Ultradian Subcutaneous Hydrocortisone Infusion in Addison Disease and Congenital Adrenal Hyperplasia

The aim of this study is to compare the effects of tablet treatment, circadian and combined circadian and ultradian subcutaneous hydrocortisone infusion on steroid metabolism and tissue responses to therapy.

Study Overview

• Status: Unknown
• Conditions: Addison Disease; Adrenal Hyperplasia Congenital
• Intervention / Treatment: Drug: Solu-Cortef; Drug: Cortef

Detailed Description

The conventional glucocorticoid replacement therapy in primary adrenal insufficiency (Addison's disease) and congenital adrenal hyperplasia renders the cortisol levels unphysiological, which may cause symptoms and long-term complications. This therapeutical approach does not enable to restore physiological circadian and ultradian rhythm of glucocorticoids. Current studies conclude that constant or unphysiological administration of glucocorticoids leads to abnormal gene transcription and causes sides effect of glucocorticoids treatment and long standing complications Glucocorticoid replacement is technically feasible by continuous subcutaneous hydrocortisone infusion, which can mimic not only the normal diurnal cortisol rhythm, but potentially also the ultradian cadence.

This is a pilot trial with an open cross-over design of 3 x minimum 2 weeks in 10 patients comparing the effects of tablet treatment versus continuous subcutaneous hydrocortisone infusion versus ultradian subcutaneous hydrocortisone infusion on serum, salivary, tissue hormonal response and glucocorticoid related gene expression.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Kristian Løvås, MD, PhD; Phone Number: 55973075; Email: kristian.lovas@helse-bergen.no
• Study Contact Backup: Name: Katerina Simunkova, MD, PhD; Phone Number: 41079948; Email: katerina.simunkova@k2.uib.no

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Recruiting
    • University Hospital Helse Bergen
    • Principal Investigator: Katerina Simunkova, MD, PhD
    • Contact: Kristian Løvås, MD, PhD; Phone Number: 55973075; Email: kristian.lovas@helse-bergen.no
    • Contact: Katerina Simunkova, MD, PhD; Phone Number: 41079948; Email: katerina.simunkova@k2.uib.no
    • Sub-Investigator: Kristian Løvås, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. clinical diagnosis of primary adrenal insufficiency
2. Written informed consent

Exclusion Criteria:.

1. Diabetes mellitus
2. Severe cardiovascular disease
3. Active malignant disease
4. Pregnancy or breast feeding
5. treatment with interfering drugs
6. Intake of grapefruit juice

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: continuous subcutaneous hydrocortisone; continuous subcutaneous hydrocortisone infusion (CSHI), Solu-Cortef ® 50mg/ml infusate	Drug: Solu-Cortef; administration by pump for minimum 2 weeks; Other Names: hydrocortisone; Drug: Cortef; tablet treatment 2 ro 3 times per day for 14 days; Other Names: hydrocortisone tablets
Active Comparator: cortef tablets; the patient regular treatment by Cortef 5 mg, produced by Nycomed Pharma two times or three times a day.	Drug: Solu-Cortef; administration by pump for minimum 2 weeks; Other Names: hydrocortisone; Drug: Cortef; tablet treatment 2 ro 3 times per day for 14 days; Other Names: hydrocortisone tablets
Experimental: ultradian subcutaneous hydrocortisone; ultradian subcutaneous hydrocortisone infusion, Solu-Cortef ® 50mg/ml infusate	Drug: Solu-Cortef; administration by pump for minimum 2 weeks; Other Names: hydrocortisone; Drug: Cortef; tablet treatment 2 ro 3 times per day for 14 days; Other Names: hydrocortisone tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum cortisol -24 hours curve	admission to hospital for 24 hours	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Salivary cortisol - 24 hours curve	admission to the hospital for 25 hours	24 hours
24 h urine cortisol and metabolites	urine samples for 24 hours	24 hours
levels of corticotropic hormone	blood samples	24 hours
24 hours curve of tissue cortisol	The tissue effect of glucocorticoid replacement - 24 hours curve of tissue cortisol (microdialysis)	24 hours
gene expression	m RNA expression of genes	24 hours

Collaborators and Investigators

• Sponsor: Haukeland University Hospital
• Investigators: Principal Investigator: Katerina Simunkova, MD, PhD, Universtity of Bergen; Study Director: Kristian Løvås, MD, PhD, Helse Bergen

Publications and helpful links

General Publications

• Lightman SL, Conway-Campbell BL. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat Rev Neurosci. 2010 Oct;11(10):710-8. doi: 10.1038/nrn2914. Epub 2010 Sep 15.
• Lovas K, Husebye ES. Continuous subcutaneous hydrocortisone infusion in Addison's disease. Eur J Endocrinol. 2007 Jul;157(1):109-12. doi: 10.1530/EJE-07-0052. Erratum In: Eur J Endocrinol. 2008 Jun;158(6):939. Dosage error in article text.
• Lightman SL, Windle RJ, Julian MD, Harbuz MS, Shanks N, Wood SA, Kershaw YM, Ingram CD. Significance of pulsatility in the HPA axis. Novartis Found Symp. 2000;227:244-57; discussion 257-60. doi: 10.1002/0470870796.ch14.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: November 28, 2013
• First Submitted That Met QC Criteria: March 24, 2014
• First Posted (Estimate): March 26, 2014

Study Record Updates

• Last Update Posted (Estimate): December 21, 2016
• Last Update Submitted That Met QC Criteria: December 20, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Addison Disease; Adrenal Hyperplasia Congenital
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Adrenal Gland Diseases; Steroid Metabolism, Inborn Errors; Adrenal Insufficiency; Hyperplasia; Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction; Addison Disease; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: 2013/1738