Abiraterone Acetate in Childen with Classic 21-Hydroxylase Deficiency

醋酸阿比特龙治疗典型 21-羟化酶缺乏症儿童

基本信息

批准号：
8864935
负责人：
PERRIN C WHITE
金额：
$ 64.37万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-17 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8864935
关键词：
10 year old 2 year old 9 year old Acetates Adrenal Cortex Adrenal Glands Adrenal gland hypofunction Adult Affect Age Anabolism Androgens Androstenedione Birth CYP17A1 gene CYP21A2 gene Child Chronic Congenital adrenal hyperplasia Corticotropin Disease Dose Double-Blind Method Estrogens Exposure to Fludrocortisone Glucocorticoids Gonadal Steroid Hormones Growth Height Hydrocortisone Hydroxyprogesterone Infant Inherited Insulin Resistance Lead Life Malignant neoplasm of prostate Measures Medical Metabolic syndrome Mineralocorticoids Mixed Function Oxygenases Obesity Patients Pharmaceutical Preparations Phase Physiological Placebos Population Population Study Prednisone Prodrugs Protocols documentation Randomized Randomized Controlled Trials Risk Specific qualifier value Steroid 17-alpha-monooxygenase Steroid 21-Monooxygenase Suspension substance Suspensions Testing Testosterone Weight Weight Gain Woman abiraterone arm bone age boys castration resistant prostate cancer cohort dehydroepiandrosterone epiphyseal closure external genitalia girls improved inhibitor/antagonist men phase 1 study phase 2 study postnatal prednisolone premature prepuberty prevent public health relevance screening skeletal treatment duration

项目摘要

DESCRIPTION (provided by applicant): Congenital adrenal hyperplasia (CAH) is an inherited inability to synthesize cortisol. More than 90% of cases are caused by deficiency of steroid 21-hydroxylase (CYP21), which occurs in the severe "classic" form in ~1:16,000 births. Infants with classic CAH are susceptible to life threatening adrenal insufficiency. Additionally, the adrenal cortex overproduces cortisol precursors, particularly 17-hydroxyprogesterone (17-OHP), which are further metabolized to androgen precursors (e.g., androstenedione) and subsequently to testosterone. Severely affected girls are born with ambiguous external genitalia. Inadequately treated patients are exposed to high levels of sex hormones which promote rapid somatic growth and accelerated skeletal maturation leading to premature epiphyseal fusion. Adult heights in classic patients average ~ 7 cm below the population mean. Patients are treated by replacing glucocorticoids (usually with hydrocortisone) and mineralocorticoids (with fludrocortisone). Both under-treatment and over-treatment with glucocorticoids put patients at risk for short stature, the former owing to premature epiphyseal closure induced by abnormal secretion of sex steroids, and the latter to glucocorticoid-induced inhibition of growth. Excess glucocorticoid exposure also puts CAH patients at risk for excess weight gain and metabolic syndrome. This project will test whether pharmacologic blockade of sex steroid synthesis in prepubescent children with CAH improves these problems. The study drug, abiraterone acetate, is a prodrug of abiraterone, an androgen biosynthesis inhibitor approved for treatment of prostate cancer. The study population includes prepubescent children with classic CAH owing to 21-hydroxylase deficiency, girls 2-8 and boys 2-9 years old. Subjects will be treated with hydrocortisone and fludrocortisone throughout each study. In a Phase 1 study, we will determine the minimum effective dose of abiraterone acetate that normalizes androstenedione levels. During the 7-day Treatment Period, up to 3 cohorts of 8 subjects each will receive, in succession, 1, 2 or 4 mg/kg/d of abiraterone acetate, until 7/8 subjects have normalized their morning androstenedione concentration on Day 7 of abiraterone administration. In a Phase 2 study, we will assess the utility of abiraterone acetate as adjunctive therapy to minimize excessive androgen secretion and allow more physiologic glucocorticoid replacement. This study is a double-blind randomized controlled trial of abiraterone acetate (dose determined in Phase 1) versus placebo for 24 months. We will randomize 54 subjects (36 to abiraterone and 18 to placebo), aiming to have 48 subjects completing the study. The primary hypothesis is that subjects receiving abiraterone will have slower skeletal maturation (i.e., advancement in radiologic bone age). The secondary hypothesis is that subjects who receive abiraterone will require lower mean daily hydrocortisone doses to normalize androstenedione. Exploratory hypotheses are that subjects receiving abiraterone will have lower increases in weight, height and BMI, and consequently less insulin resistance as measured by HOMA-IR, than subjects receiving placebo.

描述（由申请人提供）：先天性肾上腺增生症 (CAH) 是一种遗传性合成皮质醇的障碍，超过 90% 的病例是由类固醇 21-羟化酶 (CYP21) 缺乏引起的，这种情况以严重的“经典”形式出现。大约 1:16,000 患有典型 CAH 的婴儿容易出现危及生命的肾上腺皮质功能不全。过度产生皮质醇前体，特别是 17-羟基黄体酮 (17-OHP)，这些前体会进一步代谢为雄激素前体（例如雄烯二酮），并随后接受睾酮治疗。受影响严重的女孩出生时外生殖器不明确。性激素促进体细胞快速生长并加速骨骼成熟，导致成人身高过早骨骺融合。典型患者的平均身高比总体平均水平低 7 厘米，患者接受糖皮质激素（通常用氢化可的松）和盐皮质激素（氟氢可的松）替代治疗，糖皮质激素治疗不足和过度治疗都会使患者面临身材矮小的风险。性类固醇异常分泌引起的骨骺过早闭合，以及糖皮质激素引起的生长抑制。该项目还将测试青春期前患有 CAH 的儿童性类固醇合成的药物阻断是否可以改善这些问题。该研究药物醋酸阿比特龙是阿比特龙（一种雄激素生物合成）的前药。批准用于治疗前列腺癌的抑制剂。研究人群包括因 21-羟化酶缺乏而患有典型 CAH 的青春期前儿童、2-8 岁女孩和 2-9 岁男孩。在每项研究中，受试者将接受氢化可的松和氟氢可的松治疗，在 7 天的治疗期内，我们将确定使雄烯二酮水平正常化的醋酸阿比特龙的最低有效剂量，最多 3 组，每组 8 名受试者。每个受试者将连续接受 1、2 或 4 mg/kg/d 醋酸阿比特龙，直到 7/8 受试者恢复正常在第 2 期研究中，我们将评估阿比特龙作为辅助治疗的效用，以最大程度地减少雄激素分泌过多并允许更多的生理性糖皮质激素替代。醋酸阿比特龙（第一阶段确定的剂量）与安慰剂的比较，为期 24 个月。我们将随机分配 54 名受试者。（36 名受试者接受阿比特龙，18 名受试者接受安慰剂），旨在让 48 名受试者完成研究。主要假设是接受阿比特龙治疗的受试者骨骼成熟速度较慢（即放射学骨龄提前）。阿比特龙需要较低的每日平均氢化可的松剂量来使雄烯二酮正常化。探索性假设是，接受阿比特龙治疗的受试者的体重、身高和体重增加较少。与接受安慰剂的受试者相比，体重指数 (BMI) 以及因此通过 HOMA-IR 测量的胰岛素抵抗程度较低。