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

Official title

Long-term Real-world Outcomes of Chronotherapy With Modified-release Hydrocortisone in Congenital Adrenal Hyperplasia

Overview

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.

Detailed description

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.

Primary outcome measures

• Change From Baseline in Morning Serum 17- Hydroxyprogesterone and Androstenedione Concentrations [Time frame: Baseline, 6 months, 12 months, and annually thereafter]

Secondary outcome measures (10)

• Change From Baseline in Morning Serum 17-Hydroxyprogesterone (17OHP) and Androstenedione Concentrations During Modified-Release Hydrocortisone Treatment [Time frame: Baseline, 6 months, 12 months, and annually thereafter]
• Change From Baseline in Morning Plasma ACTH and Cortisol Concentrations and Midnight Salivary Cortisol Levels [Time frame: Baseline, 6 months, 12 months, and annually thereafter]
• Change From Baseline in Plasma Renin Activity and Serum Sodium and Potassium Concentrations [Time frame: Baseline and each follow-up visit]
• Number of Adrenal Crises and Episodes Requiring Glucocorticoid Stress Dosing [Time frame: Throughout follow-up]
• Change From Baseline in Body Mass Index, Waist Circumference, Blood Pressure, and Clinical Hyperandrogenism Parameters [Time frame: Baseline, 6 months, 12 months, and annually thereafter]
• Change From Baseline in Glycemia, Hemoglobin A1c, Insulin Concentrations, HOMA-IR, and Lipid Profile Parameters [Time frame: Baseline, 6 months, 12 months, and annually thereafter]
• Change From Baseline in Markers of Calcium-Phosphorus Metabolism and Bone Turnover [Time frame: Baseline, 6 months, 12 months, and annually thereafter]
• Change From Baseline in Lumbar Spine and Femoral Bone Mineral Density Measured by Dual-Energy X-Ray Absorptiometry (DXA) [Time frame: Baseline and according to routine clinical practice]
• Change From Baseline in Total Daily Glucocorticoid Dose [Time frame: Each follow-up visit]
• Change From Baseline in SF-36 and AddiQoL Questionnaire Scores [Time frame: Baseline and follow-up in prospectively enrolled patients]

Eligibility criteria

Inclusion criteria

• Age ≥18 years;
• Genetically confirmed diagnosis of 21-hydroxylase deficiency congenital adrenal hyperplasia;
• Transition from conventional glucocorticoid therapy to modified-release hydrocortisone according to routine clinical practice;
• Stable glucocorticoid and mineralocorticoid therapy before transition;
• Ability to understand study procedures and provide informed consent for prospective data collection whenever applicable

Exclusion criteria

• Age <18 years;
• Pregnancy or breastfeeding;
• Severe uncontrolled medical or psychiatric illness;
• Use of glucocorticoids for indications other than CAH;
• Use of drugs interfering with glucocorticoid metabolism;
• History of bilateral adrenalectomy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Other

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• 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 Mar;100(3):1137-45. doi: 10.1210/jc.2014-3809. Epub 2014 Dec 11. PMID 25494662
• Han TS, Walker BR, Arlt W, Ross RJ. Treatment and health outcomes in adults with congenital adrenal hyperplasia. Nat Rev Endocrinol. 2014 Feb;10(2):115-24. doi: 10.1038/nrendo.2013.239. Epub 2013 Dec 17. PMID 24342885
• Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM, Ross RJ; United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010 Nov;95(11):5110-21. doi: 10.1210/jc.2010-0917. Epub 2010 PMID 20719839
• Falhammar H, Frisen L, Norrby C, Hirschberg AL, Almqvist C, Nordenskjold A, Nordenstrom A. Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014 Dec;99(12):E2715-21. doi: 10.1210/jc.2014-2957. PMID 25279502
• Jenkins-Jones S, Parviainen L, Porter J, Withe M, Whitaker MJ, Holden SE, Morgan CL, Currie CJ, Ross RJM. Poor compliance and increased mortality, depression and healthcare costs in patients with congenital adrenal hyperplasia. Eur J Endocrinol. 2018 Apr;178(4):309-320. doi: 10.1530/EJE-17-0895. Epub 2018 Jan 25. PMID 29371334
• Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, Reynolds JC, Hanna RM, Merke DP. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012 Dec;97(12):4429-38. doi: 10.1210/jc.2012-2102. Epub 2012 Sep 18. PMID 22990093
• Auchus RJ, Arlt W. Approach to the patient: the adult with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2013 Jul;98(7):2645-55. doi: 10.1210/jc.2013-1440. PMID 23837188
• Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005 Jun 18-24;365(9477):2125-36. doi: 10.1016/S0140-6736(05)66736-0. PMID 15964450

Identifiers

NCT: NCT07622030 · HARMONY-CET1-2026

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗