The DOI matches its Crossref record; 35 of the 36 references it cites were found in a registry or an index.
A Phase 2 Study of Chronocort, a Modified-Release Formulation of Hydrocortisone, in the Treatment of Adults With Classic Congenital Adrenal Hyperplasia
Open accessAbstract
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 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]
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In the citing paper
“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]
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“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“Compared with various forms of conventional therapy prior to entry, this approach yielded decreased 17OHP and androstenedione values throughout the day, despite a reduced HC dose equivalent (28 6 11.8 vs 25.9 6 7.1 mg/d).”
From Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline (2018) · cites this paper as [312]
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Cites
Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Montori, V. M., Oberfield, S. E., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2631 · Cited by 1,468 · cited 1×
“recommended therapy in growing children (2).”
Self-citationBuckley, T. M., & Schatzberg, A. F. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1056 · Cited by 964
Congenital adrenal hyperplasia
El-Maouche, D., Arlt, W., & Merke, D. P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31431-9 · Cited by 669
Self-citationHealth status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients
Arlt, W., Willis, D. S., Wild, S. H., Krone, N., Doherty, E. J., Hahner, S., Han, T. S., Carroll, P. V., Conway, G. S., Rees, D. A., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0917 · Cited by 506
Self-citationComparison of self-reported fatigue in rheumatoid arthritis and controls.
Bl, B. (1995) · PubMed · Cited by 355
Johannsson, G., Nilsson, A. G., Bergthorsdottir, R., Burman, P., Dahlqvist, P., Ekman, B., Engström, B. E., Olsson, T., Ragnarsson, O., Ryberg, M., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1926 · Cited by 329
Modified-release hydrocortisone to provide circadian cortisol profiles
Debono, M., Ghobadi, C., Rostami-Hodjegan, A., Huatan, H., Campbell, M. J., Newell-Price, J., Darzy, K., Merke, D. P., Arlt, W., & Ross, R. J. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2380 · Cited by 322
Self-citationClinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia
Finkielstain, G. P., Kim, M. S., Sinaii, N., Nishitani, M., Van Ryzin, C., Hill, S. C., Reynolds, J. C., Hanna, R. M., & Merke, D. P. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-2102 · Cited by 313
Self-citationMah, P. M., Jenkins, R. C., Rostami‐Hodjegan, A., Newell‐Price, J., Doane, A., Ibbotson, V., Tucker, G. T., & Ross, R. J. (2004) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2004.02106.x · Cited by 243
Self-citationGlucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives
Seibel, M. J., Cooper, M. S., & Zhou, H. (2013) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(13)70045-7 · Cited by 235
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Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., Husebye, E. S., Merke, D. P., Murad, M. H., Stratakis, C. A., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1710 · Cited by 1,769
Self-citationSpeiser, P. W., Arlt, W., Auchus, R. J., Baskin, L. S., Conway, G. S., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Murad, M. H., Oberfield, S. E., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01865 · Cited by 1,234
Self-citationRussell, G., & Lightman, S. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0228-0 · Cited by 1,032
Congenital adrenal hyperplasia
El-Maouche, D., Arlt, W., & Merke, D. P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31431-9 · Cited by 669
Self-citationCongenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556
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Metadata
- 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
- 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
- bronze
- doi.org
- 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
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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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