Hydrocortisone Modified-release in Adults: Real-world Monitoring of Longitudinal Outcomes in coNgenital Adrenal hYperplasia

CAH - Congenital Adrenal Hyperplasia

chronotherapy, hydrocortisone, 21-hydroxylase deficiency CAH, outcomes

Classic congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder caused by a defect in the enzyme cascade regulating adrenal steroidogenesis; in approximately 95% of cases the defect is located in CYP21A2, the gene encoding 21-hydroxylase, and is characterized by defective adrenal steroidogenesis and cortisol deficiency. Due to the loss of physiological cortisol feedback on the hypothalamus and pituitary corticotropic cells, ACTH secretion is increased. This results in the accumulation of 17-hydroxyprogesterone (17OHP) proximal to the enzymatic defect in steroidogenesis, which in turn stimulates overproduction of the adrenal androgen precursor androstenedione and adrenal hyperplasia. Treatment of CAH is tailored to the patient and disease severity, aiming to replace cortisol and aldosterone deficiencies while controlling androgen excess and avoiding glucocorticoid overtreatment. Immediate-release hydrocortisone administered multiple times daily remains the recommended first-line treatment in growing children, whereas adult patients are frequently treated with hydrocortisone, prednisone, prednisolone or dexamethasone. However, conventional glucocorticoid regimens cannot adequately reproduce the physiological circadian rhythm of cortisol secretion. In physiological conditions, ACTH-driven cortisol secretion follows a clear circadian rhythm characterized by low evening levels, nocturnal increase between 2:00 and 4:00 a.m., a morning peak upon awakening, and progressive decline during daytime. Dual daytime dosing of immediate-release hydrocortisone in CAH can control ACTH-driven adrenal androgen secretion during the day; however, because of its rapid absorption into the bloodstream and short half-life, the evening dose of hydrocortisone cannot adequately suppress the nocturnal ACTH surge and ACTH-driven adrenal androgen overproduction. Consequently, patients are often exposed to supraphysiological glucocorticoid doses during nighttime hours in an attempt to control morning hyperandrogenism. The disruption of physiological cortisol homeostasis contributes to poor cardiometabolic profile, obesity, insulin resistance, impaired fertility, reduced quality of life, and increased cardiovascular morbidity and mortality observed in patients with CAH. Bone health may also be impaired in patients with CAH because of chronic glucocorticoid exposure and androgen imbalance. Previous studies demonstrated reduced lumbar and femoral bone mineral density and increased fracture risk in both male and female patients. Modified-release hydrocortisone (MR-HC; Efmody®) is a multiparticulate formulation developed to better reproduce physiological cortisol circadian rhythm through chronotherapy. Previous phase II and phase III studies demonstrated improved biochemical control, reduction in androgen excess, lower glucocorticoid exposure, improved fertility outcomes, and sustained long-term efficacy compared with conventional glucocorticoid regimens. However, real-world longitudinal data regarding long-term biochemical, metabolic, cardiovascular, reproductive and skeletal outcomes remain limited, particularly in adult patients transitioning from pediatric to adult endocrine care. The present study is a single-center, retrospective and prospective, longitudinal, open-label observational cohort study aimed at evaluating the long-term real-world outcomes of chronotherapy with modified-release hydrocortisone in adult patients with genetically confirmed 21-hydroxylase deficiency CAH. Retrospective clinical, biochemical and radiological data already available from routine clinical care will be collected from medical records, while prospective observational follow-up will continue according to routine endocrine clinical practice.

The study is designed as an ongoing longitudinal observational cohort intended to evaluate short-term and long-term outcomes of MR-HC treatment in a real-world setting. At the time of protocol drafting, retrospective and prospective data are available for approximately 32 patients, with follow-up extending up to 24-36 months in some cases. Additional eligible patients may be included prospectively during the observational phase of the study. Follow-up assessments are planned at approximately 2, 4, 6, and 12 months after treatment transition and yearly thereafter whenever available as part of routine clinical practice. Interim analyses may be performed on available datasets before completion of long-term follow-up in order to evaluate clinically relevant outcomes emerging from real-world experience. All procedures and laboratory assessments included in the study are part of routine clinical management of patients with CAH and do not imply additional costs for patients or for the institution.

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