Section of Vascular Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
J Vasc Surg. 2010 Dec;52(6):1525-30. doi: 10.1016/j.jvs.2010.07.044.
We have previously reported the results of a dose-finding phase II trial showing that HGF angiogenic gene therapy can increase TcPO2 compared with placebo in patients with critical limb ischemia (CLI). The purpose of this randomized placebo controlled multi-center trial was to further assess the safety and clinical efficacy of a modified HGF gene delivery technique in patients with CLI and no revascularization options.
Patients with lower extremity ischemic tissue loss (Rutherford 5 and 6) received three sets of eight intramuscular injections every 2 weeks of HGF plasmid under duplex ultrasound guidance. Injection locations were individualized for each patient based on arteriographically defined vascular anatomy. Primary safety end point was incidence of adverse events (AE) or serious adverse events (SAE). Clinical end points included change from baseline in toe brachial index (TBI), rest pain assessment by a 10 cm visual analogue scale (VAS) as well as wound healing, amputation, and survival at 3 and 6 months.
Randomization ratio was 3:1 HGF (n = 21) vs placebo (n = 6). Mean age was 76 ± 2 years, with 56% male and 59% diabetic. There was no difference in demographics between groups. There was no difference in AEs or SAEs, which consisted mostly of transient injection site discomfort, worsening of CLI, and intercurrent illnesses. Change in TBI significantly improved from baseline at 6 months in the HGF-treated group compared with placebo (0.05 ± 0.05 vs -0.17 ± 0.04; P = .047). Change in VAS from baseline at 6 months was also significantly improved in the HGF-treated group compared with placebo (-1.9 ± 1.3 vs +0.06 ± 0.2; P = .04). Complete ulcer healing at 12 months occurred in 31% of the HGF group and 0% of the placebo (P = .28) There was no difference in major amputation of the treated limb (HGF 29% vs placebo 33%) or mortality at 12 months (HGF 19% vs placebo 17%) between groups.
HGF gene therapy using a patient vascular anatomy specific delivery technique appears safe, maintained limb perfusion, and decreased rest pain in patients with CLI compared with placebo. A larger study to assess the efficacy of this therapy on more clinically relevant end points is warranted.
我们之前报告了一项剂量探索性 II 期试验的结果，该试验表明，与安慰剂相比，HGF 血管生成基因治疗可增加 TcPO2，用于治疗有严重肢体缺血（CLI）的患者。本随机安慰剂对照多中心试验的目的是进一步评估改良 HGF 基因传递技术在 CLI 患者中的安全性和临床疗效，这些患者没有血管重建的选择。
下肢缺血组织丧失（Rutherford 5 和 6）的患者接受三次共 8 个肌肉内注射，每 2 周一次，在双功超声引导下给予 HGF 质粒。根据血管造影定义的血管解剖结构，为每位患者个体化选择注射部位。主要安全性终点为不良事件（AE）或严重不良事件（SAE）的发生率。临床终点包括从基线开始的脚趾肱动脉指数（TBI）变化、10cm 视觉模拟量表（VAS）评估的静息痛变化以及 3 个月和 6 个月时的伤口愈合、截肢和生存情况。
HGF（n = 21）与安慰剂（n = 6）的随机分组比例为 3:1。平均年龄为 76 ± 2 岁，男性占 56%，糖尿病患者占 59%。两组之间的人口统计学数据没有差异。AE 或 SAE 没有差异，主要包括短暂的注射部位不适、CLI 恶化和并发疾病。与安慰剂相比，HGF 治疗组在 6 个月时 TBI 从基线开始的变化显著改善（0.05 ± 0.05 与 -0.17 ± 0.04；P =.047）。与安慰剂相比，HGF 治疗组在 6 个月时 VAS 从基线开始的变化也显著改善（-1.9 ± 1.3 与 +0.06 ± 0.2；P =.04）。HGF 组 12 个月时完全溃疡愈合的比例为 31%，安慰剂组为 0%（P =.28）。HGF 组治疗肢体的主要截肢率（29%）与安慰剂组（33%）和 12 个月时的死亡率（HGF 组 19%与安慰剂组 17%）无差异。
与安慰剂相比，使用患者血管解剖特定传递技术的 HGF 基因治疗似乎是安全的，可维持肢体灌注，并降低 CLI 患者的静息痛。需要更大规模的研究来评估这种治疗方法对更具临床意义的终点的疗效。
