From the University of Minnesota Medical School and College of Pharmacy, Minneapolis (K.S.); Children's Hospital Los Angeles and Keck School of Medicine of USC, Los Angeles (M.S.K.), the University of California at San Francisco, Benioff Children's Hospital, San Francisco (M.L.), and Neurocrine Biosciences, San Diego (G.B.G.R., E.R., G.S.J., R.H.F., J.L.C.) - all in California; Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta (E.I.F.); Endocrinologie Pédiatrique, Centre de Référence Maladies Endocriniennes Rares de la Croissance et du Développement, Hôpital Universitaire Robert-Debré, Groupe Hospitalo-Universitaire de l'Assistance Publique-Hôpitaux de Paris Nord, and Université Paris Cité, Faculté de Santé, UFR de Médecine, Paris, and Université Paris-Saclay, INSERM Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre - all in France (L.M.); the University of Colorado School of Medicine, Children's Hospital Colorado, Aurora (N.J.N.); Pediatric Endocrinology, Hospital Universitario Vall d'Hebrón, Barcelona (M.C.); the University of Washington School of Medicine, Seattle Children's Hospital, Seattle (P.Y.F.); the Children's Hospital of Philadelphia, Philadelphia (M.G.V.); Cohen Children's Medical Center of NY, New Hyde Park, and the Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Hempstead - both in New York (P.W.S.); and the Departments of Pharmacology and Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, and the Endocrinology and Metabolism Section, Medicine Services, LTC Charles S. Kettles Veterans Affairs Medical Center - both in Ann Arbor (R.J.A.).
N Engl J Med. 2024 Aug 8;391(6):493-503. doi: 10.1056/NEJMoa2404655. Epub 2024 Jun 2.
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.
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.
A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 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/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/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 (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events.
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.).
由于 21-羟化酶缺乏导致经典先天性肾上腺皮质增生症（CAH）的儿童需要接受糖皮质激素治疗，通常采用超生理剂量，以解决皮质醇不足并减少过多的肾上腺雄激素。然而，这种治疗会导致糖皮质激素相关并发症的易感性增加。在为期 2 周的 2 期临床试验中，接受新型口服促皮质素释放因子 1 型受体拮抗剂 crinecerfont 的 CAH 患者的雄烯二酮水平降低。
在这项多中心、随机的 3 期临床试验中，我们按照 2:1 的比例将患有 CAH 的儿科患者随机分配接受 crinecerfont 或安慰剂治疗 28 周。在 4 周内维持稳定的糖皮质激素剂量，然后将剂量调整为每天每平方米体表面积 8.0 至 10.0 毫克（氢化可的松等效剂量），前提是雄烯二酮水平得到控制（≤基线水平的 120%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。主要次要终点是在维持雄烯二酮控制的情况下，从基线到第 28 周糖皮质激素剂量的变化百分比。
共有 103 名参与者接受了随机分组，其中 69 名被分配到 crinecerfont 组，34 名被分配到安慰剂组；100 名（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 毫克/平方米/天，平均雄烯二酮水平为 431 纳克/分升（15.0 纳摩尔/升）。第 4 周时，crinecerfont 组的雄烯二酮显著降低（-197 纳克/分升[-6.9 纳摩尔/升]），而安慰剂组则增加（71 纳克/分升[2.5 纳摩尔/升]）（最小二乘均数差值[LSMD]，-268 纳克/分升[-9.3 纳摩尔/升]；P<0.001）；在 crinecerfont 组中，在早晨糖皮质激素剂量前测量的观察到的平均雄烯二酮值为 208 纳克/分升（7.3 纳摩尔/升），而安慰剂组为 545 纳克/分升（19.0 纳摩尔/升）。第 28 周时，crinecerfont 组的糖皮质激素剂量下降了 18.0%（同时维持了雄烯二酮的控制），而安慰剂组增加了 5.6%（LSMD，-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。
在这项 3 期试验中，与安慰剂相比，crinecerfont 可降低 CAH 儿科患者的升高的雄烯二酮水平，并在维持雄烯二酮控制的同时，使糖皮质激素剂量从超生理水平降至生理水平。（由 Neurocrine Biosciences 资助；CAHtalyst 儿科临床试验。gov 编号，NCT04806451。）
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