1. In this randomized controlled trial, twice daily crinecerfont use was associated with reduced daily glucocorticoid use in adults with congenital adrenal hyperplasia (CAH).

2. When compared to placebo, crinecerfont use was associated with reduced adrenal androgen production in adults with congenital adrenal hyperplasia.

Evidence Rating Level: 1 (Excellent)

Study Rundown: CAH is a group of disorders that cause abnormal adrenal steroidogenesis, resulting in insufficient cortisol and aldosterone production. Through feedback mechanisms, there is increased adrenocorticotropic hormone (ACTH) secretion, which causes excess production of adrenal androgens. This can result in virilization, advanced bone age, and precocious puberty. Glucocorticoids replace cortisol in patients with CAH. However, higher than physiologic ranges are being used to reduce androgen production. Long-term high-dose glucocorticoid use has deleterious effects, such as decreased bone density and negative metabolic consequences. Corticotropin-releasing factor type 1 receptor (CRF1) antagonists, like crinecerfont, present a strategy to reduce ACTH secretion, allowing for physiologic glucocorticoid administration. The present trial investigated the percent change from baseline in daily glucocorticoid use while maintaining androstenedione control after twice daily administration of crinecerfont. Compared to placebo, crinecerfont decreased glucocorticoid use to physiologic doses and was associated with decreased adrenal androgen production. The study was limited by its restricted inclusion criteria of patients receiving supraphysiologic glucocorticoid doses, the short time frame to observe changes, and the lack of racial diversity among patients included. Overall, these findings demonstrated that supraphysiological doses of glucocorticoids could be reduced to physiologic range without inducing adrenal crises by adding crinecerfont

Click here to read the study in NEJM

Relevant Reading: Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia

In-Depth [randomized controlled trial]: This phase three randomized controlled trial assessed the effect of twice daily crinecerfont on glucocorticoid use in adults with CAH. Adults with CAH receiving daily glucocorticoid doses greater than 13mg per square meter of body surface of hydrocortisone equivalent and receiving a stable dose for at least one month were eligible for this study. Adults with conditions other than CAH requiring long-term glucocorticoid therapy or evidence of overtreatment based on androgen secretion were ineligible to participate. A total of 182 adults with CAH were randomly assigned in a 2:1 ratio to receive crinecerfont (n=122) or placebo (n=60) for 24 weeks. Glucocorticoid doses were maintained for four weeks to evaluate androstenedione levels, after which glucocorticoid doses were reduced and optimized over 20 weeks to achieve the lowest dose that maintained androstenedione control. The primary outcome was the percent change in daily glucocorticoid dose compared to baseline after 24 weeks with maintenance of androstenedione control. After the 24-week intervention period, the change in glucocorticoid dose was -27.3% in the crinecerfont group and -10.3% in the placebo group (p<0.001). Physiologic glucocorticoid doses were reported in 63% of patients in the crinecerfont group and 18% in the placebo group (p<0.001). Androstenedione levels decreased with crinecerfont (-299ng per deciliter) but increased with placebo (45.5ng per deciliter) at week 4 (p<0.001). The results from this study indicated that patients with CAH receiving crinecerfont had significantly greater reductions in glucocorticoid doses, targeting physiologic doses, at week 24 while maintaining androstenedione control compared to patients receiving placebo.

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