Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial.
Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial.
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阿替普酶治疗缺血性卒中的有效性有限，部分原因是颅内和颅外出血的发生。突变型尿激酶原（m-proUK）不消耗纤维蛋白原，仅在阿替普酶诱导后溶解纤维蛋白。因此，该治疗可能比阿替普酶单药治疗更安全、更有效。本研究的目的是评估在缺血性卒中患者中，与标准阿替普酶溶栓治疗相比，由小剂量阿替普酶继以m-proUK组成的溶栓治疗的安全性和有效性。大仲马是一项多中心、II期试验，采用前瞻性、随机、开放标签、设盲终点（PROBE）设计和剂量优化的适应性设计。可纳入符合静脉（IV）阿替普酶治疗标准的缺血性卒中患者。排除了符合血管内血栓切除术条件的患者。患者被随机分配（1：1）接受静脉推注阿替普酶（5 mg），随后持续静脉输注m-proUK（40 mg/h，60 min）或常规阿替普酶治疗（0.9 mg/kg）。根据中期分析的结果，m-proUK的剂量可修订为较低剂量（60分钟内30 mg/h）或较高剂量（60分钟内50 mg/h）。我们的目标是纳入200例最终诊断为缺血性卒中的患者。主要结局是根据海德堡出血分类在24 h时神经影像学上的任何干预后颅内出血（ICH），采用二元logistic回归分析。疗效结局包括24小时和5-7天使用美国国立卫生研究院中风量表（NIHSS）测量的中风严重程度、30天评估的改良兰金量表（mRS）评分、异常灌注量的变化（治疗前与治疗后）以及24小时血栓溶解的血液生物标志物。次要安全性终点包括症状性颅内出血、死亡和严重颅外出血。本试验将采用延迟知情同意程序。当使用小剂量阿替普酶和m-proUK的双重溶栓治疗显示出对结局的预期影响时，这将导致缺血性卒中患者的ICH发生率绝对降低13%。NL 7409（2018年11月26日）/NCT 04256473（2020年2月5日）在线版本包含补充材料，可通过10.1186/s13063-022-06596-z获得。
The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5–7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. NL7409 (November 26, 2018)/NCT04256473 (February 5, 2020) The online version contains supplementary material available at 10.1186/s13063-022-06596-z.
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