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; Whitaker, Martin J.; Daley, Lori-Ann; Digweed, Dena; Eckland, D.J.A.; Ryzin, Carol Van; Nieman, Lynnette K.; Arlt, Wiebke; Ross, Richard; Merke, Deborah P.

doi:10.1210/jc.2014-3809

Cited by 124 publications

(79 citation statements)

References 34 publications

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“…In our cohort, daily hydrocortisone doses in the lower range of the recommended 10-15 mg/m 2 daily, and medication timetables resulting in a longer cortisol night gap, may have contributed to a predisposition to hypoglycemia. Thus, altered dosage recommendations for young CAH children or new drugs with a delayed hydrocortisone release providing higher cortisol levels in the early morning hours (44,45) could be promising approaches in the future. Probably not all classic CAH patients are equally at risk for hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life

Odenwald

Nennstiel-Ratzel

Dörr

et al. 2016

European Journal of Endocrinology

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Objective: To evaluate adrenal crises after the start of treatment up to the age of 6 years in children with classic congenital adrenal hyperplasia (CAH). Design: Analysis of data extracted from a population-based prospective long-term follow-up study of children detected in neonatal screening. Methods: Data of 102 Bavarian children with classic CAH due to 21-hydroxylase deficiency were analyzed, using parental questionnaires and medical reports. Parent-reported hospital admissions of children diagnosed with acute health impairment were included in the analysis if salt loss (hyponatremia) or hypoglycemia was documented in the discharge summary. Results: A total of 74 children (72.5%) had no report of hospital admissions with salt loss or hypoglycemia during the observational period. However, in 27.5% of the children, 22 salt-wasting crises (seven of these also with low blood glucose) and 16 hypoglycemic episodes without salt loss were reported. Furthermore, the cumulative incidence for seizures was elevated; 13 children experienced seizures during hyponatremia or hypoglycemia. Most adrenal crises were triggered by infections, often with inappropriate emergency management, but in 11 cases hypoglycemia occurred unexpectedly, without evidence of severe illness and without any management errors. Frequency of adrenal crises was 6.5 per 100 patient years (95% CI: 4.6-8.8). Conclusions: Crisis prevention remains a permanent challenge for families and physicians caring for children with classic CAH. Expert care and compliance with emergency recommendations are crucial. Further research on the interactions among glucocorticoid deficiency, adrenomedullary dysfunction, and glucose metabolism is necessary for the prevention of hypoglycemia, especially in young CAH patients.

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Section: Discussionmentioning

confidence: 99%

Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life

Odenwald

Nennstiel-Ratzel

Dörr

et al. 2016

European Journal of Endocrinology

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“…An additional product, Chronocort®, containing microparticulate hydrocortisone with delayed absorption, is also currently in development. 33 In line with the principle of mimicking the physiological pattern of cortisol secretion is the use of continuous subcutaneous hydrocortisone infusions (CSHI), administered using proprietary insulin pumps. A cross-over study of 33 patients comparing thrice daily oral hydrocortisone and CSHI over 12 weeks has reported higher waking salivary cortisol and better control of overnight ACTH levels during pump therapy.…”

Section: New Developmentsmentioning

confidence: 99%

Adrenal insufficiency – recognition and management

Pazderska

Pearce

2017

Clinical Medicine

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Adrenal insuffi ciency is characterised by inadequate glucocorticoid production owing to destruction of the adrenal cortex or lack of adrenocorticotropic hormone stimulation. In primary adrenal insuffi ciency, lack of mineralocorticoids is also a feature. Patients can present with an insidious onset of symptoms, or acutely in adrenal crisis, which requires prompt recognition and treatment. Chronic glucocorticoid therapy is the most common cause of adrenal insuffi ciency. The diagnosis of adrenal insuffi ciency is made by demonstrating low basal and/or stimulated serum cortisol and should be followed by appropriate investigations to establish the underlying aetiology. Maintenance glucocorticoid replacement is usually given as a twice or thrice daily hydrocortisone preparation. Patients with primary adrenal insuffi ciency also require mineralocorticoid. Regular monitoring for features of underand over-replacement is essential during follow-up. Patient education is a key feature of management of this condition. IntroductionThe adrenal cortex secretes the essential steroid hormones, cortisol and aldosterone, under the control of pituitary adrenocorticotropic hormone (ACTH), angiotensin II and plasma potassium. The most frequent cause of adrenal insufficiency is exogenous steroid use. Up to 2.5% of the population are taking such steroid medications for inflammatory or immune-mediated conditions. 1 These individuals are vulnerable to steroid deficiency if the medication is stopped suddenly. ACTH deficiency (secondary adrenal insufficiency) as a result of pituitary tumours, infiltrative diseases, head injury or congenital hypopituitarism is the next most frequent cause, present in around 1 per 3,000 individuals. 2High dose opiates, which frequently induce hypogonadotropic hypogonadism, are also increasingly recognised as a cause of hypothalamic-pituitary-adrenal (HPA) suppression.3 By comparison, primary adrenal insufficiency is rare, with a prevalence of 1 in 8,000 people. 4 In developed nations, an autoimmune attack directed against the adrenal steroidogenic enzymes (predominantly 21-hydroxylase) 5 accounts for about 85% of cases. Around 60% of patients with autoimmune ABSTRACT Adrenal insuffi ciency -recognition and managementAddison's disease have an additional autoimmune condition, most frequently autoimmune thyroid disease or type 1 diabetes.

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“…Chronocort ® , a modified-release formulation of hydrocortisone aims to replicate cortisol circadian rhythm and to suppress the overnight ACTH surge which drives excess androgen production in CAH [102]. The recently published phase 2 study for Chronocort ® demonstrated a decrease in equivalent hydrocortisone dose required, lower 24-h and afternoon androstenedione area under the curve and lower 24 h and morning 17-hydroxyprogesterone area under the curve [103]. A further dual-release hydrocortisone preparation, Plenadren™ (Duocort/ ViroPharma, Helsingborg, Sweden), has been trialled in patients with adrenal insufficiency as oncedaily dosing, compared to thrice-daily dosing [104,105].…”

Section: Sustained Release Hydrocortisone Preparationsmentioning

confidence: 99%

Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency

Webb

Krone

2015

Best Practice & Research Clinical Endocrinology & Metab

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Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive conditions leading to glucocorticoid deficiency. CAH is the most common cause of adrenal insufficiency (AI) in the paediatric population. The majority of the other forms of primary and secondary adrenal insufficiency are rare conditions. It is critical to establish the underlying aetiology of each specific condition as a wide range of additional health problems specific to the underlying disorder can be found. Following the introduction of life-saving glucocorticoid replacement sixty years ago, steroid hormone replacement regimes have been refined leading to significant reductions in glucocorticoid doses over the last two decades. These adjustments are made with the aim both of improving the current management of children and young persons and of reducing future health problems in adult life. However despite optimisation of existing glucocorticoid replacement regimens fail to mimic the physiologic circadian rhythm of glucocorticoid secretion, current efforts therefore focus on optimising replacement strategies. In addition, in recent years novel experimental therapies have been developed which target adrenal sex steroid synthesis in patients with CAH aiming to reduce co-morbidities associated with sex steroid excess. These developments will hopefully improve the health status and long-term outcomes in patients with congenital adrenal hyperplasia and adrenal insufficiency.

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A Phase 2 Study of Chronocort, a Modified-Release Formulation of Hydrocortisone, in the Treatment of Adults With Classic Congenital Adrenal Hyperplasia

Abstract: 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.

Cited by 124 publications

References 34 publications

Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life

Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life

Adrenal insufficiency – recognition and management

Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency

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