ESETT Pharmacokinetic-Pharmacodynamic Study

ESETT 药代动力学-药效研究

• 批准号: 9381810
• 负责人: JAMES C. CLOYD
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381810
• 关键词: 2 year old; Adult; Adverse effects; Age; Ancillary Study; Area; Area Under Curve; Benzodiazepines; Blinded; Child; Clinical; Clinical Pharmacology; Clinical Research; Clinical Treatment; Clinical Trials; Clinical assessments; Complex; Data; Databases; Development; Dose; Double-Blind Method; Drug Exposure; Drug Kinetics; Drug usage; Enrollment; Evaluation; Failure; Future; Gender; Incidence; Individual; Infusion procedures; Investigation; Knowledge; Lead; Levetiracetam; Morbidity - disease rate; Motor Seizures; Neurological emergencies; New Agents; Outcome Measure; Parents; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Plasma; Population; Randomized; Randomized Controlled Trials; Recommendation; Recurrence; Refractory; Regimen; Reporting; Research; Research Design; Sampling; Seizures; Status Epilepticus; Testing; Time; United States; Valproic Acid; Weighing patient; Weight; age group; base; clinical practice; effective therapy; evidence base; fosphenytoin; improved; innovation; mortality; primary outcome; response; secondary outcome; sex; success; treatment trial

Status epilepticus (SE) is a common neurological emergency associated with high morbidity and mortality. While benzodiazepines are an effective first-line therapy for many patients with SE, evidence is lacking to guide treatment when drugs in this group fail. The Established Status Epilepticus Treatment Trial (ESETT), which is underway, is a randomized, blinded, response-adaptive study whose objective is to identify the most effective treatment for children and adults with convulsive SE refractory to standard dose of a benzodiazepine defined as established SE (ESE). ESETT is comparing three drugs: fosphenytoin (FOS), valproic acid (VPA), and levetiracetam (LVT). The primary outcome is clinical cessation of status epilepticus, determined by the absence of clinically apparent seizures and improving responsiveness, at 60 minutes after the start of study drug infusion, without the use of additional anti-seizure medications. However, the pharmacokinetics and pharmacodynamics of these three drugs, when used for ESE, are poorly understood. ESETT offers a unique opportunity to investigate drug exposure-response relationships. The specific aim of this ancillary study is to relate drug exposure (partial area under the curve, pAUC, from time 0 to 60 min after start of drug infusion) with the ESETT primary outcome and key secondary outcomes measures. The following hypotheses will be tested: Hypothesis 1: Patients with higher drug exposures (pAUC based on unbound or total plasma concentrations of FOS, VPA and LEV) will more likely respond to treatment. Hypothesis 2: Patients with higher drug exposures (pAUC) will have a higher incidence of adverse effects commonly associated with the study drugs. Hypothesis 3: The relationship between drug exposure and response will differ by gender, age group, and weight or BMI. While ESETT will identify the most or least effective clinical choice overall, this ancillary study will elucidate reasons for response and non-response. Further, an understanding of the exposure-response relationships will allow evidence-based guidance on how best to use these medications in patient care. Lastly, information from this ancillary study can guide future clinical trials as new agents are tested against the best drug or drugs that is/are ultimately determined by ESETT. Thus, this study will impact clinical practice and future ESE investigations.

癫痫持续状态（SE）是一种常见的神经系统急症，发病率和死亡率高。而 苯二氮卓类药物是许多SE患者的有效一线治疗，缺乏证据指导 当这组药物失败时进行治疗。既定癫痫持续状态治疗试验（ESETT），即 是一项随机、盲法、反应适应性研究，其目的是确定最有效的 治疗标准剂量苯二氮卓类药物难治的惊厥性SE儿童和成人，定义为 建立了SE（ESE）。ESETT正在比较三种药物：磷苯妥英（FOS）、丙戊酸（VPA）和 左乙拉西坦（LVT）。主要结局是癫痫持续状态的临床停止， 在研究药物输注开始后60分钟，临床上明显的癫痫发作和反应性改善， 不使用额外的抗癫痫药物。然而，药代动力学和药效学 这三种药物，当用于ESE时，知之甚少。ESETT提供了一个独特的机会， 研究药物疗效关系。 本辅助研究的具体目的是将药物暴露（从时间点至时间点的部分曲线下面积，pAUC） 药物输注开始后0至60分钟），ESETT主要结局和关键次要结局指标。 将检验以下假设： 假设1：药物暴露较高的患者（基于未结合或总血浆浓度的pAUC FOS、VPA和LEV）更有可能对治疗产生反应。 假设2：药物暴露量（pAUC）较高的患者不良反应发生率较高 通常与研究药物相关。 假设3：药物暴露与反应之间的关系因性别、年龄组和 体重或BMI。 虽然ESETT将确定总体上最有效或最不有效的临床选择，但这项辅助研究将阐明 回答和不回答的原因。此外，对确认-响应关系的理解将 允许以证据为基础的指导，如何最好地使用这些药物在病人护理。最后，来自 这项辅助研究可以指导未来的临床试验，因为新药物将与最好的药物进行测试， 最终由ESETT决定。因此，这项研究将影响临床实践和未来的ESE 调查事务所