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 microL, 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.
Fuchs
Shmuel
S
Cardiology Department, Rabin Medical Center, Petach-Tikva, Israel. shmuelf@clalit.org.il
Dib
Nabil
N
Cohen
Barry M
BM
Okubagzi
Petros
P
Diethrich
Edward B
EB
Campbell
Ann
A
Macko
Jennifer
J
Kessler
Paul D
PD
Rasmussen
Henrik S
HS
Epstein
Stephen E
SE
Kornowski
Ran
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000787:Angina Pectoris / Q000188:drug therapy; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood / Q000652:urine; D006328:Cardiac Catheterization; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D052279:Creatine Kinase, MB Form / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D017079:Exercise Tolerance; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007267:Injections / Q000379:methods; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D010807:Physical Endurance; D010865:Pilot Projects; D011788:Quality of Life; D013997:Time Factors; D016896:Treatment Outcome; D020107:Troponin T / Q000097:blood / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D015415:Biomarkers; D020107:Troponin T; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D052279:Creatine Kinase, MB Form