CLINICAL STUDY: GENE THERAPY
Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial
Daisy F. Lazarous, MD*  ,
Ellis F. Unger, MD*,
Stephen E. Epstein, MD, FACC*,
Annette Stine, RN*,
Josefino L. Arevalo, BSN, RN*,
Emily Y. Chew, MD and
Arshed A. Quyyumi, MD, FACC*
* Cardiology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
Manuscript received November 24, 1999;
revised manuscript received March 15, 2000,
accepted June 13, 2000.
Reprint requests and correspondence: Dr. Daisy F. Lazarous, The Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Division of Cardiology, A1 East, 4940 Eastern Avenue, Baltimore, Maryland 21224
dlazaro{at}jhmi.edu
OBJECTIVES
This phase I study was designed to evaluate the safety, tolerability and pharmacokinetics of intra-arterial basic fibroblast growth factor (bFGF) in patients with atherosclerotic peripheral arterial disease (PVD) and intermittent claudication. We also assessed the effects of basic fibroblast growth factor (bFGF) on calf blood flow as a measure of biologic activity.
BACKGROUND
Preclinical studies have shown that bFGF, an angiogenic peptide, promotes collateral development in animal models of myocardial and hind limb ischemia. The safety and efficacy of bFGF in patients is unknown, and early clinical trials are underway in coronary and peripheral arterial disease.
METHODS
A double-blind, placebo-controlled, dose-escalation trial was conducted in patients with claudication demonstrating ankle/brachial index <0.8. Patients were randomly assigned to placebo (n = 6), 10 µg/kg of bFGF (n = 4), 30 µg/kg of bFGF once (n = 5) and 30 µg/kg of bFGF on two consecutive days (n = 4). Study drug was infused into the femoral artery of the ischemic leg. Detailed safety information including retinal photography for neovascularization were obtained through one year. Calf blood flow was measured with strain gauge plethysmography in the two higher dose treatment groups and in four placebo patients at baseline, one month and three to seven months after treatment.
RESULTS
Intra-arterial bFGF was safe and well-tolerated. The half-life was 46 ± 21 min. Calf blood flow increased at one month by 66 ± 26% (mean ± SEM) and at six months by 153 ± 51% in bFGF-treated patients (n = 9, p = 0.002). Flow did not change significantly in the placebo group.
CONCLUSIONS
In this initial randomized, double-blind, placebo-controlled trial in patients with atherosclerotic PVD and claudication, bFGF was well-tolerated. The data suggest a salutary biologic effect, and initiation of phase 2 trials is warranted.
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Abbreviations and Acronyms
| | ABI | = ankle/brachial index or systolic blood pressure ratio | | bFGF | = basic fibroblast growth factor | | PVD | = peripheral arterial disease | | VEGF | = vascular endothelial growth factor |
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