• Kyriakie Sarafoglou, Mimi S Kim, Maya Lodish, Eric I Felner, Laetitia Martinerie, Natalie J Nokoff, María Clemente, Patricia Y Fechner, Maria G Vogiatzi, Phyllis W Speiser, Richard J Auchus, Gelliza B G Rosales, Eiry Roberts, George S Jeha, Robert H Farber, Jean L Chan, and CAHtalyst Pediatric Trial Investigators.
• 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): 493503493-503.

BackgroundChildren 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.MethodsIn 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.ResultsA 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.ConclusionsIn 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.).Copyright © 2024 Massachusetts Medical Society.

45 keywords...

hide…