ECE2020 Oral Communications Adrenal and Cardiovascular Endocrinology (7 abstracts)
A Phase III randomized, controlled trial of a modified-release hydrocortisone formulation in the treatment of classic congenital adrenal hyperplasia
Deborah Merke 1 , Ashwini Mallappa 1 , Wiebke Arlt 2 , Aude Brac de la Perriere 3 , Angelica Hirschberg Linden 4 , Anders Juul 5 , John Newell-Price 6 , Colin Perry 7 , Alessandro Prete 2 , Aled Rees 8 , Nicole Reisch 9 , Nike Stikkelbroeck 10 , Phillippe Touraine 11 , Kerry Matlby 12 , Peter Treasure 13 , John Porter 12 & Richard Ross 6
1NIH, United States; 2University of Birmingham, United Kingdom; 3Hopital Femme Mere Enfant, France; 4Karolinska Institute, Sweden; 5Rigshospitalet, Denmark; 6University of Sheffield Medical School, United Kingdom; 7University of Glasgow, United Kingdom; 8University of Cardiff, United Kingdom; 9University of Munich Hospital, Germany; 10Radound University, Netherlands; 11Sorbonne Université, France; 12-Diurnal Ltd, United Kingdom; 13Peter Treasure Statistical Services, United Kingdom
Background: Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD-CAH) have poor health outcomes due to failure of currently available glucocorticoid preparations to control adrenocorticotropic hormone-driven androgen excess. We investigated whether modified-release hydrocortisone (MR-HC), which mimics the physiological circadian cortisol rhythm, could improve androgen control.
Methods: 122 patients with 21-OHD-CAH were randomized to receive either MR-HC or standard glucocorticoid therapy (hydrocortisone, prednisolone, prednisone and dexamethasone). Patients underwent 24-hour profiling of serum 17-hydroxyprogesterone (17-OHP) at baseline and for dose titration at 4 and 12 weeks. The change in mean 24-hour serum 17-OHP standard deviation score (SDS) at 24 weeks was defined as the primary outcome.
Results: Both groups achieved better hormonal control at 24 weeks compared to baseline. The change from baseline in 17-OHP SDS was significantly greater in MR-HC patients at 4 (P = 0.007) and 12 (P = 0.019) weeks, but not at 24 weeks. In post-hoc analyses at 24 weeks, a greater reduction was observed in the MR-HC group for the 17-OHP SDS score between 07:00 h and 15:00 h (P = 0.044) and 17-OHP AUC (P = 0.025). Good disease control (17-OHP <36 nmol/l (<1200 ng/dl) measured at 09:00 h), was achieved more often in the MR-HC group than the standard glucocorticoid group (90% vs 71%, P = 0.0018). The variability of 17-OHP over 24 hours was reduced in the MR-HC group compared to standard glucocorticoid therapy (P = 0.0001). Serum androstenedione 24-hour AUC demonstrated a greater reduction in the MR-HC arm (ratio of geometric LS means of MR-HC divided by standard glucocorticoid: 0.636; 95% CI: [0.450, 0.900]; P = 0.0110). At 24 weeks, the MR-HC and standard glucocorticoid groups were on similar glucocorticoid hydrocortisone equivalent doses (30 vs 31 mg). There were no safety concerns during the study. There were no adrenal crises in the MR-HC group compared with three (4.9%) in the standard glucocorticoid group. Glucocorticoid stress dosing was reported by 26 patients (42.6%) in the MR-HC group and 36 patients (59.0%) in the standard glucocorticoid group. Resumption of regular menses occurred in 5 patients (4 MR-HC, 1 standard glucocorticoid). The partners of two patients in the MR-HC group became pregnant during the study; one had a history of testicular adrenal rest tissue with documented sperm count improvement on MR-HC.
Conclusion: Six months of MR-HC therapy improved the biochemical control of 21-OHD-CAH in the morning and early afternoon with lower circadian variability and increased patient-reported benefits.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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