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，促进从癫痫持续状态实验室模型中发现的新药转化为人类癫痫持续状态（HSE）的治疗。本研究的目的是：1）确定犬中自然发生的癫痫持续状态是否是测试SE实验模型中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，使实验室中发现的药物可用于治疗HSE。结果将为IND和IRB申请人体临床SE试验提供必要信息。证明磷苯妥英钠（FOS），苯妥英钠（PHT）的前药，在统计学上上级安慰剂，并具有与人类相似的反应率，将建立犬SE平台作为一种有效，廉价，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，惊厥性HSE每年影响约152，000人，并导致42，000人死亡（1）。目前的治疗指南包括30至70年或更长时间前开发的药物（苯妥英，苯二氮卓类），这些药物在超过1/3至1/2的病例中不成功（4）。PHT的负荷剂量包括在HSE治疗的现行国际指南中（3）。开发FOS是为了避免IV PHT的毒性作用。FOS现在被广泛用于HSE，并将用于本研究（17）。犬癫痫持续状态（CSE）是临床兽医实践中常见的疾病。其原因和表现与HSE（10，11）中所见相似。我们建议用负荷剂量的FOS治疗已确诊CSE的犬，以达到与18 mg/kg负荷剂量后人体中达到的PHT浓度相似的PHT浓度。我们的研究将是一项随机、双盲、安慰剂对照研究，在确诊CSE的犬中比较FOS与生理盐水。它将包括一个强有力的救援协议。使用安慰剂对照大大增加了功效，并减少了所需的受试者数量。该平台的验证将基于：1）FOS（50%缓解）与安慰剂（10%缓解）相比的统计学优效性，为研究提供40%差异的动力; 2）FOS的缓解率约为50%，与HSE试验中PHT的观察结果相似。如果我们能够证明CSE作为动物模型中发现的药物测试平台的有效性，则可以启动治疗开发过程，这将使得：1）建立类似于人类神经紧急情况治疗试验（NETT）系统的兽医紧急护理部门的国家网络; 2）使用CNETT测试特定的新型试剂3）使CNETT可用于基础科学家和工业界测试HSE的新化合物; 2和3的结果可用于通知IND申请以治疗HSE。 公共卫生相关性：该申请提出了一项原理研究的证明，该研究可以导致后续项目，这些项目将促进从癫痫持续状态的实验室模型中发现的新药转化为人类癫痫持续状态的治疗。从小动物发现新药到人体试验的跳跃是非常巨大的，并且极大地限制了进展。我们建议在自然发生癫痫持续状态的犬中研究一种常用的人类癫痫持续状态药物，磷苯妥英，以表明犬对人类的反应相似，并且在犬中测试新药将开发用于获得在人类中测试这些药物的许可的有用信息。

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.