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

基本信息

批准号：
10553088
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
项目类别：
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/10553088
关键词：
12 year old 13 year old 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 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 Heterozygote 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 Pharmaceutical Preparations Phase II Clinical Trials Phenotype Phosphodiesterase Inhibitors Pituitary Gland Placebos Production Proteins Proximal Kidney Tubules Pseudohypoparathyroidism Published Comment Randomized 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 gene repression 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 randomized, clinical trials receptor receptor function response secondary outcome severe early onset obesity

项目摘要

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 GNAS 基因下调导致刺激性 G 蛋白 (Gsα) 信号传导受损而引起。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，例如早期发病的肥胖和身材矮小没有有效的治疗方案 Gsα 信号对于垂体、甲状腺、性腺、肾近端小管和肾的正常激素功能至关重要。虽然许多由此产生的激素缺乏症可以通过激素替代疗法（HRT）来治疗，但 HRT 并不是治疗 PHP 表型的主要特征的严重早发性肥胖和身材矮小的有效疗法。该提案旨在测试旨在纠正 PHP 儿童 Gsα 依赖性受体功能的上游疗法的功效，该疗法从环磷酸腺苷的增加开始。 (cAMP) 被磷酸二酯酶 (PDE) 快速降解，PDE 抑制剂通过降低降解速率来延长 cAMP 信号传导。鉴于 PHP 患者的 cAMP 产生减少，但并非完全消失，我们试图测试其作用。假设 PDE 抑制剂茶碱会通过改善 Gsα 偶联受体信号传导来降低 PHP 儿童的体重指数 (BMI)、减缓骨骺闭合速度并降低激素抵抗。对患有 PHP 的儿童进行为期 52 周的随机、安慰剂对照临床试验茶碱是一种非选择性 PDE 抑制剂，在儿科患者中具有悠久的使用历史，使其成为患有 PHP 的青少年重新利用的理想药物。此外，茶碱的药代动力学很容易测量，我们的主要结果是体重指数的变化，次要结果包括骨骺闭合和 HRT 药物剂量的变化。在该修订后的提案中，我们纳入了接受茶碱治疗的成人的额外安全性和有效性数据。为了回应审稿人的意见，我们增加了长达 2 年的开放标签延长期，以便更好地评估长期安全性和有效性。功效。