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

ZZ-3K3A-301：一项多中心、随机、安慰剂对照、双盲、3 期研究，旨在评估 3K3A-APC (RHAPSODY-2) 的有效性和安全性

• 批准号: 10305528
• 负责人: Patrick D Lyden
• 金额: $ 398.01万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305528
• 关键词: Acute; Address; Adult; Aftercare; Alteplase; Americas; Animal Model; Anticoagulants; Antiinflammatory Effect; Arteries; Aspirin; Behavioral; Blood; Blood Vessels; Brain; Cause of Death; Cell Death Process; Cells; Cerebrum; Chronic; Clinical Data; Clinical Trials; Collaborations; Cytoprotection; Data; Dose; Dose-Limiting; Double-Blind Method; Drops; Elements; Endothelial Cells; Endothelium; Event; Failure; Fright; Futility; Guidelines; Hemorrhage; Hospitals; Hour; Human; Human Volunteers; Image; Infarction; Infrastructure; Intravenous; Ischemia; Ischemic Stroke; Laboratories; Lead; Measures; Mechanics; Mediating; Membrane; Microglia; National Institute of Neurological Disorders and Stroke; Neuroglia; Neurons; Neuroprotective Agents; Outcome; PAR-1 Receptor; Patients; Pharmaceutical Preparations; Phase; Physicians; Placebo Control; Placebos; Predisposition; Primates; Program Development; Proteins; Randomized; Recombinants; Rodent; Safety; Serine Protease; Signal Pathway; Signal Transduction; Specific qualifier value; Stroke; Testing; Thrombectomy; Thrombolytic Therapy; Time; Toxic effect; United States National Institutes of Health; Variant; Weight; activated Protein C; acute stroke; artery occlusion; base; brain magnetic resonance imaging; cell type; central nervous system injury; clinically relevant; design; disability; effective therapy; efficacy evaluation; efficacy trial; first-in-human; improved; mutant; neurobehavioral; neurovascular; neurovascular unit; novel; phase 3 study; phase I trial; phase II trial; post stroke; pre-clinical; preclinical development; primary outcome; receptor; response; side effect; stroke model; stroke patient; stroke therapy; stroke trials; thrombolysis

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.

中风是美国成人残疾的主要原因，也是世界上主要的死亡原因之一。如果患者中风开始后不久到达医院，则溶栓疗法和血栓切除术的再续新化可能非常有效。并非所有患者都可以通过完整的治愈方法对重新定性做出反应，因此需要对中风进行新的，有效的辅助治疗。在设计辅助疗法时，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，神经胶质和内皮细胞），并且在中风期间，大脑每分钟失去120万个神经元。也就是说，“时间是大脑”。数十年来，辅助治疗已被测试中卒中患者的益处，但部分原因是由于候选治疗可能已经太晚了，部分原因是它们仅保护神经元，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，先前的试验不需要对候选疗法进行简单的重新启动。感谢您广泛使用血栓切除术（在有记录的脑动脉开放之后），现在可以在最佳情况下测试候选中风治疗。现在，我们提出了一种有力保护大脑中神经元，神经胶质和内皮细胞的药物。该药物3K3A-APC作用于细胞，通过多种机制诱导保护。多个实验室（在几种动物模型中使用神经行为和组织形态计量学终点）表明，即使在中风开始后长达4个小时时，3K3A-APC也有能力降低实验中风的效果。在人类志愿者中，在临床相关剂量时仅检测到轻度和中等的副作用。在接受血栓治疗或血栓切除术或两者两者的中风患者中，3K3A-APC的耐受性良好，似乎可以减少脑出血。在当前的提案中，我们试图建立一个安全有效的3K3A-APC，并进行确定的有效试验，以确定3K3A-APC是否在中风后是否改善了3个月的结果。我们还试图展示3K3A-APC是否会减少与再通疗有关的早期出血。如果该试验成功，则3K3A-APC治疗将通过增加重新定性的有益作用，减少相关的出血，并让更多的医生开处方重新定位，而不必担心出现出血并发症，从而显着改善了中风治疗。