Abiraterone Acetate in Childen with Classic 21-Hydroxylase Deficiency

 先天性肾上腺皮质增生（CAH）是一种遗传性的不能合成皮质醇的疾病。超过90%的病例是由类固醇21-羟化酶（CYP 21）缺乏引起的，这在约1：16，000的出生中以严重的“经典”形式发生。患有典型CAH的婴儿易患危及生命的肾上腺功能不全。此外，肾上腺皮质过度产生皮质醇前体，特别是17-羟孕酮（17-OHP），其进一步代谢为雄激素前体（例如，雄烯二酮）和随后的睾酮。严重受影响的女孩出生时外生殖器模糊。治疗不充分的患者暴露于高水平的性激素，促进快速的躯体生长和加速骨骼成熟，导致过早的骨骺融合。典型患者的成人身高平均比人群平均值低约7 cm。患者通过替代糖皮质激素（通常用氢化可的松）和盐皮质激素（用氟氢可的松）进行治疗。糖皮质激素治疗不足和过度治疗都使患者面临身材矮小的风险，前者是由于性类固醇分泌异常引起的骨骺过早闭合，后者是由于糖皮质激素诱导的生长抑制。过量的糖皮质激素暴露也使CAH患者处于过度体重增加和代谢综合征的风险中。本项目将测试是否药物阻断性类固醇合成的青春期前儿童CAH改善这些问题。研究药物醋酸阿比特龙是阿比特龙的前药，阿比特龙是一种雄激素生物合成抑制剂，获批用于治疗前列腺癌。研究人群包括青春期前儿童与经典CAH由于21-羟化酶缺乏症，女孩2-8岁和男孩2-9岁。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1期研究中，我们将确定使雄烯二酮水平正常化的醋酸阿比特龙的最小有效剂量。在7天治疗期内，最多3个队列（每组8例受试者）将连续接受1、2或4 mg/kg/d醋酸阿比特龙，直至7/8例受试者在阿比特龙给药第7天早晨雄烯二酮浓度恢复正常。在一项II期研究中，我们将评估醋酸阿比特龙作为连续治疗的效用，以最大限度地减少雄激素过度分泌，并允许更多的生理性糖皮质激素替代。本研究是一项为期24个月的醋酸阿比特龙（1期确定的剂量）与安慰剂的双盲随机对照试验。我们将随机分配54例受试者（36例接受阿比特龙治疗，18例接受安慰剂治疗），旨在使48例受试者完成研究。主要假设是接受阿比特龙的受试者将具有较慢的骨骼成熟（即，放射学骨龄的进展）。次要假设是接受阿比特龙的受试者将需要较低的平均每日氢化可的松剂量来使雄烯二酮正常化。探索性假设是，与接受安慰剂的受试者相比，接受阿比特龙的受试者的体重、身高和BMI增加较少，因此通过HOMA-IR测量的胰岛素抵抗较少。

 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.