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Optimising Steroid Replacement in Patients With Adrenal Insufficiency

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ClinicalTrials.gov Identifier: NCT03282487
Recruitment Status : Enrolling by invitation
First Posted : September 14, 2017
Last Update Posted : September 14, 2017
Sponsor:
Information provided by (Responsible Party):
Dr Mark Sherlock, The Adelaide and Meath Hospital, incorporating The National Children's Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Adrenal Insufficiency Drug: Modified release hydrocortisone Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Optimising Steroid Replacement in Patients With Adrenal Insufficiency
Actual Study Start Date : September 5, 2017
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : December 2019


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 Name: Plenadren

No Intervention: Healthy control group
Same research laboratory measurements performed in a healthy control group for comparison to patient group



Primary Outcome Measures :
  1. Global corticosteroid metabolism [ Time Frame: At baseline and after 12 weeks of Plenadren(intervention) treatment ]
    Urinary steroid metabolite profiles.

  2. Adipose tissue corticosteroid metabolism [ Time Frame: At baseline and after 12 weeks of Plenadren(intervention) treatment ]
    Cortisol generation profile using adipose tissue microdialysis catheter

  3. Hepatic corticosteroid metabolism [ Time Frame: At baseline and after 12 weeks of Plenadren(intervention) treatment ]
    Serum Cortisol generation profile


Secondary Outcome Measures :
  1. Quality of Life questionnaires [ Time Frame: At baseline and after 12 weeks of Plenadren(intervention) treatment ]
  2. Potential biomarkers for adequacy of hydrocortisone replacement [ Time Frame: At baseline and after 12 weeks of Plenadren(intervention) treatment ]
    Gene and protein expression of adipose tissue samples



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03282487


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

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Responsible Party: Dr Mark Sherlock, Consultant Endocrinologist, The Adelaide and Meath Hospital, incorporating The National Children's Hospital
ClinicalTrials.gov Identifier: NCT03282487     History of Changes
Other Study ID Numbers: 2016/09/05
First Posted: September 14, 2017    Key Record Dates
Last Update Posted: September 14, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr Mark Sherlock, The Adelaide and Meath Hospital, incorporating The National Children's Hospital:
cortisol
adrenal insufficiency
hypopituitarism
hydrocortisone
Additional relevant MeSH terms:
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Adrenal Insufficiency
Adrenal Gland Diseases
Endocrine System Diseases
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Epinephrine
Racepinephrine
Epinephryl borate
Anti-Inflammatory Agents
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Sympathomimetics
Vasoconstrictor Agents