ZZ-3K3A-301: A multicenter, randomized, placebo-controlled, double-blinded, Phase 3 study to evaluate the efficacy and safety of 3K3A-APC (RHAPSODY-2)

中风是美国成年人残疾的主要原因，也是世界上导致死亡的主要原因之一。如果病人在中风开始后不久就到达医院，用溶栓治疗和取栓术再通是非常有效的。然而，并非所有患者对再通都有完全治愈的反应，因此需要新的、有效的辅助治疗方法来治疗中风。在设计辅助治疗时，重要的是要考虑到大脑由许多不同类型的细胞组成（例如，神经元，胶质细胞和内皮细胞等），并且在中风期间，大脑每分钟损失120万个神经元。也就是说，“时间就是大脑”。几十年来，辅助治疗已经在中风患者身上进行了有益的测试，但失败了，部分原因是候选治疗可能来得太晚，部分原因是它们只保护了神经元，而忽略了大脑中其他重要类型的细胞。先前失败的另一个重要原因是先前的试验不需要在给予候选治疗的同时再通。由于血栓切除术的广泛应用，闭塞的脑动脉被证明是开放的，现在有可能在最好的情况下测试候选中风治疗方法。我们现在提出一种药物，可以有效地保护大脑中的神经元、神经胶质细胞和内皮细胞。这种药物，3K3A-APC，通过几种机制作用于细胞诱导保护。多个实验室——在几个动物模型中使用神经行为学和组织形态学的终点——已经表明，3K3A-APC有效地减少了实验性中风的影响，即使在中风开始4小时后给药也是如此。在人类志愿者中，仅在临床相关剂量下检测到轻度和中度副作用。在接受溶栓治疗或取栓或两者同时进行的脑卒中患者中，3K3A-APC耐受性良好，似乎可以减少脑出血。在目前的建议中，我们寻求建立一个安全、有效的3K3A-APC剂量，并进行一项明确的疗效试验，以确定3K3A-APC是否能改善中风后3个月的预后。我们还试图证明3K3A-APC是否能减少与再通治疗相关的早期出血。如果这项试验成功，3K3A-APC治疗将通过增加再通的有益效果，减少相关出血，并使更多的医生放心地开再通处方，而不必担心出血并发症，从而显著改善卒中治疗。

Stroke is a leading cause of adult disability in America, and one of the leading causes of death in the world. If patients arrive at a hospital soon after their stroke begins, recanalization with thrombolytic therapy and thrombectomy can be very effective. Not all patients respond to recanalization with a complete cure, however, so new, effective adjunctive treatments for stroke are needed. In designing adjunctive therapy, it is important to consider that the brain consists of many different types of cells (e.g., neurons, glia, and endothelial cells among others), and during stroke, the brain loses 1.2 million neurons per minute. That is to say, “time is brain”. For decades, adjunctive treatments have been tested for benefit in stroke patients but failed partly because the candidate treatment may have been given too late, and partly because they protected only the neurons, ignoring the other important types of cells in the brain. Another significant reason for previous failure is that prior trials did not require recanalization simultaneous with the administration of the candidate therapy. Thanks to the wider use of thrombectomy—after which the occluded brain artery is documented to be open—it is now possible to test candidate stroke treatments under the best possible circumstances. We now propose a drug that powerfully protects neurons, glia, and endothelial cells in the brain. This drug, 3K3A-APC, acts on cells to induce protection by several mechanisms. Multiple laboratories—using neurobehavioral and histomorphometric endpoints in several animal models—have shown that 3K3A-APC powerfully reduces the effects of experimental stroke, even when administered up to 4 hours after the stroke begins. In human volunteers, only mild and moderate side effects were detected at clinically relevant doses. In stroke patients who received thrombolytic treatment or thrombectomy or both, 3K3A-APC was well tolerated and appeared to reduce cerebral bleeding. In the current proposal, we seek to establish a safe, effective dose of 3K3A-APC and proceed to a definitive efficacy trial to determine whether 3K3A-APC improves 3-month outcome after stroke. We also seek to show whether 3K3A-APC reduces early bleeding associated with recanalization therapy. If this trial is successful, 3K3A-APC treatment will significantly improve stroke therapy by augmenting the beneficial effects of recanalization, reducing the associated bleeding, and reassuring more physicians to prescribe recanalization without fear of bleeding complications.