Continuous Subcutaneous Hydrocortisone Infusion in Congenital Adrenal Hyperplasia

Adrenal Hyperplasia, Congenital Clinical Trial

— CAH  

Official title:

Continuous Subcutaneous Hydrocortisone Infusion in Congenital Adrenal Hyperplasia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01771328
• Other study ID #: 2012/749
• Status: Recruiting
• Phase: Phase 2
• First received: January 10, 2013
• Last updated: December 20, 2016
• Start date: February 2013
• Est. completion date: January 2017

Study information

• Verified date: December 2016
• Source: Haukeland University Hospital
• Contact: Kristian Løvås, MD, PhD
• Phone: +47 55977996
• Email: kral[@]helse-bergen.no
• Is FDA regulated: No
• Health authority: Norway: Regional Ethics Commitee
• Study type: Interventional

Clinical Trial Summary

The conventional glucocorticoid replacement therapy in congenital adrenal hyperplasia (CAH) renders the cortisol levels unphysiological, which may cause symptoms and long-term complications. Glucocorticoid replacement is technically feasible by continuous subcutaneous hydrocortisone infusion (CSHI), and can mimic the normal diurnal cortisol rhythm. This method was recently applied to treat a patient through a critical phase of puberty. This is a clinical trial aiming to evaluate CSHI treatment in patients with CAH. The main objective is to determine the effects of CSHI on metabolic parameters (androstenedione and 17-hydroxyprogesterone profiles, and testosterone,adrenocorticotropic hormone(ACTH), cortisol, and bone markers), and to determine the required glucocorticoid doses. Secondary objectives are to determine effects on clinical status, body weight, blood pressure and other metabolic parameters, as well as on subjective health status (AddiQoL, SF36).

Description:

CAH patients are treated with glucocorticoids and mineralocorticoids. Ideally, the glucocorticoid doses should be sufficient to suppress the elevated ACTH secretion, and hence attenuate the increase in androgen levels. Because of this, CAH patients use higher steroid doses than patients with autoimmune adrenal insufficiency (Addison's disease) and therefore are in higher risk of developing glucocorticoid side effects. The natural glucocorticoids, hydrocortisone (cortisol) or cortisone acetate, are preferred during childhood because of the growth suppressive effects of the longer acting synthetic glucocorticoids, prednisolone and dexamethasone. There is no consensus as to which type of glucocorticoid and which doses should be used for adult CAH patients. Glucocorticoids display a typical diurnal variation, which the current therapy does not restore, leading to both to over- or undertreatment. Some CAH patients experience symptoms that may be due to unphysiological glucocorticoid replacement therapy.

For selected CAH patients with poor response to conventional replacement therapy, or with problematic side effects such as impaired growth, weight gain, metabolic syndrome, and osteoporosis, continuous subcutaneous hydrocortisone infusion (CSHI) might become a treatment option. CSHI treatment would also be facilitated by the use of the small disposable pumps now developed for insulin treatment.

CSHI: Pharmacodynamics, Pharmacokinetics, and safety Hydrocortisone is identical to cortisol; the pharmacodynamics does not depend on mode of delivery. A hydrocortisone solution can be safely applied for three days in the insulin pump without major day-to-day variation. A daily dose of 10 mg/m2 body surface area/day restores normal levels of saliva cortisol in most patients. Thus, it is possible to mimic the physiological diurnal cortisol variation seen in healthy subjects.

The study will compare two glucocorticoid replacement modalities in randomised order within each patient. Prior to Baseline there will be a period of dose adjustment for pump treatment. Patients will be educated in groups, and dose adjustments will be co-ordinated with regular visits at the outpatient clinic/telephone consultation combined with laboratory analyses.

The patients will be assigned a participation number and randomised to any of two treatment sequences (A-B or B-A). Should the need for an extra glucocorticoid dose occur (intercurrent illness) during the study, the patients should administer their previous glucocorticoid replacement for safety reasons. Extra doses should be recorded in the patient diary. Treatment A is current treatment, i.e. glucocorticoid and mineralocorticoid replacement according to best clinical judgement. Treatment B is CSHI with the initial standard dose of 10mg/m2/24hrs. Body surface area will be calculated according to the nomogram from the formula of Du Bois and Du Bois.

After 7 days after initiating pump therapy the patient should be reassessed with blood dots (17-hydroxyprogesterone) and saliva cortisol and saliva 17-hydroxyprogesterone measurements in the morning (0800-0900) and in the evening (2300-2400). Based on results of this testing the dose will be changed at the discretion of the investigator. The further new testing should be done within 7-10 days.

When the final dose is established a 24h urine measurement, blood test in the morning (17-hydroxyprogesterone and cortisol) and a salivary sample full profile (full profile Hrs. 0800, 0930, 1100, 1230, 1700, 2100, 2400, 0300), will be done before entering the study. The dose adjustment period will be unlimited but will take minimally 4 weeks (aiming to obtain normal range levels of morning serum cortisol (160- 620 nmol/l), and 3-4 times increase in morning serum 17-hydroxyprogesterone (0,3-8,6 nmol/l for females, 0,9-6,6 nmo/l for males), and midnight (24:00) saliva cortisol (<2,8 nmol/l) and a circadian pattern as indicated in figure 1.

Afterwards it will 4 weeks wash out period before starting, wash out period between treatments modalities will take 2 months.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: January 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• verified salt-wasting CAH and simple virilizing CAH, on single prednisone, or hydrocortisone therapy.

• In case of concomitant endocrine/autoimmune diseases these should be on stable treatment during the study period.

Exclusion Criteria:

• Patients with diabetes mellitus on insulin pump treatment will not be included in this study

• cardiovascular disease, active malignant disease and pregnancy, and pharmacological treatment with glucocorticoids or drugs that interfere with cortisol metabolism (antiepileptics, rifampicin, St. Johns wart).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adrenal Hyperplasia, Congenital
• Adrenocortical Hyperfunction
• Adrenogenital Syndrome
• Hyperplasia

Intervention

Drug:
• Hydrocortisone
Initial standard dose of 10mg/m2/24hrs administered by pump during the treatment period, it will take 4 months. Body surface area will be calculated according to the nomogram from the formula of Du Bois and Du Bois.
• Cortisone acetate
Patients will take this tables two times during day according to best clinical practice of therapy of congenital adrenal hyperplasia. Usually Cortisone 25 mg 1 tbl. in the morning and Cortisone 25 1/4 tbl. in the evening. This period will take 6 months.

Locations

Country	Name	City	State
Norway	Haukeland Universitetssykehus, Department of Medicine	Bergen

Sponsors (1)

Lead Sponsor	Collaborator
Haukeland University Hospital

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Androgen levels	Androgen levels as parameters of adequate suppression of androgen production	3 months	Yes
Secondary	Steroid metabolism	levels of ACTH	4 months	Yes
Secondary	bone metabolism		3 months	No
Secondary	fasting glucose		4 months	No
Secondary	body mass index		3 months	No
Secondary	Dual-energy X-ray absorptiometry (DXA)	body composition, bone mineral density	6 months	No
Secondary	Subjective health status	questionnaire	3 months	No
Secondary	waist circumference	cm	3 month	No
Secondary	hip circumference	cm	3 months	No
Secondary	blood pressure		3 months	No
Secondary	fasting insulin		3-4 months	No
Secondary	glycated haemoglobin (Hb1AC)		4 months	No
Secondary	lipid levels		4 months	No
Secondary	c-reactive protein		4 months	No
Secondary	Steroid metabolism	cortisol levels	4 months	Yes

External Links

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