Ph2a SQ HC infusion pump in congenital adrenal hyperplasia IND125,640 (9/15/2017)

摘要 先天性肾上腺皮质增生症（CAH）是一种肾上腺皮质功能不全的形式，其特征是皮质醇受损 合成和过量肾上腺雄激素产生。CAH儿童在推荐的口服 氢化可的松治疗反复暴露于低皮质醇血症的不良状态， 高皮质醇血症低皮质醇血症触发17-羟孕酮（17 OHP）的产生增加， 肾上腺雄激素（雄烯二酮; D4 A），可导致生长板过早融合，生殖器 男性化、性早熟、肾上腺休止、多囊卵巢综合征和不孕症。高皮质醇血症 也有不利的长期影响，如骨质疏松症，身材矮小，并增加发展的风险， 代谢综合征相关的动脉粥样硬化性心血管疾病在成年生活。目前口服氢化可的松 治疗是次优的，因为它不能复制昼夜节律和超昼夜皮质醇的脉动每日模式 分泌节律因此，即使是生理剂量的患者也会出现不良后果。所以一间 更接近地复制生理脉动皮质醇的改进的和个性化的药物递送系统 分泌和限制儿童低和高皮质醇血症的时期是必要的。我们的长期目标是 通过优化替代治疗的剂量和时间安排，改善CAH儿童的临床结局 治疗和避免高雄激素血症是特定的CAH。这项研究的目的是证明 脉动SQHC泵输送更接近地复制皮质醇的昼夜节律和超昼夜节律， 改善肾上腺雄激素的控制。我们的研究的基本原理是皮质醇谱更符合 皮质醇分泌的生理节律将产生更好的健康结果。我们的具体目标是设计和 实施个体化脉动SQHC泵方案，其将更接近地模拟皮质醇昼夜节律， 超昼夜节律，以减少患者经历高皮质醇血症和低皮质醇血症的时间长度，以及 延长17 OHP和D4 A血清浓度保持在可接受范围内的持续时间。这是 在CAH儿童中进行的第一项临床试验使用了脉动SQHC输送系统。我们的方法是创新的 因为这是对护理标准的实质性偏离，不仅可以显著改善长期护理， CAH患者的预后，但也改变了我们对患者糖皮质激素给药的基本方法 与其他病因的肾上腺功能不全，从而刺激激素药物治疗的新方法的发展， 交付，并刺激新的研究路线，在生理系统与严格控制的反馈 循环

ABSTRACT Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency characterized by impaired cortisol synthesis and excessive adrenal androgen production. Children with CAH under the recommended oral hydrocortisone therapy are repeatedly exposed to the undesirable states of hypocortisolemia and hypercortisolemia. Hypocortisolemia triggers increased production of 17-hydroxyprogesterone (17OHP) and adrenal androgen (androstenedione; D4A), which can lead premature fusion of the growth plates, genital virilization, precocious puberty, adrenal rests, polycystic ovarian syndrome and infertility. Hypercortisolemia also has untoward long term effects, such as osteoporosis, short stature, and increased risk for developing metabolic syndrome-related atherosclerotic cardiovascular disease in adult life. Current oral hydrocortisone therapy is suboptimal as it does not replicate the pulsatile daily patterns of both circadian and ultradian cortisol secretion rhythms. As such, even patients on physiological doses experience adverse outcomes. Therefore, an improved and personalized drug delivery system that more closely replicates physiological pulsatile cortisol secretion and limits periods of hypo- and hypercortisolemia in children is needed. Our long term goal is to improve clinical outcomes in children with CAH through optimizing the dosing and scheduling of replacement therapy and avoid the hyperandrogenemia that is specific to CAH. This study's objective is to demonstrate that pulsatile SQHC pump delivery more closely replicates circadian and ultradian rhythms of cortisol and improves control of adrenal androgens. Our study's rationale is that cortisol profiles more consistent with physiologic rhythms of cortisol secretion will produce better health outcomes. Our specific aim is to design and implement an individualized pulsatile SQHC pump regimen that will more closely mimic cortisol circadian and ultradian rhythms in order to reduce the length of time a patient experiences hyper- and hypocortisolemia, and extend the duration of time 17OHP and D4A serum concentrations remain in an acceptable range. This is the first clinical trial in children with CAH that uses a pulsatile SQHC delivery system. Our approach is innovative as it is a substantive departure from the standard of care that could not only significantly improve long-term outcomes of patients with CAH, but also alter our fundamental approach to glucocorticoid dosing of patients with adrenal insufficiency of other etiologies, thus spurring development of novel methods of hormonal drug delivery, and stimulating new lines of investigation in physiological systems with tightly controlled feedback loops.