Phase 2A Study of Exendin for the Treatment of Congenital Hyperinsulinism

描述（由申请人提供）： 先天性高胰岛素血症（CHI）是一种罕见的胰腺β细胞功能遗传性疾病，其特征是在低血糖的情况下无法抑制胰岛素分泌，如果控制不当，会导致脑损伤或死亡。 受最常见形式的CHI影响的儿童对药物治疗无反应，并且需要在出生后不久进行几乎全胰腺切除术以治疗顽固性低血糖。 初步临床前和临床数据支持使用GLP-1受体拮抗剂exendin-（9-39）作为一种新型治疗方法。本提案的目的是获得药效学数据，以评估exendin-（9- 39）暴露与空腹血糖之间的关系。研究人员提出了两种互补的方法来实现这一目标：1）对目标人群进行临床试验，2） 模拟审判目的1是一项开放标签、安慰剂对照、单次给药研究，旨在评估静脉注射exendin-（9-39）治疗CHI儿童的效果、安全性、耐受性、药代动力学和药效学。16名6个月及6个月以上因CHI而持续低血糖的儿童将在禁食期间接受6小时exendin-（9-39）或溶媒输注，采用交叉随机设计。将检查治疗对血糖的影响，并收集药代动力学和安全性数据。探索性目的是评估exendin-（9-39）的免疫原性。假设毒蜥外泌肽-（9-39）将以剂量依赖性方式升高空腹血糖，并且耐受性良好，足以允许继续进行临床研究。目的2是一项试验模拟，旨在评价试验设计结构，以最大限度地提高后续II/III期试验临床试验成功的可能性。生成的药代动力学和药效学数据将用于基于模型预测预期达到未来关键临床试验目标临床终点的剂量和方案。

DESCRIPTION (provided by applicant): Congenital hyperinsulinism (CHI) is a rare genetic disorder of pancreatic beta-cell function characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if inadequately controlled. Children affected by the most common form of CHI are unresponsive to medical therapy and require a near-total pancreatectomy shortly after birth for intractable hypoglycemia. Preliminary preclinical and clinical data suppor the use of the GLP-1 receptor antagonist, exendin-(9-39) as a novel therapeutic approach. The goal of this proposal is to obtain pharmacodynamics data for assessing the relationship between exendin-(9- 39) exposure and fasting blood glucose. The investigators propose two complimentary approaches to achieve this goal: 1) a clinical trial on the target population, and 2) a trial simulation. Aim 1 is an open label, placebo-controlled, single dose study to assess the effect, safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous exendin-(9-39) in children with CHI. Sixteen children 6 months of age and older with persistent hypoglycemia due to CHI will receive a six hour infusion of exendin-(9-39) or vehicle during fasting in a cross-over randomized design. The effect of treatment on blood glucose will be examined and pharmacokinetics and safety data will be collected. An exploratory aim will be to assess the immunogenicity of exendin-(9-39). The hypothesis is that exendin-(9-39) will elevate fasting blood glucose in a dose dependent manner and will be sufficiently well tolerated to permit continued clinical investigation. Aim 2 is a trial simulation to evaluate trial design constructs in an attempt to maximize the likelihood of clinical trial success for subsequent Phase 2/3 trials. The pharmacokinetics and pharmacodynamics data generated will be used for model-based prediction of doses and regimens expected to achieve target clinical endpoints for a future pivotal clinical trial.