Canine Status Epilepticus: A Translational Platform for Human Therapeutic Trials

犬癫痫持续状态：人类治疗试验的转化平台

• 批准号: 8027499
• 负责人: ILO E LEPPIK
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8027499
• 关键词: Advisory Committees; Affect; Animal Model; Animals; Ataxia; Authorization documentation; Basic Science; Benzodiazepines; Biological Assay; Blood; Blood Pressure; Canis familiaris; Cessation of life; Clinical; Confusion; Data; Development; Diagnosis; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Electrocardiogram; Emergency Care; Emergency treatment; Experimental Models; Future; Goals; Guidelines; Half-Life; Hour; Human; Industry; Indwelling Catheter; Infusion procedures; International; Intravenous; Investigation; Laboratories; Laboratory Study; Lead; Liquid substance; Masks; Measures; Modeling; Monitor; Neurological emergencies; Outcome; Performance; Persons; Pharmaceutical Preparations; Phase; Phenytoin; Physiologic pulse; Placebo Control; Placebo Effect; Placebos; Plasma; Process; Prodrugs; Protocols documentation; Randomized; Recovery; Regimen; Reporting; Research; Research Ethics Committees; Role; Safety; Saline; Scientist; Sedation procedure; Seizures; Status Epilepticus; System; Testing; Therapy Clinical Trials; Time; Toxic effect; Translating; Translations; Validation; Veterinary Medicine; Weight; base; design; drug testing; fosphenytoin; improved; interest; meetings; novel; prospective; public health relevance; randomized placebo controlled trial; response; therapeutic development; treatment trial

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.

描述(申请人提供)：这项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发现的新药转化为人类癫痫持续状态(HSE)的治疗。这项研究的目标是：1)确定在狗身上自然出现的癫痫持续状态是否是测试在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；以及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INDS和IRB在人类临床SE试验中的应用提供必要的信息。苯妥英(PHT)的前体药物磷苯妥因(FOS)在统计学上优于安慰剂，具有与人类相似的响应率，这一证明将建立犬SE平台，作为一种有效、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，每年估计有152,000人受到惊厥性HSE影响，并导致42,000人死亡(1)。目前的治疗指南包括30至70年前开发的药物(苯妥英、苯二氮卓类)，在超过1/3至1/2的病例中不成功(4)。PHT的负荷量包括在目前的国际HSE治疗指南中(3)。FOS的开发是为了避免PHT IV的毒性作用。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)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。我们建议用负荷量的FOS治疗已确诊为CSE的狗，以达到与人类在负荷量为18 mg/kg后获得的PHT浓度相似的剂量。我们的研究将是一项随机、双盲、安慰剂对照的研究，对确诊为CSE的狗进行FOS和生理盐水对照研究。它将包括一项强有力的救援方案。使用安慰剂对照极大地增加了研究的力量，并减少了所需的受试者数量。该平台的验证将基于：1)FOS(50%反应)与安慰剂(10%反应)的统计优势，使这项研究有40%的差异；以及2)FOS的反应率约为50%，类似于在HSE试验中观察到的PHT的反应率。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，就可以启动治疗开发进程，从而能够：1)建立类似于人类神经紧急情况治疗试验(NETT)系统的国家兽医紧急护理部门网络；2)使用CNETT测试特定的新型制剂3)使CNETT可供基础科学家和行业用于测试新化合物的HSE；并且2和3的结果可用于为IND治疗HSE的申请提供信息。 公共卫生相关性：这项申请提出了一个原则研究的证据，可以导致后续的项目，这些项目将促进将从癫痫持续状态实验室模型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飞跃是非常巨大的，并且极大地限制了进展。我们建议研究一种治疗人类癫痫状态的常用药物，磷苯妥因，在自然发生癫痫状态的狗身上，以表明狗的反应与人类相似，在狗身上测试新药将开发出有助于获得在人类身上测试这些药物的许可的信息。