Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02716818 NCT03062280.

Keywords: 21-hydroxylase deficiency; adrenal insufficiency; congenital adrenal hyperplasia; glucocorticoid; hydrocortisone.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Patient screening, randomization treatment, and follow-up. The safety population included all randomly assigned patients who received at least one dose of trial treatment. *Patients could have more than one reason for study exclusion and withdrawn patients are included in patients excluded.

Figure 2.

Twenty-four–hour endocrine profiles for 17-hydroxyprogesterone (17OHP) and androstenedione at week 24 vs baseline (geometric mean ± 95% CIs, patients meeting the criteria for the efficacy analysis) and 09:00hrs 17OHP during the extension study. A, At week 24, the 17OHP 24-hour profile for patients receiving modified-release hydrocortisone (MR-HC) was flat, and the morning rise in 17OHP observed at baseline was no longer present. B, Similar results were observed for androstenedione. Patients in the standard glucocorticoid group had improvement in hormonal control with glucocorticoid dose adjustments according to the protocol, but the pattern of hormone secretion did not change: C, 17OHP, and D, androstenedione, profiles continued to display a morning increase. At week 24, the MR-HC vs standard groups differed during the morning hours but not throughout the 24 hours for E, 17OHP, and F, androstenedione. G, During the extension study, the geometric mean 09:00h 17OHP fell from baseline into the optimal range and remained there despite a reduction in MR-HC daily dose.