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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2404655

摘要内容如下：

背景

由于21-羟化酶缺乏导致的典型先天性肾上腺皮质增生症（CAH）患儿需要糖皮质激素治疗，通常为超生理剂量，以解决皮质醇不足和减少肾上腺雄激素过多。然而，这种治疗易导致糖皮质激素相关的并发症。在为期2周的2期临床试验中，接受新型口服促肾上腺皮质激素释放因子1型受体拮抗剂CRINECERFONT治疗的CAH患者的雄烯二酮水平下降。

方法

在这项3期、多国、随机试验中，我们将患有CAH的儿童参与者以2:1的比例分配接受CRINECERFONT或安慰剂治疗28周。维持稳定的糖皮质激素剂量4周，然后将剂量调整至每天每平方米体表面积8.0至10.0 mg的目标剂量（氢化可的松剂量当量），前提是雄烯二酮水平得到控制（≤120%基线水平或在参考范围内）。主要疗效终点是从基线到第4周雄烯二酮水平的变化。关键的次要终点是从基线到第28周糖皮质激素剂量的百分比变化，同时维持雄烯二酮控制。

结果

共有103名参与者接受了随机分组，其中69人被分配到CRINECERFONT组，34人被分配到安慰剂组。100例（97%）在28周时仍留在试验中。基线时，平均糖皮质激素剂量为16.4 mg/m2/d，平均雄烯二酮水平为431 ng/DL（15.0 nmol/L）。第4周时，Crinecerfont组的雄烯二酮水平显著降低（-197 ng/DL[-6.9 nmol/L]），但安慰剂组的雄烯二酮水平升高（71 ng/DL[2.5 nmol/L]）（最小二乘均数差，-268 ng/DL[-9.3 nmol/L]；P<0.001）；Crinecerfont组在早晨糖皮质激素给药前观察到的平均雄烯二酮值为208 ng/DL（7.3 nmol/L），而安慰剂组为545 ng/DL（19.0 nmol/L）。在第28周，CRINECERFONT组的平均糖皮质激素剂量减少了18.0%（同时维持雄烯二酮控制），但安慰剂组增加了5.6%（最小二乘均数差，-23.5个百分点；P<0.001）。头痛、发热和呕吐是最常见的不良事件。

结论

在该3期试验中，Crinecerfont在降低CAH儿童受试者升高的雄烯二酮水平方面优于安慰剂，并且在维持雄烯二酮控制的同时，还与糖皮质激素剂量从超生理水平降至生理水平相关。（由Neurocrine Biosciences资助；Cahtalyst Pediatric ClinicalTrials.gov Number，NCT04806451.）

英文原文如下：

Abstracts

BACKGROUND  Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels.

METHODS  In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained.

RESULTS  A total of 103 participants underwent randomization, of whom 69 were assigned to the crinecerfont group and 34 to the placebo group; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol per liter). At week 4, the androstenedione level was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol per liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol per liter]) (least-squares mean difference, -268 ng per deciliter [-9.3 nmol per liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol per liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol per liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (least-squares mean difference, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events.

CONCLUSIONS  In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

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