavage and Retain Collagenase Activity

“…Also, collagenase was loaded on GO and GO-CS to probe its activity before/after loading using gel zymography analysis. Collagenase (matrix metalloproteinase, MMP) is one of the important therapeutic proteins in medical treatments for several diseases, including necrotic tissue, Dupuytren’s contracture and Peyronie 45 , chronic total occlusion 46 , lumbar disc herniation 47 , oral submucus fibrosis 48 , and tumors 49 50 .…”

Coronary chronic total occlusion intervention: A pathophysiological perspective

“…The expectation is that collagenase would degrade connective tissue for rapid and reliable wire navigation. A dose finding study reported excellent clinical results 24 . In TOSCA-5 trial, 75 CTO patients with prior documented failed PCI were randomized to placebo control or either 900 ug or 1200 ug intra-microcatheter injection of the collagenase the day before they underwent antegrade CTO PCI.…”

Peripheral Endovascular Interventions in the Era of Precision Medicine

“…20 A novel approach under investigation involves using local injections of collagenase to enzymatically degrade collagenous CTOs. A first-in-man phase 1 clinical trial using collagenase in coronary CTOs 39 showed improvement in facilitating guidewire passage. Ultrasound stimulated microbubbles have also been investigated to potentiate the effects of collagenase penetration into the lesion.…”