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

摘要 先天性肾上腺增生(CAH)是一种以皮质醇受损为特征的肾上腺功能不全。 合成和过量的肾上腺雄激素分泌。建议口服CAH的儿童 氢化可的松治疗反复暴露于低皮质醇血症和 高皮质醇血症。低皮质醇血症触发17-羟孕酮(17OHP)的产生增加 肾上腺雄激素(雄烯二酮；D4A)，可导致生长板、生殖器过早融合 男性化、性早熟、肾上腺休息、多囊卵巢综合征和不孕症。高皮质醇血症 也有不好的长期影响，如骨质疏松症、矮小和增加发展的风险。 成人生活中代谢综合征相关的动脉粥样硬化性心血管疾病。现代口服氢化可的松 治疗是次优的，因为它不能复制昼夜节律和超短程皮质醇的搏动性每日模式。 分泌节律。因此，即使是生理剂量的患者也会出现不良后果。因此，一个 改进的个性化给药系统，更紧密地复制生理脉搏皮质醇 儿童低皮质醇和高皮质醇血症的分泌和限制期是必要的。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儿童CAH的临床结局 治疗和避免CAH特有的高雄激素血症。这项研究的目的是证明 脉动的SQHC泵输送更紧密地复制了皮质醇和皮质醇的昼夜节律和超常节律 改善对肾上腺雄激素的控制。我们研究的理论基础是皮质醇的特征更符合 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 实施个性化脉冲式SQHC泵方案，将更接近皮质醇昼夜节律和 超常节律，以减少患者经历高和低皮质醇血症的时间，以及 延长17OHP和D4A血药浓度维持在可接受范围的持续时间。这是 首次在使用脉动SQHC给药系统的CAH儿童中进行临床试验。我们的方法是创新的 因为这是对护理标准的实质性背离，不仅可以显著改善长期 CAH患者的预后，但也改变了我们对患者使用糖皮质激素剂量的基本方法 肾上腺功能不全的其他原因，从而刺激了激素药物的新方法的发展 提供，并通过严格控制的反馈在生理系统中激发新的研究路线 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.