Objective: The objective of this study was to evaluate the safety and tolerance of increasing single and repeated (n = 2) doses of intramuscular naked plasmid DNA encoding for fibroblast growth factor (FGF) type 1 (NV1FGF) administered to patients with unreconstructible end-stage peripheral arterial occlusive disease (PAD). The secondary objectives were to determine the biologic activity of NV1FGF on hemodynamic and clinical parameters associated with improved perfusion. Methods: Fifty-one patients with unreconstructible peripheral arterial occlusive disease with rest pain or tissue necrosis underwent treatment with intramuscular NV1FGF. Increasing single (500, 1000, 2000, 4000, 8000, and 16,000 μg) and repeated (2 × 500, 2 × 1000, 2 × 2000, 2 × 4000, and 2 × 8000 μg) doses of NV1FGF were injected into the ischemic thigh and calf. Arteriography was performed before treatment and was repeated 12 weeks after treatment. Side effects and serious adverse events were monitored. Measurements of plasma and urine levels were performed to evaluate NV1FGF plasmid distribution. Serum FGF-1 was measured as an analysis of gene expression at the protein level. Transcutaneous oxygen pressure, ankle brachial index, toe brachial index, pain assessment with visual analog scale, and ulcer healing also were assessed. The safety results are presented for 51 patients, and the clinical outcomes are presented for the first 15 patients (500 to 4000 μg) who completed the 6-month follow-up study. Results: NV1FGF was well tolerated. Sixty-six serious adverse events were reported; however, none were considered to be related to NV1FGF. Four patients had adverse events that were possibly or probably related to the study treatment: injection site pain, pain, peripheral edema, myasthenia, and paresthesia. No laboratory adverse events were related to the study treatment. Two deaths remote from the treatment were considered not related. Biodistribution of plasmid was limited and transient in plasma and absent in urine. No increase in the FGF-1 serum level was detected. A significant reduction in pain (P <.001) and aggregate ulcer size (P <.01) was associated with an increased transcutaneous oxygen pressure (P <.01) as compared with baseline pretreatment values. A significant increase in ankle brachial index (P <.01) was seen. Conclusion: NV1FGF is well tolerated and potentially could be effective for the treatment of patients with end-stage limb ischemia. Biologic parameters indicate improved perfusion after NV1FGF administration. Dose response is not yet evident. The safety of NV1FGF and the magnitude of improvement observed in this study encourage further investigation with a placebo-controlled, double-blind clinical trial. (J Vasc Surg 2002;35:930-6.)

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