Official Title: “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 Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Active Control, Crossover Assignment, Pharmacokinetics/Dynamics Study

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.

Primary:

• Chronocort vs. Cortef cortisol concentrations (max, min, AUC).

Secondary:

• Changes in adrenal hormone concentrations, changes in fatigue, changes in weight.

INCLUSION CRITERIA:

• 1. Known CAH due to 21-hydroxylase deficiency based on hormonal and/or genetic testing. Patients with classic CAH only.
• 2. Male or female patients, age 16 and above. Patients less than 18 must have fusion of epiphyses on bone age X-ray of the left hand.
• 3. Provision of signed written informed consent and written assent from patients less than 18 years old, as applicable.
• 4. Good general health.
• 5. 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 a medically acceptable method of contraception.
• 6. Plasma renin activity must be less than 1.5 times the upper limits of normal.

EXCLUSION CRITERIA:

• 1. Co-morbid condition requiring daily administration of a medication that induces hepatic enzymes or interferes with the metabolism of glucocorticoids.
• 2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine above the normal range or elevated liver function tests (ALT or AST greater than 1.5 the upper limits of normal).
• 3. Females who are pregnant or lactating.
• 4. Iatrogenic suppression of the HPA axis defined as recent (within one month) 17-hydroxyprogesterone undetectable.
• 5. Patients with any other significant medical or psychiatric conditions that in the opinion of the Investigator would preclude participation in the trial.
• 6. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study.

Lead Sponsor: National Institute of Child Health and Human Development (NICHD)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda Maryland 20892 United States

Overall Clinical Trial Officials and Contacts

Overall Contact: Patient Recruitment and Public Liaison Office (800) 411-1222 prpl@mail.cc.nih.gov

Information obtained from ClinicalTrials.gov on July 18, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00519818

Study ID Number: 070211

ClinicalTrials.gov Identifier: NCT00519818

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page