Modified-release hydrocortisone in congenital 1 adrenal hyperplasia

Deborah P Merke, Ashwini Mallappa, Wiebke Arlt, Aude Brac De La Perriere, Angelica L Hirschberg, Anders Juul, John Newell-Price, Colin G Perry, Alessandro Prete, Aled Rees, Nicole Reisch, Nike Stikkelbroeck, Phillippe Tourraine, Kerry Maltby, Peter Treasure, John Porter, Richard J Ross

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Abstract

Background: Standard glucocorticoid therapy in congenital adrenal hyperplasia regularly fails to control androgen excess, causing glucocorticoid over-exposure and poor health outcomes. We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods: 6-month randomized phase III study, MR-HC versus standard glucocorticoid, followed by single-arm MR-HC extension study. Primary outcomes were change in 24-hour standard deviation score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase III, and efficacy, safety and tolerability of MR-HC for the extension study. Results: The phase III study recruited 122 adult CAH patients. While 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=0.007) and 12 (P=0.019) weeks, and between 07:00h to 15:00h (P=0.044) 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=0.002), and 80% for MR-HC at 18 months extension. The median daily hydrocortisone dose was 25mg at baseline, at 6 months 31mg for standard therapy and 30mg for MR-HC, and after 18 months 20mg MR-HC. Three adrenal crises occurred in phase III, none on MR-HC and 4 in extension study. MR-HC resulted in patient-reported benefit including menses restoration in eight patients (one 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.
Original languageEnglish
Pages (from-to)1-15
JournalJournal of Clinical Endocrinology and Metabolism
Volume2021
Issue number00
DOIs
Publication statusPublished - 29 Jan 2021

Bibliographical note

Financial Support: This work was supported by Diurnal Ltd UK, with further support from the Intramural Research Program of the National Institutes of Health (NIH).

Clinical Trial Information: EudraCT registration Nos. 2015-000711-40 and 2015-005448-32 (registered February 10, 2015); Clinicaltrials.gov registration Nos. NCT02716818 and NCT03062280 (registered March 22, 2016).

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