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.

Trial registration: ClinicalTrials.gov NCT01735617.

Figures

Figure 1.. Phase 2 study of Chronocort, a modified-release formulation of hydrocortisone.

GC, glucocorticoid. Fasting labs obtained on visit 1 (day 2, day 5 and day 6), visit 2 - visit 4 (day 2) included insulin, glucose, testosterone, supine plasma renin activity, bone turn-over markers (cross-linked telopeptide, osteocalcin) and biochemistry panels. Serial blood sampling included: adrenocorticotropic hormone (ACTH), androstenedione, 17-hydroxyprogesterone (17-OHP) and cortisol. Chronocort was initiated on visit 1, day 2 at 2300 h.

Figure 2.. Comparison of 24-hour hormone profiles on Conventional (baseline) versus Chronocort therapy (6 months) (mean ± SEM) for a, ACTH, b, androstenedione and c, 17-OHP.