Abiraterone Acetate in Childen with Classic 21-Hydroxylase Deficiency

 描述(申请人提供)：先天性肾上腺增生症(CAH)是一种遗传性皮质醇合成障碍。超过90%的病例是由类固醇21-羟基酶(CyP21)缺乏引起的，在1/16,000名新生儿中以严重的“经典”形式发生。患有经典型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)，进一步代谢为雄激素前体(如雄烯二酮)，随后代谢为睾酮。受严重影响的女孩出生时外生殖器不明确。治疗不充分的患者暴露在高水平的性激素中，这些激素促进了身体的快速生长和骨骼的加速成熟，导致了骨盆过早融合。典型患者的成人身高平均比人群平均身高低7厘米。患者的治疗方法是用糖皮质激素(通常用氢化可的松)和盐皮质激素(用氟可的松)。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，前者是由于性激素分泌异常导致骨骺提前关闭，后者是由于糖皮质激素导致的生长抑制。过量的糖皮质激素暴露也会使CAH患者面临体重过度增加和代谢综合征的风险。该项目将测试药物阻断患有CAH的青春期前儿童的性类固醇合成是否改善了这些问题。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，被批准用于治疗前列腺癌。研究人群包括因21-羟基酶缺乏而患有典型CAH的青春期前儿童，女孩2-8岁，男孩2-9岁。在每项研究中，受试者都将接受氢化可的松和氟可的松治疗。在第一阶段研究中，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。在为期7天的治疗期间，最多3组8名受试者每人将连续服用1、2或4 mg/kg/d的阿比特龙，直到7/8受试者在服用阿比特龙的第7天早上雄烯二酮浓度恢复正常。在第二阶段研究中，我们将评估醋酸阿比特龙作为辅助治疗的有效性，以最大限度地减少雄激素的过度分泌，并允许更多的生理性糖皮质激素替代。这项研究是一项为期24个月的双盲随机对照试验，分别为醋酸阿比特龙(剂量在第一阶段确定)和安慰剂。我们将随机选择54名受试者(36名服用阿比特龙，18名服用安慰剂)，目标是让48名受试者完成这项研究。主要的假设是，服用阿比特龙的受试者骨骼成熟较慢(即放射学骨龄提前)。第二个假设是，接受阿比特龙治疗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，与服用安慰剂的受试者相比，服用阿比特龙的受试者在体重、身高和BMI方面的增长较少，因此HOMA-IR测量的胰岛素抵抗也较少。

 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.