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Introduction: VM202 is a plasmid encoding two isoforms of hepatocyte growth factor (HGF). In preclinical studies, HGF stimulated angiogenesis and muscle regeneration. This preliminary clinical trial tested the hypothesis that VM202 injections in gastrocnemius muscle would improve walking performance in people with mild to moderate and symptomatic lower extremity peripheral artery disease (PAD)., Methods: In a double-blind clinical trial, people with PAD were randomized to gastrocnemius muscle injections of either 4 mgs of VM202 or placebo every 14 days for four doses. The primary outcome was 6-month change in 6-minute walk distance. Secondary outcomes included 3-month change in treadmill walking time and gastrocnemius muscle biopsy measures. In this preliminary trial, statistical significance was pre-specified as a one-sided P value <0.10., Results: 39 participants with PAD (64.1% Black, 28.2% female) were randomized. Adjusting for age, race, smoking, and baseline performance, VM202 did not improve 6-minute walk at 6-month follow-up, compared to placebo (-13.5 meters, 90% confidence interval (CI): -38.5,+∞). At 3-month follow-up, VM202 improved maximum treadmill walking time (+2.38 minutes (90% CI: +1.08, +∞), P=0.014) and increased central nuclei abundance in gastrocnemius muscle (+5.86, 90% CI: +0.37,+∞, P=0.088), compared to placebo. VM202 did not significantly improve pain-free walking distance (difference: +0.30 minutes, 90% CI:-1.10,+∞, P=0.39), calf muscle perfusion (difference: +1.80 ml/minute per 100 g tissue, 90% CI: -3.80,+∞, P=0.33), or the WIQ distance score (difference: +2.02, 90% CI: -8.11,+∞, P=0.40). In post-hoc analyses, VM202 significantly improved 6-minute walk in PAD participants with diabetes mellitus at 6-month follow-up (+34.19 (90% CI: 4.04,+∞), P=0.075), but had no effect in people without diabetes (interaction P value=0.079)., Conclusions: These data do not support gastrocnemius injections of VM202 to improve 6-minute walk in PAD. Secondary outcomes suggested potential benefit of VM202 on skeletal muscle measures and treadmill walking, while post-hoc analyses suggested benefit in PAD participants with diabetes., (Copyright © 2025 Society for Vascular Surgery. All rights reserved.)