Phase II Trial of Tiopronin in Aneurysmal Subarachnoid Hemorrhage

描述（由申请人提供）： 目前还没有治疗脑缺血后的损伤。许多神经毒素，包括3-氨基丙醛（3AP），在缺血脑中产生，产生脑细胞死亡的恶性循环。迄今为止，假定的神经保护药物在急性中风背景下的临床试验尚未成功。 然而，这些药物试验中有许多是基于临床前动物研究，这些研究显示，如果在缺血发作之前开始用药，结果是有希望的。 与急性卒中不同，aSAH后脑血管痉挛后的缺血可允许预处理缺血，因为血管痉挛的风险期开始于首次出血发生后约72小时。本研究的目的是检查硫普罗宁（FDA批准的用于胱氨酸肾结石适应症的药物）对aSAH后临床结局和体内神经毒素3AP水平的影响。该研究将遵循2期，多中心，随机，双盲，安慰剂对照药物试验形式，在三个主要的学术医疗中心招募60名患者。aSAH患者将获得知情同意，并随机分配至安慰剂组或药物组。在首次出血后的14天内，他们将接受药物或安慰剂治疗并进行临床评估。在此期间，血清和（如果患者有脑室导管）脑脊液（CSF）将与临床采血一起收集沿着。将使用酶联免疫吸附试验（ELISA）试剂盒分析这些样本，以确定3AP水平。还将在出血后14天（或出院，以先发生者为准）以及首次出血后3个月和12个月时使用问卷评价患者的临床结局。 主要结局将是显示与安慰剂相比，接受药物的患者的CSF和血液中3AP水平降低。次要结局将显示药物组和安慰剂组之间的临床结局差异，并继续验证硫普罗宁在aSAH人群中的安全性。如果这项研究成功，3期药物试验将进一步分析硫普罗宁在aSAH中的临床效果。这将引发进一步的研究，可以进一步探索脑缺血的神经保护性预处理，从而有助于消除这种疾病过程中发病率和死亡率的主要来源。

DESCRIPTION (provided by applicant): Currently there is no treatment for the damage that follows cerebral ischemia. Many neurotoxins, including 3-aminopropanal (3AP), are produced in ischemic brain producing a vicious cycle of brain cell death. Clinical trials of putative neuroprotective drugs in the setting of acute stroke have thus far not succeeded. However, many of those drug trials were based on pre-clinical animal studies which showed promising results if drug was started before the onset of ischemia. Unlike in acute stroke, the ischemia that follows cerebral vasospasm following aSAH feasibly allows for pretreatment of the ischemia since the onset of the risk period for vasospasm starts approximately 72 hours after the onset of the initial bleed. It is the intention of this study to examine the effect of tiopronin, an FDA approved drug for the indication of cystine kidney stones, on clinical outcome and levels of the neurotoxin 3AP in the body following aSAH. The study will follow a Phase 2, multicenter, randomized, double-blinded, placebo-controlled drug trial format, enrolling 60 patients at three major academic medical centers. Patients who present with aSAH will be consented and randomized to either placebo or drug group. For up to 14 days after their initial bleed, they will be given drug or placebo and evaluated clinically. During this time, serum and (if the patient has a ventricular catheter) cerebrospinal fluid (CSF) will be collected along with the clinical draws. These samples will be analyzed with an enzyme-linked immunosorbent assay (ELISA) kit to determine 3AP levels. Patients will also be evaluated for clinical outcome with questionnaires at 14 days after the bleed (or discharge whichever comes first) and at 3 and 12 months after the initial bleed. The primary outcome will be to show a reduction in levels of 3AP in the CSF and blood of patients who received drug compared to placebo. Secondary outcomes will be to show clinical outcome differences between the drug and placebo group and to continue to validate the safety of tiopronin in the aSAH population. If this study is successful, a Phase 3 drug trial will further analyze the clinical effects of tiopronin in aSAH. This would spark further study that could further explore neuroprotective pre-treatment of cerebral ischemia, and thus help neutralize a major source of morbidity and mortality in this disease process.