Background

Non-immunogenic staphylokinase is modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and selectivity to fibrin. We aimed to assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with acute ischaemic stroke within 4·5 h after symptom onset.

Methods

We did a randomised, open-label, multicentre, parallel-group, non-inferiority trial in 18 clinical sites in Russia. We included patients aged 18 years and older with a diagnosis of acute ischaemic stroke (up to 25 points on the National Institutes of Health Stroke Scale). The study drug had to be administered within 4·5 h after the onset of symptoms. Patients were randomly assigned to receive either non-immunogenic staphylokinase (10 mg) or alteplase (0·9 mg/kg, maximum 90 mg), both administered intravenously. The randomisation sequence was created by an independent biostatistician using computer-generated random numbers. 84 blocks (block size of four) of opaque sealed envelopes were numbered sequentially from 1 to 336 and were opened in numerical order. Patients were unaware of their assigned treatment and were assessed by the study investigators who were also unaware of the treatment assignment on all trial days. Emergency department staff, who administered the assigned drug and opened the envelopes, were not masked to treatment. The primary efficacy endpoint was a favourable outcome, defined as a modified Rankin scale (mRS) score of 0–1 on day 90. The margin of non-inferiority was established as 16% for the difference in mRS score of 0–1 on day 90. Non-inferiority was tested using Welch's t-test for the primary outcome only. Endpoints were analysed in the per-protocol population, which comprised all randomly assigned patients who completed treatment without any protocol violations; this population was identical to the intention-to-treat population. This trial is completed and registered at ClinicalTrials.gov, NCT03151993.

Findings

Of 385 patients recruited from March 18, 2017, to March 23, 2019, 336 (87%) were included in the trial. 168 (50%) patients were randomly assigned to receive non-immunogenic staphylokinase and 168 (50%) to receive alteplase. The median duration of follow-up was 89 days (IQR 89–89). 84 (50%) of 168 patients in the non-immunogenic staphylokinase group had a favourable outcome at day 90 compared with 68 (40%) of 168 patients in the alteplase group (odds ratio [OR] 1·47, 95% CI 0·93 to 2·32; p=0·10). The difference in the rate of favourable outcome at day 90 was 9·5% (95% CI –1·7 to 20·7) and the lower limit did not cross the margin of non-inferiority (p_{non-inferiority} <0·0001). Symptomatic intracranial haemorrhage occurred in five (3%) patients in the non-immunogenic staphylokinase group and in 13 (8%) patients in the alteplase group (p=0·087). On day 90, 17 (10%) patients in the non-immunogenic staphylokinase group and 24 (14%) patients in the alteplase group had died (p=0·32). 22 (13%) patients in the non-immunogenic staphylokinase group had serious adverse events, compared with 37 (22%) patients in the alteplase group (p=0·044).

Interpretation

Non-immunogenic staphylokinase was non-inferior to alteplase for patients with acute ischaemic stroke. Mortality, symptomatic intracranial haemorrhage, and serious adverse events did not differ significantly between groups. Future studies are needed to continue to assess the safety and efficacy of non-immunogenic staphylokinase in patients with acute ischaemic stroke within the 4·5 h time window, and to assess the drug in patients with acute ischaemic stroke outside this time window with reperfusion CT or magnetic resonance angiography followed by thrombectomy if necessary.

Funding

The Russian Academy of Sciences.

中文翻译：

---

非免疫原性重组葡萄激酶与阿替普酶在俄罗斯（FRIDA）症状发作后 4·5 小时治疗急性缺血性卒中患者的对比：一项随机、开放标签、多中心、平行组、非劣效性试验

背景

非免疫原性葡激酶是经修饰的重组葡激酶，具有低免疫原性、高溶栓活性和对纤维蛋白的选择性。我们旨在评估与阿替普酶相比，非免疫原性葡萄激酶单次静脉推注在急性缺血性卒中患者出现症状后 4·5 小时内的安全性和有效性。

方法

我们在俄罗斯的 18 个临床地点进行了一项随机、开放标签、多中心、平行组、非劣效性试验。我们纳入了 18 岁及以上诊断为急性缺血性卒中的患者（美国国立卫生研究院卒中量表最高 25 分）。研究药物必须在症状出现后 4·5 小时内给药。患者被随机分配接受非免疫原性葡萄激酶（10 mg）或阿替普酶（0·9 mg/kg，最大 90 mg），均静脉给药。随机序列由独立的生物统计学家使用计算机生成的随机数创建。84 块（4 块大小）不透明密封信封从 1 到 336 依次编号，并按数字顺序打开。患者不知道他们分配的治疗，并由研究调查人员进行评估，他们也不知道在所有试验日的治疗分配。管理指定药物并打开信封的急诊科工作人员没有戴口罩接受治疗。主要疗效终点是有利的结果，定义为第 90 天改良的 Rankin 量表 (mRS) 评分为 0-1。非劣效性界限设定为 16%，因为第 0-1 天 mRS 评分的差异90. 非劣效性仅使用 Welch t 检验测试主要结果。终点在符合方案人群中进行分析，该人群包括所有随机分配的完成治疗且未违反任何方案的患者；该人群与意向治疗人群相同。

发现

在 2017 年 3 月 18 日至 2019 年 3 月 23 日期间招募的 385 名患者中，336 名（87%）被纳入试验。168 名 (50%) 患者被随机分配接受非免疫原性葡萄激酶治疗，168 名 (50%) 患者接受阿替普酶治疗。中位随访时间为 89 天（IQR 89-89）。与阿替普酶组 168 名患者中的 68 名 (40%) 相比，非免疫原性葡激酶组 168 名患者中有 84 名 (50%) 在第 90 天获得了良好的结果（优势比 [OR] 1·47，95% CI 0 ·93 到 2·32；p=0·10)。第 90 天的良好结局率为 9·5%（95% CI –1·7 至 20·7），下限未超过非劣效性界限（p_{非劣效性）}<0·0001)。非免疫原性葡激酶组 5 名 (3%) 患者和阿替普酶组 13 名 (8%) 患者发生症状性颅内出血 (p=0·087)。在第 90 天，非免疫原性葡激酶组 17 名 (10%) 患者和阿替普酶组 24 名 (14%) 患者死亡 (p=0·32)。非免疫原性葡萄球菌激酶组有 22 名 (13%) 患者出现严重不良事件，而阿替普酶组有 37 名 (22%) 患者 (p=0·044)。

解释

对于急性缺血性卒中患者，非免疫原性葡萄球菌激酶不劣于阿替普酶。死亡率、有症状的颅内出血和严重不良事件在组间没有显着差异。未来的研究需要继续评估非免疫原性葡萄激酶在 4·5 小时时间窗内对急性缺血性卒中患者的安全性和有效性，并在该时间窗外用再灌注 CT 评估该药物在急性缺血性卒中患者中的应用。或磁共振血管造影，然后在必要时进行血栓切除术。

资金

俄罗斯科学院。