Canine Status Epilepticus: A Translational Platform for Human Therapeutic Trials

描述（由申请人提供）：本申请提出了一项研究，如果成功，将直接导致后续项目，这些项目将促进从癫痫持续状态实验室模型中发现的新药转化为治疗人类癫痫持续状态（HSE）。本研究的目的是：1)确定自然发生的犬癫痫持续状态是否为测试在SE实验模型中发现的有效化合物的有效性、安全性和耐受性的有效平台；2)启动治疗开发过程，使实验室发现的药物可用于治疗HSE。结果将为人类临床SE试验的ind和IRB申请提供必要的信息。证明苯妥英（PHT）的前药fosphenytoin （FOS）在统计学上优于安慰剂，其反应率与人类相似，将使犬SE平台成为一种有效、廉价和快速的手段，将从实验室SE模型中发现的药物转化为HSE研究。在美国，痉挛性HSE每年影响约152,000人，导致42,000人死亡(1)。目前的治疗指南包括30至70年前或更早开发的药物（苯妥英、苯二氮卓类药物），这些药物在超过1/3至1/2的病例中不成功(4)。PHT的负荷剂量包含在目前的HSE治疗国际指南中(3)。FOS是为了避免IV PHT的毒性作用而开发的。FOS现在被广泛用于HSE，并将在本研究中使用（17）。犬癫痫持续状态（CSE）在临床兽医实践中经常遇到。原因和表现与HSE相似（10,11）。我们建议用FOS负荷剂量治疗患有CSE的狗，使其达到与人类在负荷剂量为18 mg/kg时达到的PHT浓度相似的浓度。我们的研究将是一项随机、双盲、安慰剂对照的研究，对患有CSE的狗进行FOS和生理盐水的对比。它将包括一个强有力的救援协议。使用安慰剂对照极大地增加了功效并减少了所需受试者的数量。该平台的验证将基于：1)FOS（50%应答）与安慰剂（10%应答）的统计优势，为研究提供40%的差异；2) FOS的反应率约为50%，与HSE试验中PHT的反应率相似。如果我们能够证明CSE作为测试在动物模型中发现的药物的平台的有效性，则可以启动治疗开发过程，这将使：1)建立一个类似于人类神经紧急治疗试验（NETT）系统的国家兽医急诊部门网络；2)使用CNETT测试特定的新药3)使CNETT可用于基础科学家和工业界测试新的HSE化合物；2和3的结果可用于通知HSE处理的IND申请。

DESCRIPTION (provided by applicant): This application proposes a study that, if successful, will lead directly to subsequent projects that will facilitate the translation of new drugs discovered from laboratory models of status epilepticus to treatment of human status epilepticus (HSE). The goals of this study are to: 1) determine if naturally occurring status epilepticus in dogs is a valid platform to test compounds found effective in experimental models of SE for efficacy, safety and tolerability; and 2) initiate a process of therapeutic development to make drugs discovered in the laboratory available for the treatment of HSE. Results will provide information essential for INDs and IRB applications for human clinical SE trials. Demonstration that fosphenytoin (FOS), a prodrug of phenytoin (PHT), is statistically superior to placebo and has a response rate similar to that in humans will establish the canine SE platform as a valid, inexpensive, and rapid means to translate agents discovered from laboratory SE models into studies of HSE. Convulsive HSE affects an estimated 152,000 persons and causes 42,000 deaths each year in the USA (1). Current guidelines for treatment incorporate drugs developed 30 to 70 or more years ago (phenytoin, benzodiazepines), which are not successful in more than 1/3 to 1/2 of cases (4). Loading doses of PHT are included in the current international guidelines for the treatment of HSE (3). FOS was developed to avoid the toxic effects IV PHT. FOS is now widely prescribed for HSE and will be used in this study (17). Canine status epilepticus (CSE) is commonly encountered in clinical veterinary practice. The causes and presentation are similar to those seen in HSE (10,11). We propose to treat dogs with established CSE with loading doses of FOS designed to attain PHT concentrations similar to those attained in humans following loading doses of 18 mg/kg. Our study will be a randomized, double-blind, placebo-controlled investigation of FOS vs. saline in dogs with established CSE. It will include a robust rescue protocol. Using a placebo control greatly increases the power and decreases the number of subjects needed. Validation of the platform will be based on: 1) statistical superiority of the FOS (50% response) vs. placebo (10% response), powering the study for a 40% difference; and 2) a response rate of approximately 50% for FOS, similar to that observed for PHT in HSE trials. If we are able to demonstrate the validity of CSE as a platform for testing drugs discovered in animal models, a process of therapeutic development can be initiated that will enable: 1) establishment of a national network of veterinary emergency care departments similar to the human Neurological Emergencies Treatment Trials (NETT) system; 2) use the CNETT to test specific novel agents 3) make the CNETT available to basic scientists and industry to test new compounds for HSE; and results from 2 and 3 may be used to inform IND applications for treatment of HSE. PUBLIC HEALTH RELEVANCE: This application proposes a proof of principle study that can lead to subsequent projects that will facilitate the translation of new drugs discovered from laboratory models of status epilepticus to treatment of human status epilepticus . The jump from small animal discovery of new drugs to human testing is very great and has greatly limited progress. We propose to study a commonly used drug for human status epilepticus, fosphenytoin, in dogs with naturally occurring status epilepticus, to show that dogs respond similarly to humans and that testing new drugs in dogs will develop information useful for obtaining permission to test these in humans.