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

4 juni 2026 bijgewerkt door: 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.

Studie Overzicht

Toestand

Nog niet aan het werven

Conditie

Gedetailleerde beschrijving

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.

Studietype

Observationeel

Inschrijving (Geschat)

100

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Contact Back-up

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Bemonsteringsmethode

Niet-waarschijnlijkheidssteekproef

Studie Bevolking

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

Beschrijving

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Cohorten en interventies

Groep / 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.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Change From Baseline in Morning Serum 17- Hydroxyprogesterone and Androstenedione Concentrations
Tijdsspanne: 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

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Change From Baseline in Morning Serum 17-Hydroxyprogesterone (17OHP) and Androstenedione Concentrations During Modified-Release Hydrocortisone Treatment
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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)
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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

Andere uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Change From Baseline in Bone Turnover Markers and DXA-Derived Bone Mineral Density During Long-Term Follow-Up
Tijdsspanne: 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
Tijdsspanne: Annual follow-up
Long-term biochemical, endocrine, metabolic, anthropometric, reproductive, and clinical outcomes during continued MR-HC treatment.
Annual follow-up

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

IRCCS San Raffaele

Onderzoekers

  • Studie directeur: Andrea Giustina, MD, IRCCS San Raffaele

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Geschat)

31 juli 2026

Primaire voltooiing (Geschat)

31 augustus 2026

Studie voltooiing (Geschat)

31 juli 2031

Studieregistratiedata

Eerst ingediend

27 mei 2026

Eerst ingediend dat voldeed aan de QC-criteria

27 mei 2026

Eerst geplaatst (Werkelijk)

2 juni 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

8 juni 2026

Laatste update ingediend die voldeed aan QC-criteria

4 juni 2026

Laatst geverifieerd

1 juni 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • HARMONY-CET1-2026

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

JA

Beschrijving IPD-plan

results publication

IPD-tijdsbestek voor delen

Approximatly November 2026 - December 2026

IPD-toegangscriteria voor delen

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

IPD delen Ondersteunend informatietype

  • LEERPROTOCOOL
  • SAP

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .

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