Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia
Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia
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DOI：
10.1161/01.cir.0000015982.70785.b7
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发表时间：
2002-04-30
期刊：
影响因子：
37.8
通讯作者：
Kuntz, RE
中科院分区：
文献类型：
--
作者：
Losordo, DW;Vale, PR;Kuntz, RE
背景：这项前瞻性、随机、双盲、安慰剂对照的1/2期研究探讨了经皮导管将编码血管内皮生长因子2 （phVEGF2）的裸质粒DNA基因转移到左心室（LV）心肌的安全性。III级或IV级心绞痛不能手术患者的剂量递增研究。方法与结果：将一根可操纵可偏转的817导管经皮置管至左室心内膜表面19例（年龄55岁）。61 +/- 2岁)慢性心肌缺血，不适合常规血运重建术。患者以双盲方式随机接受6次注射（总容积6.0 mL）安慰剂或phVEGF2，剂量分别为200杯（n=9）、800杯（n=9）或2000杯（n=1），由低压电机（NOGA）定位指导，基因与安慰剂的比例为2:1。总共进行了114次左室注射，没有引起血流动力学改变、持续的室性心律失常、梗死的心电图证据或心室穿孔。12周的终点分析显示，在加拿大心血管学会（CCS）中，接受phvegf2治疗的患者与接受安慰剂治疗的患者相比，心绞痛等级有统计学上的显著改善（-1.3 vs -0.1）。P = 0.04)。剩余的疗效终点——包括运动时间的改变（91.8秒对3.9秒）、2个CCS分级的功能改善（12个分级中的9个对6个分级中的1个）和西雅图心绞痛问卷数据——都显示出与安慰剂治疗相比，phVEGF2的疗效有明显的趋势。结论：这项1/2期、双盲、随机试验提供了初步数据，支持phVEGF2导管介导心肌基因转移的安全性。统计上显著的心绞痛类型减少和剩余终点的强烈积极趋势表明，需要进行更大规模的2/3期试验。
Background-This phase 1/2 study investigated the safety of percutaneous catheter-based gene transfer of naked plasmid DNA encoding for vascular endothelial growth factor 2 (phVEGF2) to left ventricular (LV) myocardium in a prospective, randomized, double-blind, placebo-controlled. dose-escalating study of inoperable patients with class III or IV angina.Methods and Results-A steerable deflectable 817 catheter with a 27-gauge needle at its distal tip was advanced percutaneously to the endocardial surface of the LV in 19 patients (age. 61 +/- 2 years) with chronic myocardial ischemia who were not candidates for conventional revascularization. Patients were randomized in a double-blind fashion to receive 6 injections (total volume, 6.0 mL) of placebo or phVEGF2 in doses of 200 mug (n=9), 800 mug (n=9), or 2000 mug (n=1) guided by LV electromechanical (NOGA) mapping with a gene-to-placebo ratio of 2:1. A total of 114 LV injections were delivered and caused no hemodynamic alterations, sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforation. End-point analysis at 12 weeks disclosed a statistically significant improvement in Canadian Cardiovascular Society (CCS) angina class in phVEGF2-treated versus placebo-treated patients (-1.3 versus -0.1. P=0.04). Remaining efficacy end points-including change in exercise duration (91.8 versus 3.9 seconds), functional improvement by 2 CCS classes (9 of 12 versus I of 6). and Seattle Angina Questionnaire data-all showed strong trends favoring efficacy of phVEGF2 versus placebo treatment.Conclusions-This phase 1/2, double-blind, randomized trial provides preliminary data that support safety of phVEGF2 catheter-mediated myocardial gene transfer. The statistically significant reduction in anginal class and strong positive trends for remaining end points suggest that a larger phase 2/3 trial is warranted.