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Cited by 167Sexual Differentiation and DisordersAdrenal Hormones and DisordersHormonal Regulation and Hypertension

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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Mallappa, Ashwini, Sinaii, Ninet, Kumar, Parag, Whitaker, Martin J., Daley, Lori-Ann, Digweed, Dena, Eckland, David J. A., Van Ryzin, Carol +4 more·2015·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2014-3809PMC PMC5393506
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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.

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  • Both once-daily and twice-daily modified-release hydrocortisone versions are closer mimics of the physiological circadian rhythm than the conventional multiple-dose regimen.

    “Both the once-daily (56) and twice-daily (57) modified-released versions have been shown to be a closer mimic of the physiological circadian rhythm, compared to the conventional multiple-dose regimen.”

    From Hypoglycaemia in adrenal insufficiency (2023) · cites this paper as [57]

  • Infants prenatally exposed to betamethasone have altered responses of the HPA axis and a higher incidence of mental and behavioral disorders.

    “Infants prenatally exposed to betamethasone have altered responses of the HPA axis and a higher incidence of mental and behavioral disorders (490,491).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [490]

    The Results (p. 9) describe adults with congenital adrenal hyperplasia, and the Abstract (p. 3) reports outcomes of modified-release hydrocortisone treatment. Searches for betamethasone, prenatal exposure, infant HPA-axis responses, and mental or behavioral disorders found no passage addressing the cited claim. (LLM, conf=0.78)

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  • Continuous subcutaneous hydrocortisone infusion has shown adequate ACTH suppression with lower total hydrocortisone dose compared to conventional treatment.

    “Continuous subcutaneous hydrocortisone infusion via an insulin pump mimicking cortisol circadian rhythm, has similarly shown adequate ACTH suppression with lower total hydrocortisone dose compared to conventional treatment, 139-142”

    From Congenital adrenal hyperplasia (2017) · cites this paper as [140]

  • A modified-release oral hydrocortisone preparation, Chronocort, was successful in achieving lower androgen levels while decreasing the hydrocortisone equivalent dose using a twice-daily regimen in a Phase 2 study of 16 patients with classic 21OH deficiency.

    “A modified-release oral hydrocortisone preparation, Chronocort ® , was successful in achieving lower androgen levels while decreasing the hydrocortisone equivalent dose using a twice-daily regimen in a Phase 2 study of 16 patients with classic 21OH deficiency.140”

    From Congenital adrenal hyperplasia (2017) · cites this paper as [140]

  • Chronocort capsules controlled adrenal androgens throughout the day despite down-titration, with no serious adverse events.

    “Chronocort capsules demonstrated control of adrenal androgens throughout the day despite down-titration, with no serious adverse events109.”

    From Management challenges and therapeutic advances in congenital adrenal hyperplasia (2022) · cites this paper as [109]

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Authors
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.
Affiliations
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
  • National Institutes of Health (US)
  • Diurnal (United Kingdom) (GB)
Corresponding author
  • Mallappa, Ashwini
  • Ross, Richard J.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2015-03
Volume
100
Issue
3
Pages
1137-1145
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2014-3809
PMC
PMC5393506
OpenAlex
W1976145935
Cited by
167
References
36
Citations by year
2026: 11 · 2025: 16 · 2024: 17 · 2023: 11 · 2022: 16 · 2021: 10 · 2020: 11 · 2019: 16 · 2018: 18 · 2017: 17 · 2016: 19 · 2015: 5
FWCI
5.61
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
  • Spiral (Imperial College London) (submittedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
congenital adrenal hyperplasia, cortisol, modified-release formulation, diurnal cortisol rhythm, androstenedione, 17-hydroxyprogesterone, hyperandrogenism, treatment tolerability
MeSH terms
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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