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

doi:10.1210/jc.2014-3809

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

Metabolism and Systems Science

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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 language	English
Pages (from-to)	1137-45
Number of pages	9
Journal	The Journal of clinical endocrinology and metabolism
Volume	100
Issue number	3
Early online date	11 Dec 2014
DOIs	https://doi.org/10.1210/jc.2014-3809
Publication status	Published - 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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Mallappa_et_al_Phase_2_Study_Chronocort_JCEM_2014_Post-Print
Final publisher version available at: http://dx.doi.org/10.1210/jc.2014-3809 Checked Jan 2016
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Mallappa, A., Sinaii, N., Kumar, P., Whitaker, M. J., Daley, L.-A., Digweed, D., Eckland, D. J. A., Van Ryzin, C., Nieman, L. K., Arlt, W., Ross, R. J., & Merke, D. P. (2015). A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. The Journal of clinical endocrinology and metabolism, 100(3), 1137-45. https://doi.org/10.1210/jc.2014-3809

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title = "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.",

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",

author = "Ashwini Mallappa and Ninet Sinaii and Parag Kumar and Whitaker, {Martin J} and Lori-Ann Daley and Dena Digweed and Eckland, {David J A} and {Van Ryzin}, Carol and Nieman, {Lynnette K} and Wiebke Arlt and Ross, {Richard J} and Merke, {Deborah P}",

year = "2015",

month = mar,

doi = "10.1210/jc.2014-3809",

language = "English",

volume = "100",

pages = "1137--45",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "3",

}

Mallappa, A, Sinaii, N, Kumar, P, Whitaker, MJ, Daley, L-A, Digweed, D, Eckland, DJA, Van Ryzin, C, Nieman, LK, Arlt, W, Ross, RJ & Merke, DP 2015, 'A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia', The Journal of clinical endocrinology and metabolism, vol. 100, no. 3, pp. 1137-45. https://doi.org/10.1210/jc.2014-3809

A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. / Mallappa, Ashwini; Sinaii, Ninet; Kumar, Parag et al.
In: The Journal of clinical endocrinology and metabolism, Vol. 100, No. 3, 03.2015, p. 1137-45.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia

AU - Mallappa, Ashwini

AU - Sinaii, Ninet

AU - Kumar, Parag

AU - Whitaker, Martin J

AU - Daley, Lori-Ann

AU - Digweed, Dena

AU - Eckland, David J A

AU - Van Ryzin, Carol

AU - Nieman, Lynnette K

AU - Arlt, Wiebke

AU - Ross, Richard J

AU - Merke, Deborah P

PY - 2015/3

Y1 - 2015/3

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adrenal Hyperplasia, Congenital

KW - Adult

KW - Capsules

KW - Circadian Rhythm

KW - Delayed-Action Preparations

KW - Drug Administration Schedule

KW - Female

KW - Humans

KW - Hydrocortisone

KW - Male

KW - Middle Aged

KW - Quality of Life

KW - Young Adult

U2 - 10.1210/jc.2014-3809

DO - 10.1210/jc.2014-3809

M3 - Article

C2 - 25494662

SN - 0021-972X

VL - 100

SP - 1137

EP - 1145

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 3

ER -

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

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