A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia.

Abstract

CONTEXT:

Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm.

OBJECTIVES:

The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration.

DESIGN, SETTING, AND PATIENTS:

Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology.

MAIN OUTCOME MEASURES:

The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP).

RESULTS:

In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC.

CONCLUSIONS:

Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.

• Authors: Ashwini Mallappa, Ninet Sinaii, Parag Kumar, Martin J Whitaker, Lori-Ann Daley, Dena Digweed, David J A Eckland, Carol Van Ryzin, Lynnette K Nieman, Wiebke Arlt, Richard J Ross, Deborah P Merke
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 3 Pg. 1137-45 (Mar 2015) ISSN: 1945-7197 [Electronic] United States
• PMID: 25494662 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Capsules
• Delayed-Action Preparations
• Hydrocortisone

Topics

• Adolescent
• Adrenal Hyperplasia, Congenital (drug therapy, metabolism)
• Adult
• Capsules
• Circadian Rhythm
• Delayed-Action Preparations
• Drug Administration Schedule
• Female
• Humans
• Hydrocortisone (administration & dosage, pharmacokinetics)
• Male
• Middle Aged
• Quality of Life
• Young Adult