Merke, Deborah P., Mallappa, Ashwini, Arlt, Wiebke, Brac de la Perriere, Aude, Lindén Hirschberg, Angelica, Juul, Anders, Newell-Price, John, Perry, Colin G., Prete, Alessandro, Rees, D. Aled, Reisch, Nicole, Stikkelbroeck, Nike, Touraine, Philippe, Maltby, Kerry, Treasure, F. Peter, Porter, John, Ross, Richard J., Merke, Deborah P., Mallappa, Ashwini, Arlt, Wiebke, Brac de la Perriere, Aude, Lindén Hirschberg, Angelica, Juul, Anders, Newell-Price, John, Perry, Colin G., Prete, Alessandro, Rees, D. Aled, Reisch, Nicole, Stikkelbroeck, Nike, Touraine, Philippe, Maltby, Kerry, Treasure, F. Peter, Porter, John, and Ross, Richard J.
CONTEXT: Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. OBJECTIVE: We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. METHODS: A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. RESULTS: The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months' extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). CONCLUSION: MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.