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To describe the baseline characteristics of individuals enrolled in CAHtalyst (NCT04490915), a randomized, double-blind, placebo-controlled, Phase 3 study evaluating the safety and efficacy of crinecerfont (a corticotropin-releasing factor type 1 receptor CRF1 antagonist) in adults with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD). The study included adults (age ≥18 yrs) with classic 21OHD. Key eligibility criteria included glucocorticoid dose >13 mg/m2/day in hydrocortisone equivalents (HCe; conversion factors: 4x for prednisolone, 60x for dexamethasone) adjusted for body surface area (BSA) with stable dose for ≥1 month prior to screening, and normal or elevated androstenedione (A4). Baseline demographics and characteristics were summarized descriptively in all randomized participants. Of 182 enrolled participants, 51% were men and 90% were White. Mean (±SD) age was 30.8±9.9 yrs (range: 18-58 yrs), mean BSA was 1.8±0.2 m2, and mean body mass index (BMI) was 29.8±7.0 kg/m2 (with BMI ≥30 kg/m2 in 47% of participants). The mean total daily glucocorticoid dose was 17.6±4.9 mg/m2/d (32.3±9.3 mg/d) HCe, with 57% on hydrocortisone alone, 30% on a predniso(lo)ne-containing regimen, and 13% on a dexamethasone-containing regimen. In addition, 86% of participants were on fludrocortisone (mean dose: 136±72 mcg/d). Mean (±SD) hormone concentrations prior to the morning glucocorticoid dose were as follows: adrenocorticotropic hormone, 264±317 pg/mL; 17-hydroxyprogesterone, 9467±8829 ng/dL; A4, 620±729 ng/dL; testosterone (T) in females, 86±85 ng/dL; A4/T in males, 2.2±2.4; follicle-stimulating hormone in males, 6.3±9.4 IU/L; and luteinizing hormone in males, 4.6±5.0 IU/L. Among the 90 females, 42 (47%) reported a history of hirsutism; of the 66 females of childbearing potential not on hormonal or intrauterine contraception, 35 (53%) reported a history of amenorrhea or menstrual irregularities. Among the 92 males, 44 (48%) reported ta history of testicular adrenal rest tumors (TARTs) while 53 (58%)s had evidence of TARTs by ultrasound at baseline. Comorbidities included osteopenia (15%), hypertension (10%), osteoporosis (5%), and diabetes mellitus (2%). In a Phase 3 trial evaluating crinecerfont (a CRF1 antagonist) in adults with classic 21OHD, clinical evidence of glucocorticoid and androgen excess (e.g., high prevalence of obesity, hirsutism females, and TARTs males) were observed at baseline. Androgens and other steroid biomarkers were elevated despite treatment with supraphysiological doses of glucocorticoids. These findings emphasize the urgent need for novel glucocorticoid-sparing treatments for this chronic condition.
Hamidi et al. (Wed,) studied this question.