Phase 2 Study of Theophylline for the Treatment of Psuedohypoparathyroidism

茶碱治疗假性甲状旁腺功能减退症的 2 期研究

• 批准号: 10322452
• 负责人: Ashley Hall Shoemaker
• 金额: $ 67.03万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322452
• 关键词: 12 year old; 13 year old; Adenosine Monophosphate; Adolescent; Adult; Anterior Pituitary Gland; Body Weight; Body Weight decreased; Body mass index; Calcitriol; Child; Childhood; Clinical Research; Clinical Trials; Coupled; Cyclic AMP; Data; Disease; Dose; Double-Blind Method; Down-Regulation; Drug Kinetics; Energy Metabolism; Enrollment; Enzymes; Epiphysial cartilage; Foundations; Funding; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic Diseases; Goals; Gonadal structure; Hormonal; Hormone replacement therapy; Hormones; Hypothalamic structure; Impairment; Investigational New Drug Application; Measures; Melanocortin 4 Receptor; Monitor; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome Measure; PTH gene; Patient Recruitments; Patients; Periodicity; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Phosphodiesterase Inhibitors; Pituitary Gland; Placebos; Production; Proteins; Proximal Kidney Tubules; Pseudohypoparathyroidism; Published Comment; Randomized; Randomized Clinical Trials; Rare Diseases; Receptor Signaling; Recording of previous events; Resistance; Rest; Safety; Serum; Signal Transduction; Somatotropin; Sympathetic Nervous System; Testing; Theophylline; Thyroid Gland; Thyrotropin; Thyroxine; Treatment Efficacy; Youth; bone; bone age; bone epiphysis; drug repurposing; early-onset obesity; effective therapy; efficacy testing; high risk; hormonal signals; hormone deficiency; hormone regulation; hormone resistance; hormone sensitivity; improved; open label; parathyroid hormone-related protein; pediatric patients; phase 2 study; phosphoric diester hydrolase; premature; primary outcome; randomized placebo-controlled clinical trial; rare genetic disorder; receptor; response; secondary outcome; severe early onset obesity

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.

假性甲状旁腺功能减退症（PHP）是一种罕见的遗传性疾病，由刺激性G蛋白（Gsα）信号通过下调基因GNAS受损引起。由此产生的激素异常可以通过激素替代疗法来治疗，但该疾病的其他方面，例如早发性肥胖和身材矮小，却没有有效的治疗方案。Gsα信号对于垂体、甲状腺、性腺、肾近端小管和下丘脑的正常激素功能是必不可少的。虽然许多由此产生的激素缺乏症可以用激素替代疗法（HRT）治疗，但是HRT对于作为PHP表型的主要特征的严重早发性肥胖和身材矮小不是有效的疗法。因此，本提案的目的是测试旨在纠正PHP儿童中Gsα依赖性受体功能的上游治疗的疗效。Gsα偶联受体信号级联反应始于环磷酸腺苷（cAMP）的增加，cAMP被磷酸二酯酶（PDE）迅速降解。PDE抑制剂通过降低降解速率延长cAMP信号传导而起作用。考虑到PHP患者的cAMP产生减少，但并非完全消失，我们试图验证PDE抑制剂茶碱通过改善Gsα偶联受体信号传导降低PHP儿童的体重指数（BMI）、减缓骨骺闭合速度和降低激素抵抗的假设。我们将进行一项为期52周的随机、安慰剂对照的茶碱治疗PHP儿童的临床试验。茶碱是一种非选择性PDE抑制剂，一般可用于儿科患者，具有悠久的使用历史，使其成为青少年PHP的理想药物。此外，茶碱的药代动力学是很好理解的，血清药物浓度很容易测量。我们的主要结果是BMI的变化。次要结局指标包括骨骺闭合和HRT药物剂量的变化。在本修订提案中，我们纳入了接受茶碱治疗的成人和青少年的额外安全性和疗效数据。为了回应审评员的意见，我们增加了长达2年的开放标签扩展期，以更好地评价长期安全性和疗效。