Phase 2 Study of Theophylline for the Treatment of Psuedohypoparathyroidism

假性甲状旁腺功能减退症是一种罕见的遗传性疾病，其原因是刺激性G蛋白(Gs-α)信号下调。由此产生的激素异常可以用激素替代疗法来治疗，但这种疾病的其他方面，如早发性肥胖和身材矮小，没有有效的治疗选择。GSα信号对垂体、甲状腺、性腺、肾近端小管和下丘脑的正常激素功能至关重要。虽然许多由此导致的激素缺乏可以通过激素替代疗法(HRT)来治疗，但HRT对严重的早发性肥胖和身材矮小并不是一种有效的治疗方法，这些都是PHP表型的主要特征。因此，这项建议的目标是测试上游疗法的有效性，目的是纠正PHG儿童的Gsα依赖受体的功能。GSα偶联受体信号通路始于cAMP的增加，cAMP被磷酸二酯酶迅速降解。PDE抑制剂的作用是通过降低降解速度延长cAMP信号。鉴于PHP患者cAMP的产生减少了，但并非完全消失，我们试图验证这样的假设，即PDE抑制剂茶碱可以通过改进Gsα偶联受体信号来降低体重指数，减缓骨骺关闭的速度，并降低PHP儿童的激素抵抗。我们将对患有PHP的儿童进行为期52周的随机、安慰剂对照的茶碱临床试验。茶碱是一种非选择性的PDE抑制剂，在儿科患者中有很长的使用历史，使其成为青年PHP患者重新调整用途的理想药物。此外，茶碱的药代动力学被很好地理解，而且很容易测量血清药物浓度。我们的主要结果是体重指数的变化。次要结果测量包括骨骺闭合和激素替代疗法用药剂量的变化。在这项修订后的建议中，我们纳入了使用茶碱治疗的青少年成人的额外安全性和有效性数据。为了回应审查者的意见，我们增加了长达2年的开放标签延长期，以更好地评估长期安全性和有效性。

Pseudohypoparathyroidism (PHP) is a rare, genetic disorder caused by impaired stimulatory G protein (Gsα) signaling through downregulation of the gene, GNAS. The resultant hormone abnormalities can be treated with hormone replacement therapy, but other aspects of the disorder such as early-onset obesity and short stature are without effective treatment options. Gsα signaling is essential for the normal hormonal function of the pituitary, thyroid, gonads, renal proximal tubules and hypothalamus. While many of the resulting hormone deficiencies can be treated with hormone replacement therapy (HRT), HRT is not an effective therapy for the severe early-onset obesity and short stature which are major features of the PHP phenotype. Therefore, the goal of this proposal is to test the efficacy of upstream therapy aimed at correcting the function of Gsα-dependent receptors in children with PHP. Gsα-coupled receptor signaling cascade begins with an increase in cyclic adenosine monophosphate (cAMP) which is rapidly degraded by the enzyme phosphodiesterase (PDE). PDE inhibitors act by prolonging cAMP signaling by decreasing the rate of degradation. Given that patients with PHP have reduced, but not completely absent, cAMP production, we seek to test the hypothesis that the PDE inhibitor theophylline will reduce body mass index (BMI), slow the rate of epiphyseal closure, and decrease hormone resistance in children with PHP through improved Gsα-coupled receptor signaling. We will conduct a 52-week randomized, placebo-controlled clinical trial of theophylline in children with PHP. Theophylline is a non-selective PDE inhibitor that is generically available and has a long history of use in pediatric patients, making it an ideal drug for repurposing in youth with PHP. Furthermore, the pharmacokinetics of theophylline are well understood, and serum drug levels are easily measured. Our primary outcome is change in BMI. Secondary outcome measures include change in epiphyseal closure and HRT medication doses. In this revised proposal, we have included additional safety and efficacy data from adults in adolescents treated with theophylline. In response to reviewer comments, we have added an open-label extension period of up to 2 years in order to better evaluate long-term safety and efficacy.