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

Douglas W. Losordo, Peter R. Vale, Robert Hendel, Charles E. Milliken, F. David Fortuin, Nancie Cummings, Richard A. Schatz, Takayuki Asahara, Jeffrey M. Isner, Richard E. Kuntz

Research output: Contribution to journalArticle

406 Citations (Scopus)

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. Methods and 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 μg (n=9), 800 μg (n=9), or 2000 μg (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 ≥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.

Original languageEnglish
Pages (from-to)2012-2018
Number of pages7
JournalCirculation
Volume105
Issue number17
DOIs
StatePublished - Apr 30 2002
Externally publishedYes

Fingerprint

Vascular Endothelial Growth Factor A
Myocardial Ischemia
Catheters
Placebos
Genes
Safety
Injections
Infarction
Needles
Cardiac Arrhythmias
Myocardium
Electrocardiography
Plasmids
Hemodynamics
Exercise
DNA
Therapeutics

Keywords

  • Angina
  • Angiogenesis
  • Gene therapy
  • Growth substances
  • Ischemia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

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. / Losordo, Douglas W.; Vale, Peter R.; Hendel, Robert; Milliken, Charles E.; Fortuin, F. David; Cummings, Nancie; Schatz, Richard A.; Asahara, Takayuki; Isner, Jeffrey M.; Kuntz, Richard E.

In: Circulation, Vol. 105, No. 17, 30.04.2002, p. 2012-2018.

Research output: Contribution to journalArticle

Losordo, Douglas W. ; Vale, Peter R. ; Hendel, Robert ; Milliken, Charles E. ; Fortuin, F. David ; Cummings, Nancie ; Schatz, Richard A. ; Asahara, Takayuki ; Isner, Jeffrey M. ; Kuntz, Richard E. / 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. In: Circulation. 2002 ; Vol. 105, No. 17. pp. 2012-2018.
@article{97b817c9c9b74562830d6cc835e4a898,
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. Methods and 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 μg (n=9), 800 μg (n=9), or 2000 μg (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 ≥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.",
keywords = "Angina, Angiogenesis, Gene therapy, Growth substances, Ischemia",
author = "Losordo, {Douglas W.} and Vale, {Peter R.} and Robert Hendel and Milliken, {Charles E.} and Fortuin, {F. David} and Nancie Cummings and Schatz, {Richard A.} and Takayuki Asahara and Isner, {Jeffrey M.} and Kuntz, {Richard E.}",
year = "2002",
month = "4",
day = "30",
doi = "10.1161/01.CIR.0000015982.70785.B7",
language = "English",
volume = "105",
pages = "2012--2018",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "17",

}

TY - JOUR

T1 - 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

AU - Losordo, Douglas W.

AU - Vale, Peter R.

AU - Hendel, Robert

AU - Milliken, Charles E.

AU - Fortuin, F. David

AU - Cummings, Nancie

AU - Schatz, Richard A.

AU - Asahara, Takayuki

AU - Isner, Jeffrey M.

AU - Kuntz, Richard E.

PY - 2002/4/30

Y1 - 2002/4/30

N2 - 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. Methods and 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 μg (n=9), 800 μg (n=9), or 2000 μg (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 ≥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.

AB - 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. Methods and 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 μg (n=9), 800 μg (n=9), or 2000 μg (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 ≥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.

KW - Angina

KW - Angiogenesis

KW - Gene therapy

KW - Growth substances

KW - Ischemia

UR - http://www.scopus.com/inward/record.url?scp=0037197740&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037197740&partnerID=8YFLogxK

U2 - 10.1161/01.CIR.0000015982.70785.B7

DO - 10.1161/01.CIR.0000015982.70785.B7

M3 - Article

VL - 105

SP - 2012

EP - 2018

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 17

ER -