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

June 4, 2026 updated by: Prof. Paola Loli, IRCCS San Raffaele

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

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.

Study Overview

Status

Not yet recruiting

Conditions

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.

Study Type

Observational

Enrollment (Estimated)

100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

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

Description

Inclusion Criteria:

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

Exclusion Criteria:

  1. Age <18 years;
  2. Pregnancy or breastfeeding;
  3. Severe uncontrolled medical or psychiatric illness;
  4. Use of glucocorticoids for indications other than CAH;
  5. Use of drugs interfering with glucocorticoid metabolism;
  6. History of bilateral adrenalectomy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Morning Serum 17- Hydroxyprogesterone and Androstenedione Concentrations
Time Frame: Baseline, 6 months, 12 months, and annually thereafter
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Morning serum 17OHP and androstenedione concentrations measured during conventional glucocorticoid therapy and after transition to MR-HC.
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
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
Time Frame: Baseline and each follow-up visit
Plasma renin activity and serum sodium and potassium concentrations as indicators of mineralocorticoid control.
Baseline and each follow-up visit
Number of Adrenal Crises and Episodes Requiring Glucocorticoid Stress Dosing
Time Frame: Throughout follow-up
Occurrence of adrenal crises and episodes requiring stress-dose glucocorticoid administration.
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
Anthropometric and clinical measures including BMI, waist circumference, blood pressure, and signs of hyperandrogenism.
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
Metabolic parameters including fasting glucose, HbA1c, insulin levels, HOMA-IR, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides.
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
Serum calcium, phosphorus, parathyroid hormone (PTH), vitamin D, C-terminal telopeptide (CTX), osteocalcin, alkaline phosphatase (ALP), and urinary calcium/phosphorus excretion.
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
Lumbar spine and femoral neck bone mineral density assessed by DXA.
Baseline and according to routine clinical practice
Change From Baseline in Total Daily Glucocorticoid Dose
Time Frame: Each follow-up visit
Total daily glucocorticoid dose expressed as hydrocortisone-equivalent dose.
Each follow-up visit
Change From Baseline in SF-36 and AddiQoL Questionnaire Scores
Time Frame: Baseline and follow-up in prospectively enrolled patients
Health-related quality of life assessed using SF-36 and AddiQoL questionnaires.
Baseline and follow-up in prospectively enrolled patients

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Bone Turnover Markers and DXA-Derived Bone Mineral Density During Long-Term Follow-Up
Time Frame: Annual follow-up
Longitudinal assessment of skeletal outcomes including biochemical bone turnover markers and DXA-derived bone mineral density.
Annual follow-up
Longitudinal Changes in Integrated Biochemical and Clinical Outcomes Beyond 12 Months of Follow-Up
Time Frame: Annual follow-up
Long-term biochemical, endocrine, metabolic, anthropometric, reproductive, and clinical outcomes during continued MR-HC treatment.
Annual follow-up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS San Raffaele

Investigators

  • Study Director: Andrea Giustina, MD, IRCCS San Raffaele

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 31, 2026

Primary Completion (Estimated)

August 31, 2026

Study Completion (Estimated)

July 31, 2031

Study Registration Dates

First Submitted

May 27, 2026

First Submitted That Met QC Criteria

May 27, 2026

First Posted (Actual)

June 2, 2026

Study Record Updates

Last Update Posted (Actual)

June 8, 2026

Last Update Submitted That Met QC Criteria

June 4, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HARMONY-CET1-2026

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

results publication

IPD Sharing Time Frame

Approximatly November 2026 - December 2026

IPD Sharing Access Criteria

sharing the interim analysis of retrospective data the statistical methods for approved by independent review.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on CAH - Congenital Adrenal Hyperplasia

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Uruguay

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe