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Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia

Abstract

Hepatocyte growth factor (HGF) is a potent angiogenic factor. The efficacy and safety of intramuscular injection of a naked plasmid encoding human HGF gene (beperminogene perplasmid, Collategene) was investigated in patients with critical limb ischemia (CLI) in a multicenter, randomized, double-blind, placebo-controlled trial. The randomization ratio for plasmid to placebo was 2:1. Injection sites were selected in each patient limb based on angiographic findings. Placebo or plasmid was injected on days 0 and 28. Evaluation of efficacy was carried out after 12 weeks. The primary end point was the improvement of rest pain in patients without ulcers (Rutherford 4) or the reduction of ulcer size in patients with ulcer(s) (Rutherford 5). Secondary end points were ankle-brachial pressure index, amputation, and quality of life (QOL). Forty-four patients were treated, and we performed interim analysis of efficacy in 40 patients. The overall improvement rate of the primary end point was 70.4% (19/27) in HGF group and 30.8% (4/13) in placebo group, showing a significant difference (P=0.014). In Rutherford 5 patients, HGF achieved a significantly higher improvement rate (100% [11/11]) than placebo (40% [2/5]; P=0.018). HGF plasmid also improved QOL. There were no major safety problems. HGF gene therapy is safe and effective for CLI.

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Acknowledgements

We thank Data and Safety Monitoring Board (DSMB), which consisted of Kensuke Esato (Yamaguchi Prefectural University), Kenichiro Okadome (Saiseikai Fukuoka General Hospital), Tohru Ohe (The Sakakibara Heart Institute of Okayama), Masayasu Matsumoto (Hiroshima University Hospital), and Yasuo Saijo (Hirosaki University Hospital) as the core members. Shiro Takahara (Osaka University Hospital) and Noriaki Tanaka (Okayama University Hospital) were special invited members of the DSMB. We also thank Independent Data Monitoring Committee (IDMC) consisting of Fumimaro Takaku (Jichi Medical University), Seiichiro Yamamoto (National Cancer Center), and the core members of the DSMB. This trial was funded by AnGes MG, Inc. (Osaka, Japan).

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Correspondence to H Shigematsu.

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Competing interests

All authors attended 1-day meetings sponsored by Anges MG, Inc. several times, and they received an honorarium for participation. The eligibility judgment committee (Drs Shigematsu, Iwai, Sasajima, and Ishimaru) received remuneration for their contribution. Drs Ogihara and Morishita own stock in AnGes MG, Inc. and Dr Morishita is a founder and board member of the company. Although they were involved in designing the trial and writing the report after the treatment codes were opened, they did not take part in the conduct of this trial. Specifically, they were not involved in enrollment, allocation, or evaluation of patients. The other authors do not have any interest in AnGes MG, Inc.

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Shigematsu, H., Yasuda, K., Iwai, T. et al. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Ther 17, 1152–1161 (2010). https://doi.org/10.1038/gt.2010.51

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Keywords

  • angiogenesis
  • critical limb ischemia
  • hepatocyte growth factor
  • HGF

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