title: Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia.
abstract: BACKGROUND
  This phase 1/2 study investigated the safety of percutaneous catheter-based gene transfer of naked plasmid DNA encoding for vascular endothelial growth factor 2 (phVEGF2) to left ventricular (LV) myocardium in a prospective, randomized, double-blind, placebo-controlled, dose-escalating study of inoperable patients with class III or IV angina.
  
  
  RESULTS
  A steerable deflectable 8F catheter with a 27-gauge needle at its distal tip was advanced percutaneously to the endocardial surface of the LV in 19 patients (age, 61+/-2 years) with chronic myocardial ischemia who were not candidates for conventional revascularization. Patients were randomized in a double-blind fashion to receive 6 injections (total volume, 6.0 mL) of placebo or phVEGF2 in doses of 200 microg (n=9), 800 microg (n=9), or 2000 microg (n=1) guided by LV electromechanical (NOGA) mapping with a gene-to-placebo ratio of 2:1. A total of 114 LV injections were delivered and caused no hemodynamic alterations, sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforation. End-point analysis at 12 weeks disclosed a statistically significant improvement in Canadian Cardiovascular Society (CCS) angina class in phVEGF2-treated versus placebo-treated patients (-1.3 versus -0.1, P=0.04). Remaining efficacy end points--including change in exercise duration (91.8 versus 3.9 seconds), functional improvement by > or =2 CCS classes (9 of 12 versus 1 of 6), and Seattle Angina Questionnaire data--all showed strong trends favoring efficacy of phVEGF2 versus placebo treatment.
  
  
  CONCLUSIONS
  This phase 1/2, double-blind, randomized trial provides preliminary data that support safety of phVEGF2 catheter-mediated myocardial gene transfer. The statistically significant reduction in anginal class and strong positive trends for remaining end points suggest that a larger phase 2/3 trial is warranted.
authors: Division of Cardiology, Tufts School of Medicine/St Elizabeth's Medical Center, Boston, Mass 02135, USA. douglas.losordo@tufts.edu
authors: Douglas W
authors: DW
authors: Losordo
authors: Peter R
authors: PR
authors: Vale
authors: Robert C
authors: RC
authors: Hendel
authors: Charles E
authors: CE
authors: Milliken
authors: F David
authors: FD
authors: Fortuin
authors: Nancie
authors: N
authors: Cummings
authors: Richard A
authors: RA
authors: Schatz
authors: Takayuki
authors: T
authors: Asahara
authors: Jeffrey M
authors: JM
authors: Isner
authors: Richard E
authors: RE
authors: Kuntz
mesh_terms: D000787:Angina Pectoris / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000628:therapy; D018780:Body Surface Potential Mapping; D002404:Catheterization; D002908:Chronic Disease; D004311:Double-Blind Method; D016228:Endothelial Growth Factors / Q000235:genetics*; D005080:Exercise Test; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D006352:Heart Ventricles; D006801:Humans; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000628:therapy*; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors