Optimising Steroid Replacement in Patients With Adrenal Insufficiency

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.

Study Overview

• Status: Unknown
• Conditions: Adrenal Insufficiency
• Intervention / Treatment: Drug: Modified release hydrocortisone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland
    • Adelaide and Meath Hospital incorporating the National Childrens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: Conventional immediate release hydrocortisone
ACTIVE_COMPARATOR: Modified release Hydrocortisone; 12 weeks of modified release hydrocortisone (Plenadren)	Drug: Modified release hydrocortisone; Patients will switch from their usual conventional immediate release hydrocortisone to daily dose equivalent of modified release hydrocortisone (Plenadren®); Other Names: Plenadren
NO_INTERVENTION: Healthy control group; Same research laboratory measurements performed in a healthy control group for comparison to patient group

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Adelaide and Meath Hospital, incorporating The National Children's Hospital
• Investigators: Principal Investigator: Mark Sherlock, Adelaide and Meath Hospital incorporating the national childrens hospital, Tallaght, Dublin, Ireland

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 5, 2017
• Primary Completion (ANTICIPATED): September 1, 2019
• Study Completion (ANTICIPATED): December 1, 2019

Study Registration Dates

• First Submitted: September 12, 2017
• First Submitted That Met QC Criteria: September 12, 2017
• First Posted (ACTUAL): September 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 14, 2017
• Last Update Submitted That Met QC Criteria: September 12, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: cortisol; hydrocortisone; adrenal insufficiency; hypopituitarism
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenal Gland Diseases; Adrenal Insufficiency; Anti-Inflammatory Agents; Hydrocortisone
• Other Study ID Numbers: 2016/09/05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No