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

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

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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.

Original languageEnglish
Pages (from-to)1137-45
Number of pages9
JournalThe Journal of clinical endocrinology and metabolism
Volume100
Issue number3
Early online date11 Dec 2014
DOIs
Publication statusPublished - Mar 2015

Keywords

  • Adolescent
  • Adrenal Hyperplasia, Congenital
  • Adult
  • Capsules
  • Circadian Rhythm
  • Delayed-Action Preparations
  • Drug Administration Schedule
  • Female
  • Humans
  • Hydrocortisone
  • Male
  • Middle Aged
  • Quality of Life
  • Young Adult

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