Congenital Adrenal Hyperplasia Once Daily Hydrocortisone Treatment (CareOnTIME)

Congenital Adrenal Hyperplasia: Innovative Once Daily Dual Release Hydrocortisone Treatment

This is a controlled, open study designed to compare the effects of dual-release hydrocortisone preparations versus conventional glucocorticoid therapy on clinical, anthropometric parameters, metabolic syndrome, hormonal profile, bone status, quality of life, reproductive, sexual and psychological functions and treatment compliance in patients affected by congenital adrenal hyperplasia due to 21 OH deficiency.

Study Overview

• Status: Recruiting
• Conditions: Congenital Adrenal Hyperplasia
• Intervention / Treatment: Drug: Conventional Glucocorticoids (immediate release hydrocortisone, cortisone acetate, prednisone, prednisolone, dexamethasone); Drug: Dual release hydrocortisone (plenadren)

Detailed Description

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder characterized by cortisol and in some cases aldosterone deficiency, associated with androgen excess. Treatment goals are to replace cortisol deficiency, to control androgen levels, while avoiding the adverse effects of exogenous glucocorticoids. A variety of glucocorticoid treatments have been used in an attempt to control the overnight increase in adrenal androgens. However, there is no consensus on the optimum management of congenital adrenal hyperplasia adults. Current evidence in patients with adrenal insufficiency suggests that the inability of current regimens to replace physiological circadian cortisol levels, leads to adverse clinical outcomes, including metabolic syndrome, insulin resistance, increased risk factors for cardiovascular diseases, bone and immune alterations, sleep disturbances and quality of life impairment. Moreover, the risk for poor treatment compliance, in case of multiple daily doses treatment regimens, should not be excluded. In this trial a dual-release hydrocortisone preparation, that been able to mimic the circadian pattern of circulating cortisol, was studied in patients with adrenal insufficiency due to congenital adrenal hyperplasia.

All patients with a diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, irrespective of glucocorticoid treatment, are eligible for the inclusion in the study and may be asked to participate in the study. Patients are followed during the course of routine clinical practice for the duration of time that the study is active.

ARM1: Conventional glucocorticoid therapy is continued as before entering the study

ARM2: Dual release hydrocortisone oral tablets is administered once-daily in the fasting state. The dose is kept the same as patients had before entering the trial.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Rosario Pivonello, M.D., PhD, Professor; Phone Number: +390817464983; Email: rosario.pivonello@unina.it

Study Locations

• Italy
  • Naples, Italy, 80131
    • Recruiting
    • Federico II University
    • Contact: Rosario Pivonello, MD,PhD,Professor; Phone Number: +390817464983; Email: rosario.pivonello@unina.it
    • Principal Investigator: Rosario Pivonello, MD, PhD, Professor
    • Sub-Investigator: Chiara Simeoli, MD
    • Sub-Investigator: Maria Cristina De Martino, MD, PhD
    • Sub-Investigator: Rosario Ferrigno, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• males and females aged >18 years;
• established diagnosis of adrenal insufficiency in congenital adrenal hyperplasia due to 21-hydroxylase deficiency;
• stably treated with conventional glucocorticoids, available to change their regimen according to random allocation
• written informed consent/assent to participate in the study in compliance with local regulations.

Exclusion Criteria:

• clinical or laboratory signs of severe cerebral, respiratory, hepatobiliary or pancreatic diseases, renal dysfunction, gastrointestinal emptying, or motility disturbances (i.e. chronic diarrhea), significant psychiatric illnesses;
• history of/or current alcohol and/or drug abuse;
• night shift workers;
• underlying diseases that could necessitate treatment with glucocorticoids;
• therapies with hepatic enzyme induction drugs interfering with glucocorticoid kinetics, or immunosuppressive steroid therapy;
• patients with a documented intolerance/known hypersensitivity to dual release hydrocortisone;
• vulnerable populations, such as elderly, cancer patients, pregnant and lactating women;
• history of non-compliance to medical regimens, or potentially unreliable patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dual-release hydrocortisone	Drug: Conventional Glucocorticoids (immediate release hydrocortisone, cortisone acetate, prednisone, prednisolone, dexamethasone); Treatment of congenital adrenal hyperplasia; Drug: Dual release hydrocortisone (plenadren); Treatment of congenital adrenal hyperplasia
Active Comparator: Conventional glucocorticoids	Drug: Conventional Glucocorticoids (immediate release hydrocortisone, cortisone acetate, prednisone, prednisolone, dexamethasone); Treatment of congenital adrenal hyperplasia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in measurement of total and LDL cholesterol (mg/dl)	Single outcome measurement of cholesterol levels (mg/dl)	0, + 6 months, + 12 months, +24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in measurement of glycaemia (mg/dl)	Measure of glycaemia (mg/dl)	0, + 6 months, + 12 months, +24 months
Change from baseline in measurement of BMI (Kg/m2)	Measure of BMI (Kg/m2)	0, + 6 months, + 12 months, +24 months
Change from baseline in measurement of blood pressure (mmHg)	Measure of blood pressure (mmHg)	0, + 6 months, + 12 months, +24 months
Change from baseline in measurement of insulinemia (μU/mL)	Measure of insulinemia (μU/mL)	0, + 6 months, + 12 months, +24 months
Change from baseline in measurement of triglycerides (mg/dl)	Measure of triglycerides (mg/dl)	0, + 6 months, + 12 months, +24 months
Change from baseline in measurement of HDL-cholesterol (mg/dl)	Measure of HDL-cholesterol (mg/dl)	0, + 6 months, + 12 months, +24 months
Change from baseline in measurement of Glycated Haemoglobin (%)	Measure of Glycated Haemoglobin (%)	0, + 6 months, + 12 months, +24 months
Changes in bone mineral density	Bone mineral density quantified by Dual X-Ray Absorptiometry (DEXA)]	0, + 12 months, +24 months
Changes in quality of life	Quality of life will be measured by Addison Quality of Life (AddiQol) questionnaire, used to assess quality of life in patients suffering from adrenal insufficiency. Each question has a score ranging from 1 to 4. Total score (minimum: 30; maximum: 120) is obtained summing each question score. The higher the scores are, the better the quality of life is. No clear cut-offs are defined.	0, + 6 months, + 12 months, +24 months
Changes in sex function in males	Sex function will be measured by International Index of Erectile Function (IIEF) questionnaire. IIEF is divided into five function domains: Erectile function (Q1-5, Q15; score range Q1-5: 0-5; score range Q15: 1-5), Orgasmic function (Q9-10; score range Q9: 0-5; score range Q10: 1-5), Sexual desire (Q11-12; score range: 1-5), Intercourse satisfaction (Q6-8; score range: 0-5), Overall satisfaction (Q13-14; score range: 1-5). The higher the domain scores are, the better the male sexual functions are.	0, + 6 months, + 12 months, +24 months
Changes in sex function in females	Sex function will be measured by Female Sexual Function Index (FSFI) questionnaire. FSFI is divided into six domains: Desire (Q1-2; score range: 1-5), Arousal (Q3-6; score range: 0-5), Lubrification (Q7-10; score range: 0-5), Orgasm (Q11-13; score range: 0-5), Satisfaction (Q14-16; score range Q14: 0-5; score range Q15-16: 1-5), Pain (Q17-19; score range: 0-5). To obtain the full scale score (ranging from 2 to 36), each domain score range should be corrected by an individual factor (Desire: 0.6; Arousal and Lubrification: 0.3; Orgasm, Satisfaction and Pain: 0.4). The higher the score is, the better the female sexual function is.	0, + 6 months, + 12 months, +24 months
Changes in depression status	Depression status will be measured by Beck Depression Inventory Test (BDI-II) questionnaire. Each question has a score ranging from 0 to 3. Total score (minimum: 0; maximum: 63) is obtained summing each question score. Scores range from minimum (0-13), mild (14-19), moderate (20-28), severe (29-63)	0, + 6 months, + 12 months, +24 months
Incidence of Treatment Adverse Events (safety analysis)	Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events version 4.0 (not a scale)	0, + 6 months, + 12 months, +24 months
Changes in androgens levels	Measure of androstenedione/testosterone ratio	0, + 6 months, + 12 months, +24 months
Changes in sperm concentration	Evaluation of sperm concentration according to WHO criteria	0, + 6 months, + 12 months, +24 months
Changes in ovarian follicles reserve	Evaluation of number of ovarian follicles by conventional ultrasound imaging	0, + 6 months, + 12 months, +24 months

Collaborators and Investigators

• Sponsor: Federico II University

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2016
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: November 9, 2018
• First Submitted That Met QC Criteria: November 29, 2018
• First Posted (Actual): November 30, 2018

Study Record Updates

• Last Update Posted (Estimated): September 16, 2025
• Last Update Submitted That Met QC Criteria: September 10, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: congenital adrenal hyperplasia; glucocorticoid treatment; dual release hydrocortisone
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Gonadal Disorders; Congenital Abnormalities; Adrenal Gland Diseases; Disorders of Sex Development; Urogenital Abnormalities; Steroid Metabolism, Inborn Errors; Adrenogenital Syndrome; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Adrenal Hyperplasia, Congenital; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Pregnadienetriols; Pregnadienediols; Pregnenes; Hydroxycorticosteroids; Adrenal Cortex Hormones; 17-Hydroxycorticosteroids; Dexamethasone; Prednisone; Prednisolone; Cortisone
• Other Study ID Numbers: 140/16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No