CLINICAL TRIAL PROTOCOLS FOR ACUTE ISCHEMIC STROKE

急性缺血性中风的临床试验方案

基本信息

批准号：
8940090
负责人：
John Hallenbeck
金额：
$ 20.26万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8940090
关键词：
Acute Adult Adverse event Aftercare Alteplase Am 80 Binding Blinded Blood - brain barrier anatomy Boston Brain Edema Caring Cessation of life Clinical Clinical Treatment Clinical Trials Clinical trial protocol document Collaborations Conduct Clinical Trials Confidence Intervals Data Data Analyses Deterioration Diagnostic Diffusion Dose Dose-Limiting Double-Blind Method Drug Kinetics Enrollment Evaluation Female Gelatinase B General Hospitals Goals Growth Hemorrhage Hour Human Image Interferon beta-1a Interferon-beta Intracranial Hemorrhages Intravenous Ischemic Stroke Lesion Magnetic Resonance Imaging Massachusetts Maximum Tolerated Dose Modeling Monitor Names Neurologic Outcome Patients Pharmaceutical Preparations Phase Placebo Control Placebos Plasma Protocols documentation Randomized Recombinants Safety Series Specificity Staging Stroke Symptoms Thrombolytic Therapy Time Toxic effect active method acute stroke base clinical efficacy cohort design improved male novel open label phase 1 study prevent primary outcome safety study secondary outcome thrombolysis yeast two hybrid system

项目摘要

We have implemented a protocol toward the long term goal of expanding the indications for thrombolytic therapy for ischemic stroke. The study name is MR Witness: A Phase IIa Safety Study of Intravenous Thrombolysis with Alteplase in MRI-Selected Patients. The objectives of this study are to: 1) determine the safety of intravenous alteplase (tPA) in subjects with unwitnessed stroke onset, last known well less than 24 hours before, and MRI evidence of early stroke (less than 6 hours from onset), 2) validate novel MRI profiles to improve the sensitivity while maintaining high specificity for detecting subjects with acute stroke, and 3) explore the clinical efficacy of using imaging surrogates in subjects with unwitnessed stroke onset who are treated with thrombolysis. Eighty adult male and female subjects with acute ischemic stroke who present within 24 hours since the time they were last known well and are outside the standard tPA time window, but have an MRI suggestive of early stroke treatable with thrombolysis. This is an open-label, Phase IIa safety study to determine if it is safe to extend intravenous thrombolytic treatment to subjects who are evaluated within 24 hours from last known well and eligible to receive thrombolytic treatment within 4.5 hours from symptom discovery with the assistance of an MRI-based witness when no human witness of stroke onset is available. The study is designed to investigate the safety in using standard diagnostic MRI in selecting patients for thrombolytic therapy when the last known well time places the patient beyond the current IV thrombolytic time window. We will apply the following definition of treatable stroke as diffusion-positive, FLAIR-negative approach (DPFN) shown by us and several other centers to be indicative of early stage stroke. During the study course we will also consider comparable MRI models. A posttreatment safety evaluation using non-contrast CT will be performed for all treated subjects, consistent with standards of care after treatment with IV tPA. The maximum total number of subjects treat with tPA will be 80. A DSMB will independently monitor for safety, and stopping rules are defined to stop the study early if excessive symptomatic intracranial hemorrhage (sICH) rates occur. The stopping boundary for the trial is a hybrid of two conditions such that if an unacceptably high hemorrhage rate is detected by either condition, the trial will be terminated for safety concerns. The two conditions are the lower 95% confidence bound for the true hemorrhage rate is >5.3% or the absolute number of sICH exceeds 6. The primary outcome variable is sICH. Symptomatic hemorrhage is defined as any hemorrhage with neurological deterioration with an NIHSS score that increased by 4 or more points over baseline value or the lowest value in the first 7 days or any hemorrhage leading to death. The primary hypothesis is the rate of sICH will not exceed that observed in ECASS 3, a clinical trial that demonstrated the clinical efficacy of rt-PA up to 4.5 hours from last known well (5.3%, 95% exact Confidence Interval: 3.3% to 7.9%). Secondary outcomes will be clinical outcomes and other imaging features of ischemic stroke, e.g., brain edema, lesion volume growth. At 3 months from treatment, clinical outcome will be evaluated by modified Rankin Scale scores and compared to historical controls for both non-tPA and standard tPA treated patients. The clinical trial was designed and will be conducted in collaboration with colleagues from Massachusetts General Hospital in Boston. We are investigating the potential of interferon beta-1a to protect the blood brain barrier in acute ischemic stroke and prevent hemorrhagic complications of thrombolytic therapy. The first clinical trial in this series, Recombinant human interferon beta-1a in acute ischemic stroke: a dose escalation and safety study, completed enrollment this year. The purpose of this randomized double-blind placebo-controlled sequential dose escalation, phase 1 study is to investigate the safety of IFN-beta-1a in patients with acute ischemic stroke 3-24 hours from onset and to determine the maximum tolerated dose of administration in this setting. Five dose cohorts of 5 patients (4:1 active: placebo) at 11 mcg, 22 mcg, 44 mcg, 66 mcg and 88 mcg were planned. Patients receive interferon beta 1a or placebo once daily for 7 days (dose 1 is given intravenously; doses 2-7 are injected subcutaneously). Dose escalation is continuous unless drug-related toxicity reaches a predetermined level of one dose-limiting adverse event (1 of 4 treated) within a dose cohort, in which case a second cohort of 5 patients (4:1) will be treated at that dose. The study is to be terminated at a dose level at which 2 of 4 or 3 of 8 patients on active treatment have a severe dose limiting toxicity or when all planned dose cohorts are completed. This stopping rule was reached at the 44mcg dose. Blinded data verification and analysis, including pharmacokinetic and plasma MMP-9 concentrations, are ongoing. Upon unblinding, the results will be reviewed with the DSMB. Data analysis is on-going.

我们已经实施了一项方案，以扩大缺血性中风的溶栓治疗迹象的长期目标。研究名称是先生证人：在MRI选择的患者中对静脉溶栓的IA期安全研究。这项研究的目的是：1）确定静脉静脉静脉外脱酶（TPA）的安全性，在不知不觉中发作的受试者中，在不到24小时前已知的最后一个已知的人，以及早期中风的MRI证据（距离发病少于6小时），距离发病少于6小时），2）验证新颖的MRI特征，以提高敏感性，同时使用高度特异性，同时使用高度特异性，并使用效果促进了效果，并探索了3个敏感性，并以3的效果，并以3的效果，并以3的效果，并以3的效果，以示为敏感性。在接受溶栓治疗的受试者中的替代受试者中的替代。八十名成年男性和女性受试者患有急性缺血性中风，自从他们最后一个良好的时间以来，他们在24小时内就出现，并且超出了标准TPA时间窗口，但有MRI暗示可通过溶栓治疗的早期中风。这是一项开放标签，IIA期安全研究，可以确定是否可以安全地将静脉溶栓治疗延伸到从最后一个已知井内24小时内评估的受试者，并且有资格在没有MRI基于MRI的证人的协助下在4.5小时内从症状发现的4.5小时内接受溶栓治疗，而当没有人类证人的证人发作。该研究旨在调查使用标准诊断MRI选择患者进行血栓疗法的安全性，当时最后一个已知的良好时间将患者置于当前IV溶栓时窗口之外。我们将把以下可处理的中风的定义用作美国和其他几个中心所示的扩散阳性，天赋的方法（DPFN），以表明早期中风。在学习课程中，我们还将考虑可比较的MRI模型。使用非对比度CT进行治疗后的安全评估，将针对所有治疗受试者进行，这与IV TPA治疗后的护理标准一致。用TPA治疗的最大受试者总数为80。DSMB将独立监控安全性，并定义停止规则以尽早停止研究，如果发生过度症状性内部出血（SICH）率。试验的停止边界是两个条件的杂种，因此，如果通过任何一种情况检测到令人难以置信的高出血率，则试验将出于安全问题而终止。这两个条件是对真实出血率的较低的95％置信度> 5.3％或绝对数量超过6。主要结果变量是SICH的。有症状的出血被定义为神经系统恶化的任何出血，NIHSS得分高于基线值或最低值在前7天或任何导致死亡的出血。主要的假设是SICH的速率不会超过ECASS 3中观察到的，这是一项临床试验，该试验表明，从最后一个已知的井（5.3％，95％，精确的置信区间：3.3％至7.9％），RT-PA的临床功效高达4.5小时。次要结果将是缺血性中风的临床结果和其他成像特征，例如脑水肿，病变体积生长。治疗3个月时，将通过改进的Rankin量表评分评估临床结果，并将其与非TPA和标准TPA治疗患者的历史对照进行比较。该临床试验是设计的，将与波士顿马萨诸塞州综合医院的同事合作进行。我们正在研究干扰素β-1A的潜力保护急性缺血性中风中的血脑屏障并防止溶栓疗法的出血并发症。该系列的首次临床试验是急性缺血性中风中的重组人干扰素β-1A：一项剂量升级和安全研究，今年完成了入学率。这种随机的双盲安慰剂对照顺序剂量升级的目的是，第1阶段的研究是研究IFN-beta-1a在急性缺血性中风的患者中3-24小时从发病开始，并确定在这种情况下给药的最大耐受剂量。计划了5例MCG，22 MCG，44 MCG，66 MCG和88 MCG的5例患者（4：1活跃：安慰剂）的5剂队列。患者每天每天接受干扰素β1A或安慰剂7天（静脉注射剂量1；皮下注入2-7剂量）。剂量升级是连续的，除非与药物相关的毒性达到剂量队列中的一个限制性不良事件（1中的1个中的1个）的预定水平，在这种情况下，将在该剂量下进行第二个队列5例（4：1）。该研究应以剂量水平终止，在该剂量水平上，有8例活跃治疗患者中有2个或3例患有严重的剂量限制毒性，或者完成所有计划的剂量队列时。以44mcg剂量达到了这种停止规则。盲目的数据验证和分析，包括药代动力学和血浆MMP-9浓度，正在进行中。不闪烁后，将使用DSMB审查结果。数据分析正在进行中。