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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2404656

摘要内容如下：

背景

糖皮质激素替代疗法治疗典型21-羟化酶缺乏症先天性肾上腺皮质增生症（CAH）患者的肾上腺功能不全。控制肾上腺源性雄激素过多通常需要超生理糖皮质激素剂量，这使患者易患糖皮质激素相关并发症。CRINECERFONT是一种口服促肾上腺皮质激素释放因子1型受体拮抗剂，在涉及CAH患者的2期试验中降低了雄烯二酮水平。

方法

在该3期试验中，我们将患有CAH的成人以2:1的比例随机分配接受CRINECERFONT或安慰剂治疗24周。糖皮质激素治疗维持在稳定水平4周，以评估雄烯二酮值，然后在20周内减少和优化糖皮质激素剂量，以达到维持雄烯二酮控制的最低糖皮质激素剂量（≤基线值的120%或在参考范围内）。主要疗效终点是从基线到第24周维持雄烯二酮控制的每日糖皮质激素剂量的百分比变化。

结果

所有182名接受随机分组的患者（122名进入CRINECERFONT组，60名进入安慰剂组）均被纳入24周分析，并对缺失值进行估算。176名患者（97%）在第24周仍留在试验中。基线时的平均糖皮质激素剂量为17.6 mg/m2体表面积/天氢化可的松当量；平均雄烯二酮水平升高至每分升620纳克。24周时，CRINECERFONT组糖皮质激素剂量（含雄烯二酮对照组）的变化为-27.3%，安慰剂组为-10.3%（最小二乘均数差，-17.0个百分点；P<0.001）。Crinecerfont组中有63%的患者报告了生理性糖皮质激素剂量（雄烯二酮对照），安慰剂组中有18%的患者报告了生理性糖皮质激素剂量（P<0.001）。在第4周，服用CRINECERFONT的雄烯二酮水平下降（-299纳克/分升），但服用安慰剂的雄烯二酮水平升高（45.5纳克/分升）（最小二乘均数差，-345纳克/分升；P<0.001）。疲劳和头痛是两个试验组中最常见的不良事件。

结论

在CAH患者中，在评估肾上腺雄激素水平后，与安慰剂相比，使用CRINECERFONT导致平均每日糖皮质激素剂量较基线更大的下降，包括降至生理范围。（由Neurocrine Biosciences资助；Cahtalyst ClinicalTrials.gov编号，NCT04490915。）

英文原文如下：

Abstracts

BACKGROUND  Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH.

METHODS  In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control.

RESULTS  All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups.

CONCLUSIONS  Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).

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