A randomized, double-blind, placebo-controlled, multicenter, pilot study of the safety and feasibility of catheter-based intramyocardial injection of AdVEGF121 in patients with refractory advanced coronary artery disease

Background: The experience with direct myocardial injection of adenovirus encoding angiogenic growth factor is limited to invasive surgical approach. Accordingly, we sought to evaluate, for the first time, in a randomized, double-blind, placebo-controlled, phase I pilot study the safety and feasibility of percutaneous catheter-based intramyocardial delivery of a replication-deficient adenovector encoding the 121-amino-acid isoform of vascular endothelial growth factor (AdVEGF121). Methods: Ten "no-option" patients with severe coronary artery disease were randomized (2:1) to receive AdVEGF121 (4 x 10(10) pu) or placebo as fifteen 100 mu L, evenly distributed, endomyocardial injections using a nonflouroscopic, 3-dimensional mapping and injection (NOGA) catheter-based system. Results: Injection procedure was successfully completed in all cases and was associated with no major adverse events. AdVEGF121 was considered potentially associated with a single serious adverse event of transient moderate fever. Elevated postprocedure CK and CK-MB fraction levels were recorded in two placebo-treated and three AdVEGF121 -treated patients; all CK measured values were <1.5 times upper limit of normal. All adenoviral cultures (urine and throat swab) were negative 24-hr after dosing, and no significant changes in serial plasma VEGF levels were noted over time. At 12 months follow-up, no cancers, proliferative retinal changes, or significant abnormalities in hepatic, renal or hematological indices were observed. Conclusions: Percutaneous, catheter-based AdVEGF121 intramyocardial injection is a practical, feasible, and potentially safe approach for intramyocardial gene transfer. A larger randomized, phase II efficacy study is warranted. (C) 2006 Wiley-Liss, Inc.