Comparison of Two Forms of Hydrocortisone in Patients With Congenital Adrenal Hyperplasia

A Phase 2, Open Label, Crossover Pharmacokinetic and Pharmacodynamic Study to Compare Chronocort Versus Cortef in Patients With CAH

This study will test a new, extended release form of hydrocortisone called Chronocort in patients with congenital adrenal hyperplasia (CAH). People with CAH do not make enough of the adrenal hormones cortisol and aldosterone, and their adrenal glands make too much of the sex hormone androgen. Medicines called glucocorticoids (hydrocortisone, dexamethasone and prednisone) are currently used to treat CAH, but finding the best dose of these drugs that effectively lowers androgens without causing undesirable side effects, such as weight gain and slow growth rate in children, is often difficult to achieve.

Adolescents and adults with CAH due to 21-hydroxylase deficiency may be eligible for this study. Children 16 years of age and older are eligible with confirmation by bone age that they are no longer growing.

Participants undergo the following tests and procedures during two inpatient visits one month apart at the NIH Clinical Center:

• Medical history and physical examination.
• Medications: Following 7 days of Cortef (standard drug treatment for CAH), patients begin taking Chronocort on day 3 of hospitalization and continue the tablets once a day for 1 month.
• Blood tests: A catheter (plastic tube) is inserted in a vein and left in place for frequent blood draws in order to avoid repeated needlesticks. Blood is drawn for chemistries, blood count, pregnancy test in women, and for serial tests (up to 26 samples in a 24-hour period) to measure hormone levels.
• 24-hour urine test.
• Height and weight measurements.

Between the two hospitalizations, patients are contacted by NIH weekly to check for possible side effects from Chronocort. Two weeks after the first visit, patients also will have blood drawn by their regular doctor or a local clinic. A few days before the second hospitalization, patients undergo a 20-minute telephone questionnaire about energy level and well being.

About 30 days after discharge from the second hospitalization, patients are followed up with a telephone call to see how they are doing.

Study Overview

• Status: Completed
• Conditions: Adrenogenital Syndrome; Congenital Adrenal Hyperplasia; 21-Hydroxylase Deficiency
• Intervention / Treatment: Drug: Chronocort; Drug: Cortef

Detailed Description

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a disease of the adrenal cortex characterized by cortisol deficiency with or without aldosterone deficiency, and androgen excess. The severe or classic form occurs in 1 in 15,000 births worldwide, while the mild non-classic form is a common cause of hyperandrogenism. The discovery of glucocorticoid therapy as a treatment for CAH occurred in the 1950's resulting in patients with classic CAH surviving to live a normal lifespan. However, existing treatment is suboptimal and many unresolved clinical problems exist. Standard hormone replacement often fails to normalize the growth and development of children with CAH, and adults may experience iatrogenic Cushing syndrome, hyperandrogenism, infertility or the development of the metabolic syndrome. Chronocort, a newly-developed formulation of hydrocortisone, results in a slow release of hydrocortisone that is designed to mimic the normal cortisol circadian rhythm. This new medical strategy, physiologic cortisol replacement, offers the prospect of an improved outcome of treatment. Chronocort has been safely given to healthy adult males in pharmacokinetic studies. This first ever study in patients with CAH is a pharmacokinetic/pharmacodynamic study comparing Chronocort to Cortef, the conventional immediate-release form of hydrocortisone.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Satisfactory pre-trial screening

Provision of signed written informed consent and written assent from patients less than 18 years old, as applicable.

Good general health.

Females of childbearing potential must have a negative pregnancy test initially and at all visits. Females who are engaging in sexual intercourse must be using medically acceptable method of contraception.

EXCLUSION CRITERIA:

Co-morbid condition requiring daily administration of a medication that induces hepatic enzymes or interferes with the metabolism of glucocorticoids.

Clinical or biochemical evidence of hepatic or renal disease. Creatinine above the normal range or elevated liver function tests (Transaminases greater than 1.5 the upper limits of normal).

Females who are pregnant or lactating.

Patients with any other significant medical or psychiatric conditions that in the opinion of the Investigator would preclude participation in the trial.

Participation in another clinical trial of an investigational or licensed drug or device within 3 months prior to inclusion in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cortef and Chronocort; Cortef 3 times daily(total dose 30 mg)for minimum of 7 days followed by Chronocort 30 mg once daily nigh time dose for 28 +/- 3 days duration	Drug: Chronocort; Chronocort 30 mg once daily nigh time dose for 28 +/- 3 days duration; Other Names: Hydrocortisone modified release tablet treatment; Drug: Cortef; Cortef 3 times daily(total dose 30 mg)for minimum of 7 days; Other Names: Hydrocortisone immediate release tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Chronocort vs. Cortef Cortisol Concentrations (AUC Over 24 Hours - Time Points 0,.5,1,1.5,2,3,4,5,6,7,8,10,10.5,11, 11.5,12,13,15,17,17.5,18,18.5,19,20,22,24 Post Dose).	Cortef after one week, Chronocort after one month

Secondary Outcome Measures

Outcome Measure	Time Frame
17 Hydroxyprogesterone at 08.00 Hours	Cortef after one week compared with Chronocort after one month

Collaborators and Investigators

• Sponsor: Diurnal Limited
• Collaborators: National Institutes of Health Clinical Center (CC)
• Investigators: Principal Investigator: Deborah Merck, MD, National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001 Mar;30(1):15-30. doi: 10.1016/s0889-8529(08)70017-3.
• Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005 Jun 18-24;365(9477):2125-36. doi: 10.1016/S0140-6736(05)66736-0.
• Krieger DT, Allen W, Rizzo F, Krieger HP. Characterization of the normal temporal pattern of plasma corticosteroid levels. J Clin Endocrinol Metab. 1971 Feb;32(2):266-84. doi: 10.1210/jcem-32-2-266. No abstract available.

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: August 22, 2007
• First Submitted That Met QC Criteria: August 22, 2007
• First Posted (Estimate): August 23, 2007

Study Record Updates

• Last Update Posted (Actual): April 26, 2022
• Last Update Submitted That Met QC Criteria: April 5, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Congenital Adrenal Hyperplasia; Pharmacokinetic; Pharmacodynamic; Hydrocortisone
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Endocrine System Diseases; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Adrenal Gland Diseases; Steroid Metabolism, Inborn Errors; Hyperplasia; Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: 070211