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

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Abstract
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 × 1010 pu) or placebo as fifteen 100 μL, 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.