Results of a double-blind, placebo-controlled Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients with Critical Limb Ischemia

Background - The Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia (HGF-STAT trial) determined the effect of hepatocyte growth factor (HGF) plasmid on safety and limb tissue perfusion as measured by transcutaneous oxygen tension (TcPO(2)) in patients with critical limb ischemia (CLI). Methods and Results - Randomized patients with rest pain or ischemic ulcers and TcPO2 < 40 mm Hg and/or toe pressure < 50 mm Hg received placebo or HGF-plasmid intramuscular injection as follows: 0.4 mg at days 0, 14, and 28 (low dose); 4.0 mg at days 0 and 28 (middle dose); or 4.0 mg at days 0, 14, and 28 ( high dose). Patients were evaluated for safety, changes in TcPO(2) and ankle and toe pressure, amputation, and wound healing. Ninety-three of 104 treated patients were evaluated for safety (mean age 70 years, 63% male, 53% diabetic, 64% with tissue loss, mean ankle-brachial index 0.41, and mean toe pressure 26 mm Hg). Adverse events occurred in 86% of the patients, most of which were related to CLI or comorbid conditions and were not different between groups. TcPO(2) (mean +/- SE) increased at 6 months in the high-dose group (24.0 +/- 4.2 mm Hg, 95% CI 15.5 to 32.4 mm Hg) compared with the placebo (9.4 +/- 4.2 mm Hg, 95% CI 0.9 to 17.8), low-dose (11.1 +/- 3.7 mm Hg, CI 3.7 to 18.7 mm Hg), and middle-dose (7.3 +/- 4.8 mm Hg, CI -2.2 to 17.0 mm Hg) groups (ANCOVA P=0.0015). There was no difference between groups in secondary end points, including ankle-brachial index, toe-brachial index, pain relief, wound healing, or major amputation. Conclusions - Intramuscular injection of HGF plasmid was safe and well tolerated. Larger studies to determine whether HGF plasmid can improve wound healing and limb salvage in patients with CLI are warranted.