人尿激肽原酶治疗急性脑梗死多中心随机双盲安慰剂对照试验

A multicenter,randomized,double-blinded and placebo-controlled study of acute brain infarction treated by human urinary kallidinogenase

目的在Ⅱ期临床试验初步有效基础上,进一步验证人尿激肽原酶治疗急性脑梗死的有效性和安全性。方法多中心随机双盲安慰剂3:1平行对照设计;起病48h 内急性脑梗死患者为入选对象;剂量为0.15 PANU/d 慢速静脉点滴,共3周。结果共入组466例,完成意向治疗数据集分析的446例,其中治疗组330例,对照组116例。治疗前两组基线差异无统计学意义。治疗1周时,治疗组欧洲卒中量表(ESS)增分率已优于对照组;3周时治疗组 ESS 较治疗前增加55.1%±33.0%,而对照组增加44.7%±32.8%,P=0.0022;等级疗效有效率治疗组为71.21%,对照组为52.59%,两组比较,Fisher 确切概率 P=0.0004。3个月回访者374例,治疗组(280例)中 Barthel 指数≥50者高于对照组(94例),P=0.0228。与试验药物肯定有关或可能有关的不良反应发生率为7.74%。4例严重不良反应,其中2例死亡,但判定与研究药物无关;另2例发生血压突然下降,考虑与合用血管紧张素转换酶抑制剂和尤瑞克林滴速过快有关,及时给予升压药物后,血压很快回升,未留不良后果。其他不良反应有恶心呕吐、胸闷心慌、头胀痛、脸潮红、心悸等,程度较轻,多数无需特殊处理。结论尤瑞克林能有效地改善急性脑梗死的神经功能缺损。

Objective To evaluate the efficacy and safety of a new drug, human urinary kallidinogenase, against acute brain infarction. Method A 15-center, randomized, double-blinded and 3：1 placebo-controlled study was carried out. Acute brain infarction within 48 hours of onset in the territory of the middle cerebral artery were indicated as subjects; kallidinogenase or placebo which was dissolved in 50 ml saline, was slowly injected intraveousely within 30 minutes daily for 3 weeks. The European Stroke Scale and Barthel Index were used to evaluate the neurological deficit and the activities of daily living（ ADL）, followed by a follow-up at the end of the third month. Results 446 patients were enrolled, who completed ITT analysis, including 330 in kallidinogenase group and 116 in placebo group, meanwhile 421 proceeded with PP analysis（ 311 and 110 respectively）. There were no significant differences of the baseline data between the 2 groups. At the end of treatment, the ESS scores increased by 55. 1% ±33.0% and 44. 7% ±32. 8% respectively in kallidinogenase group （KG） and placebo group（ PG,P = 0. 0022）, the difference being significant. PP analysis had similar results. As for ADL, follow-up 90 days after the treatment showed 374 cases followed, 280 in KG and 94 in PG; 1 died in PG, while none in KG. In KG, the cases whose BI≥50 were significantly more than those in PG （P =0. 0228 ）. Adverse events possibly or definitely attributable to the drug were observed in 27 cases （ 7. 74% ） , mostly were mild, such as palpitation, flush, dizziness, nausea etc, without special management needed. Only 2 died which was confirmed not correlated to kallidinogenase, and another 2 cases of sudden blood pressure drop were observed. The blood pressure drop, quickly restoring soon after the withdrawal of kallidinogenase and use of hemopiesic drugs, was considered to be caused by the combination use of anti-hypertensive drug ACEI and quick infusion speed. Conclusion Kallidinogenase is efficacious for acute brain infarction in imoroving the neurological deficits, which is safe in clinical use.