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

NCT07622030 | Not Yet Recruiting DMC

• 1 other identifier: HARMONY-CET1-2026
• Study Type: observational
• Target: 100
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

CAH - Congenital Adrenal Hyperplasia

Keywords

chronotherapy; hydrocortisone; 21-hydroxylase deficiency CAH; outcomes

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Morning Serum 17- Hydroxyprogesterone and Androstenedione Concentrations

  Morning serum 17-OH progesterone (17OHP) and D4-androstenedione levels under conventional therapy and during MR-HC treatment

  Baseline, 6 months, 12 months, and annually thereafter

Secondary Outcomes (10)

• Change From Baseline in Morning Serum 17-Hydroxyprogesterone (17OHP) and Androstenedione Concentrations During Modified-Release Hydrocortisone Treatment

  Baseline, 6 months, 12 months, and annually thereafter

• Change From Baseline in Morning Plasma ACTH and Cortisol Concentrations and Midnight Salivary Cortisol Levels

  Baseline, 6 months, 12 months, and annually thereafter

• Change From Baseline in Plasma Renin Activity and Serum Sodium and Potassium Concentrations

  Baseline and each follow-up visit

• Number of Adrenal Crises and Episodes Requiring Glucocorticoid Stress Dosing

  Throughout follow-up

• Change From Baseline in Body Mass Index, Waist Circumference, Blood Pressure, and Clinical Hyperandrogenism Parameters

  Baseline, 6 months, 12 months, and annually thereafter

Other Outcomes (2)

• Change From Baseline in Bone Turnover Markers and DXA-Derived Bone Mineral Density During Long-Term Follow-Up

  Annual follow-up

• Longitudinal Changes in Integrated Biochemical and Clinical Outcomes Beyond 12 Months of Follow-Up

  Annual follow-up

Study Arms (1)

longitudinal observational cohort intended to evaluate short-term and long-term outcomes of MR-HC

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.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Approximately 32 patients are currently available for retrospective and prospective analysis. Additional eligible patients may be enrolled prospectively during the observational phase. All patients who come for an appointment at the endocrinology clinics of IRCCS San Raffaele for routine clinical evaluations

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Related Publications (8)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 Aug 18.

  PMID: 20719839 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Adrenal Hyperplasia, Congenital

Condition Hierarchy (Ancestors)

Adrenogenital Syndrome; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Andrea Giustina, MD

  IRCCS San Raffaele

  STUDY DIRECTOR

Central Study Contacts

Paola Loli, MD

CONTACT

+39 02 2643; loli.paola@hsr.it

Umberto Terenzi, MD

CONTACT

+39 02 2643; trials.endocrinologia@hsr.it

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Target Duration: 5 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 27, 2026
• First Posted: June 2, 2026
• Study Start: July 31, 2026
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): July 31, 2031
• Last Updated: June 8, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Approximatly November 2026 - December 2026
• Access Criteria: sharing the interim analysis of retrospective data the statistical methods for approved by independent review.