Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial.
Despite advances in revascularization techniques, limb salvage and relief of pain cannot be achieved in many diabetic patients with diffuse peripheral vascular disease. Our objective was to determine the effect of intramuscular administration of phVEGF165 (vascular endothelial growth factor gene-carrying plasmid) on critical limb ischemia (CLI) compared with placebo (0.9% NaCl). A double-blind, placebo-controlled study was performed in 54 adult diabetic patients with CLI. The primary end point was the amputation rate at 100 days. Secondary end points were a 15% increase in pressure indices (ankle-to-brachial index and toe-to-brachial index), clinical improvement (skin, pain, and Quality of Life score), and safety. In patients (n=27) treated with placebo versus phVEGF165-treated patients (n=27) the following results were found: 6 amputations versus 3 (p=not significant [NS]); hemodynamic improvement in 1 versus 7 (p=0.05); improvement in skin ulcers, 0 versus 7 (p=0.01); decrease in pain, 2 versus 5 (p=NS); and overall, 3 versus 14 responding patients (p=0.003). No grade 3 or 4 adverse effects were seen in these patients. We conclude that this small, randomized gene therapy study failed to meet the primary objective of significant amputation reduction. However, significant and meaningful improvement was found in patients treated with a VEGF165-containing plasmid. There were no substantial adverse events.
Kusumanto
Y H
YH
Department of Internal Medicine, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
van Weel
V
V
Mulder
N H
NH
Smit
A J
AJ
van den Dungen
J J A M
JJ
Hooymans
J M M
JM
Sluiter
W J
WJ
Tio
R A
RA
Quax
P H A
PH
Gans
R O B
RO
Dullaart
R P F
RP
Hospers
G A P
GA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000671:Amputation, Surgical; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000209:etiology / Q000601:surgery / Q000628:therapy*; D007866:Leg / Q000098:blood supply; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000209:etiology / Q000601:surgery / Q000628:therapy*; D010919:Placebos / Q000008:administration & dosage; D011788:Quality of Life; D012883:Skin Ulcer / Q000209:etiology / Q000601:surgery / Q000628:therapy; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use
D010919:Placebos; D042461:Vascular Endothelial Growth Factor A