ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 8.3 | DOI: 10.1530/ey.18.8.3

J Clin Endocrinol Metab 2021; 106(5): e2063–e2077.

The authors report the findings of a 6-month, randomized, phase 3 trial, with a single arm extension, to investigate the efficacy, safety and tolerability of modified release hydrocortisone (MC-HC) replacement therapy versus standard glucocorticoid replacement therapy in 122 adult patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). The primary end-point was a change in 24-h 17-OHP concentrations. MC-HC improved morning and early afternoon biochemical control of CAH compared with standard therapy.

Standard glucocorticoid therapy in CAH regularly fails to control hyperandrogenism, leading to virilization, glucocorticoid overexposure and poor health outcomes. This modified-release hydrocortisone formulation (MR-HC) has a delayed-release action. When given twice daily, it mimics the physiological overnight rise in cortisol (1, 2), and improved CAH control in a phase 2 study (2).

This was the first randomized, controlled trial of glucocorticoid treatment in patients with CAH due to 21-OHD. Patients who received MR-HC had superior hormonal control during the morning and early afternoon than those on standard therapy, and this was sustained over 18 months of follow-up, with a higher proportion of patients (91%) having a morning (09:00h) serum 17OHP concentration < 1200 ng/dL (36 nmol/L) than on standard treatment (71%) (P=0.002). MR-HC improved the clinically relevant end point of morning biochemical control, with reduced AUC and 17OHP amplitude. The improvement in biochemical control was maintained at 18 months, with 80% displaying good control for 17OHP and 96% for androstenedione vs 52% and 45% at baseline, despite reduction of the hydrocortisone dose by 33%, to doses typical for adrenal replacement therapy. After 18 months on MC-HC, the median HC dose was 20 mg. MR-HC also led to menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). The number of adrenal crisis were not reduced.

These findings indicate that MR-HC improved morning and early afternoon biochemical control of CAH due to 21-OHD compared with standard glucocorticoid therapy. This improvement was sustained for 18 months on hydrocortisone doses typical for adrenal replacement therapy and lower than doses normally used in CAH. MR-HC was safe and well-tolerated.

Reference: 1. Whitaker M, Debono M, Huatan H, Merke D, Arlt W, Ross RJ. An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure. Clin Endocrinol (Oxf). 2014; 80(4): 554–561.2. Mallappa A, Sinaii N, Kumar P, Whitaker MJ, Daley LA, Digweed D, Eckland DJ, Van Ryzin C, Nieman LK, Arlt W, Ross RJ, Merke DP. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2015; 100(3): 1137–1145.

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