Firsching Raimund, Piek Jürgen, Skalej Martin, Rohde Veit, Schmidt Uwe, Striggow Frank
Klinik für Neurochirurgie, Universitätsklinikum, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
J Neurol Surg A Cent Eur Neurosurg. 2012 Aug;73(4):204-16. doi: 10.1055/s-0032-1304815. Epub 2012 Jun 13.
BACKGROUND AND STUDY OBJECT: Despite many drug trials, no substance has yet been identified that improves the outcome of severe head injury. The dual cannabinoid CB1/CB2 receptor agonist KN38-7271 mediates potent neuroprotection in animal models. We describe here the first randomized, double-blind, prospective, placebo-controlled clinical phase IIa proof-of-concept trial to investigate the safety, pharmacokinetics, and potential efficacy of a cannabinoid receptor agonist in humans.
Out of the 439, 97 comatose patients at 14 European neurosurgical centers met the inclusion criteria. KN38-7271 was administered within 4.5 hours of the injury, and the patients received 1000, 500 μg, or placebo. The primary analysis was pharmacokinetic; efficacy was measured by survival and by neurological improvement or deterioration 7 and 14 days and 1, 3, and 6 months after the injury. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were analyzed from start of treatment to end of day 7.
Survival rates within 1 month of the injury were significantly better in the treatment groups than in the placebo group (high-dose, Kaplan-Meier difference on day 30 + 0.12 with p = 0.043; low-dose, difference +0.15 with p = 0.011) but this effect was not seen after 6 months. Critical ICP and CPP were less extreme and less frequent in the treatment group. There were no severe and no serious adverse effects that could be attributed to KN38-7271.
KN38-7271 appeared beneficial in the acute early phase of the comatose patient after a head injury. Its use was safe and well tolerated by patients. These results may provide the basis for further phase II/III trials in larger study populations.
背景与研究目的：尽管进行了许多药物试验，但尚未发现能改善重度颅脑损伤预后的物质。双重大麻素CB1/CB2受体激动剂KN38 - 7271在动物模型中具有强大的神经保护作用。我们在此描述了首个随机、双盲、前瞻性、安慰剂对照的临床IIa期概念验证试验，以研究大麻素受体激动剂在人体中的安全性、药代动力学及潜在疗效。
在欧洲14个神经外科中心的439例患者中，97例昏迷患者符合纳入标准。KN38 - 7271在受伤后4.5小时内给药，患者接受1000μg、500μg或安慰剂治疗。主要分析为药代动力学；疗效通过生存率以及受伤后7天、14天、1个月、3个月和6个月时神经功能的改善或恶化情况来衡量。从治疗开始至第7天结束分析颅内压（ICP）和脑灌注压（CPP）。
治疗组受伤后1个月内的生存率显著高于安慰剂组（高剂量组，第30天Kaplan - Meier差异为 +0.12，p = 0.043；低剂量组，差异为 +0.15，p = 0.011），但6个月后未观察到这种效果。治疗组的危急ICP和CPP情况不那么严重且发生频率较低。没有可归因于KN38 - 7271的严重和严重不良反应。
KN38 - 7271在颅脑损伤昏迷患者的急性早期似乎有益。其使用安全且患者耐受性良好。这些结果可为在更大研究人群中进行进一步的II/III期试验提供依据。
