From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »
Chicago, IL - June 21, 2014
A phase 2 study of Chronocort®, a modified release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia
A Mallappa, L-A Daley, N Sinaii, C Van Ryzin, H Huatan, D Digweed, D Eckland, M Whitaker, LK Nieman, RJ Ross, DP Merke
Summary: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and aldosterone deficiency and androgen excess. Current conventional glucocorticoid therapy is suboptimal as it cannot replace the normal cortisol circadian rhythm and inadequate or inappropriate suppression of adrenal androgens are common. In the preliminary results of a phase 2 study of Chronocort®, a modified release hydrocortisone capsule formulation, researchers found that Chronocort®, a novel modified release hydrocortisone capsule formulation, approximates physiological cortisol secretion, and improves biochemical control of CAH. Further analyses are underway.
Methods:
Methods:
- The study objectives were to characterize pharmacokinetics and examine disease control following 6 months dose titration.
- Serial profiling was obtained at baseline (conventional glucocorticoid) and every 2 months.
- Twice-daily Chronocort® was initiated: 20 mg at 2300 h, 10 mg at 0700 h.
- Dose titration was based on clinical status and optimal hormonal ranges (17OHP 300-1200 ng/dL, normal androstenedione (males: 40-150, females: 30-200 ng/dL), with androstenedione prioritized.
- Chronocort® cortisol pharmacokinetic profile was the primary endpoint.
- Secondary endpoints included biomarkers of disease control.
- A total of 16 adults (8 females; age 29 ±13 years) with classic CAH (12 salt-wasting, 4 simple virilizing) participated.
- Conventional therapy varied (5 dexamethasone, 7 prednisone, 4 hydrocortisone).
- Chronocort® cortisol pharmacokinetic profile approximated physiological cortisol secretion.
- Ten patients required Chronocort® dose adjustments (decrease in 8, increase in 2; mean hydrocortisone equivalent dose conventional vs 6 months: 16.1 ± 6.4 vs 14.7 ± 6.4 mg/m2).
- Serial androstenedione levels were in the normal range in 8 (50%) of patients on conventional therapy compared with 12 (75%) on Chronocort® at 6 months.
- The majority of patients on Chronocort® achieved 17O HP levels within the normal range, rather than within the mildly elevated range currently used for management.
- At 6 months, Chronocort® resulted in lower 24-hr (P=0.02), morning (0700-1500; P=0.008), and afternoon (1500-2300; P=0.03) area-under-the-curve androstenedione compared with conventional therapy.
- No serious adverse events occurred.
- Common adverse events were headache, fatigue, early awakening, and anemia.
- Three patients had unexpected carpal tunnel syndrome, which resolved with wrist splints.