Optimising Steroid Replacement in Patients With Adrenal Insufficiency

Study Overview
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Brief Summary
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Adrenal insufficiency is a condition where the adrenal glands do not produce an adequate amount of steroid hormones. The aetiology of adrenal insufficiency can be primary or secondary. Patients will adrenal insufficiency have increased morbidity and mortality. In recent years there has been concern regarding what is the optimal dose and regimen of steroid replacement for patients. Unfortunately there is no accurate way of monitoring if a patient is on too much or too little steroid. We have shown in hypopituitary patients with secondary adrenal insufficiency that higher doses of hydrocortisone may be harmful. This reason for this is not fully understood. In recent years, a modified release hydrocortisone tablet (Plenadren) taken once per day (unlike conventional immediate release hydrocortisone which requires twice or thrice daily regimen) has come on the market. This tablet has shown to a have a steroid profile that more closely resembles normal physiology, avoiding the peak steroid levels that occur during thrice daily regimens, which may be of importance for improving outcome in adrenal insufficiency patients. It also shown improved cardiovascular risk factors, glucose metabolism and quality of life in compared to conventional treatment. The aim of our study is to assess the effect of hydrocortisone therapy on how the body uses and breaks down (metabolises) steroids. This will be done by several different research methods: by measuring markers of steroid action and metabolism in blood, urine and within the fat tissue under the skin in the abdomen. These results will be compared in the same patient while on their usual hydrocortisone and after switching to modified release hydrocortisone for 12 weeks, and to results from a normal healthy control group who are not on steroid replacement. This will be the first study to assess the impact of this new modified release hydrocortisone in relation to tissue steroid metabolism. The results will potentially help us to improve the treatment of patients with steroid deficiency and reduce the side effects seen in these patients.

Detailed Description
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This is a prospective, cross-over study. This study cannot be blinded or placebo controlled due to the risk of adrenal crisis in the study population with primary and secondary adrenal insufficiency. The aim of study is to assess the effect of immediate release and modified release hydrocortisone therapy on corticosteroid metabolism and 11-HSD1 in vivo (by assessment of urine metabolites and liver/ adipose tissue metabolism) by using several translational research approaches. This will also be compared to normal healthy controls to assess which treatment protocol is most physiological. Study Objectives To assess the effect of changing to modified release hydrocortisone therapy on global corticosteroid metabolism as assessed by urinary steroid metabolite profiles. To assess the effect of changing to modified release hydrocortisone therapy on adipose tissue corticosteroid metabolism and action To assess the effect of changing to modified release hydrocortisone on hepatic corticosteroid metabolism. To assess the effect of changing to modified release hydrocortisone therapy on patient quality of life (QoL) as assessed through validated QoL questionnaires. To compare results to normal healthy controls to assess which treatment protocol is most physiological. To assess potential biomarkers for adequacy of hydrocortisone replacement therapy. Patients will switch from their usual conventional immediate release hydrocortisone to daily dose equivalent of modified release hydrocortisone (Plenadren®) for 12 weeks.Other hormone replacement therapy regimens will not be adjusted during the study period. Research laboratory measurements will be performed at baseline and 12 weeks of modified release hydrocortisone. At the end of the intervention treatment period, the patients will be shifted to their usual hydrocortisone treatment and will be followed at the outpatient clinic according to the directives of the clinic.

Official Title
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Optimising Steroid Replacement in Patients With Adrenal Insufficiency

Conditions
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Adrenal Insufficiency

Intervention / Treatment
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* Drug: Modified release hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥ 18years of age with Primary Adrenal Insufficiency (Addison's disease) confirmed on biochemical testing. Male or female patients ≥ 18years of age with ACTH deficiency defined by a stimulated peak cortisol in response to insulin-induced hypoglycaemia or short synacthen testing <400 nmol/l, with known organic pituitary disease, and no adjustment in hormone replacement for at least 3 months prior to study entry. Signed informed consent to participate in the study Exclusion Criteria: Age < 18 years Patients with acute medical or surgical illness Patients with advanced cardiac/pulmonary disease Patients with a terminal illness Patients on glucocorticoids for purposes other than ACTH deficiency Patients on agents that interfere with corticosteroid metabolism

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Conventional immediate release hydrocortisone<br> | |
| Active Comparator: Modified release Hydrocortisone<br>12 weeks of modified release hydrocortisone (Plenadren) | Drug: Modified release hydrocortisone<br>* Patients will switch from their usual conventional immediate release hydrocortisone to daily dose equivalent of modified release hydrocortisone (Plenadren®)<br>* Other names: Plenadren;|
| No Intervention: Healthy control group<br>Same research laboratory measurements performed in a healthy control group for comparison to patient group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global corticosteroid metabolism | Urinary steroid metabolite profiles. | At baseline and after 12 weeks of Plenadren(intervention) treatment | 
| Adipose tissue corticosteroid metabolism | Cortisol generation profile using adipose tissue microdialysis catheter | At baseline and after 12 weeks of Plenadren(intervention) treatment | 
| Hepatic corticosteroid metabolism | Serum Cortisol generation profile | At baseline and after 12 weeks of Plenadren(intervention) treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life questionnaires |  | At baseline and after 12 weeks of Plenadren(intervention) treatment | 
| Potential biomarkers for adequacy of hydrocortisone replacement | Gene and protein expression of adipose tissue samples | At baseline and after 12 weeks of Plenadren(intervention) treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cortisol, adrenal insufficiency, hypopituitarism, hydrocortisone