<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03282487</url>
  </required_header>
  <id_info>
    <org_study_id>2016/09/05</org_study_id>
    <nct_id>NCT03282487</nct_id>
  </id_info>
  <brief_title>Optimising Steroid Replacement in Patients With Adrenal Insufficiency</brief_title>
  <official_title>Optimising Steroid Replacement in Patients With Adrenal Insufficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Adelaide and Meath Hospital, incorporating The National Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Adelaide and Meath Hospital, incorporating The National Children's Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Adrenal insufficiency is a condition where the adrenal glands do not produce an adequate&#xD;
      amount of steroid hormones. The aetiology of adrenal insufficiency can be primary or&#xD;
      secondary. Patients will adrenal insufficiency have increased morbidity and mortality. In&#xD;
      recent years there has been concern regarding what is the optimal dose and regimen of steroid&#xD;
      replacement for patients. Unfortunately there is no accurate way of monitoring if a patient&#xD;
      is on too much or too little steroid. We have shown in hypopituitary patients with secondary&#xD;
      adrenal insufficiency that higher doses of hydrocortisone may be harmful. This reason for&#xD;
      this is not fully understood.&#xD;
&#xD;
      In recent years, a modified release hydrocortisone tablet (Plenadren) taken once per day&#xD;
      (unlike conventional immediate release hydrocortisone which requires twice or thrice daily&#xD;
      regimen) has come on the market. This tablet has shown to a have a steroid profile that more&#xD;
      closely resembles normal physiology, avoiding the peak steroid levels that occur during&#xD;
      thrice daily regimens, which may be of importance for improving outcome in adrenal&#xD;
      insufficiency patients. It also shown improved cardiovascular risk factors, glucose&#xD;
      metabolism and quality of life in compared to conventional treatment.&#xD;
&#xD;
      The aim of our study is to assess the effect of hydrocortisone therapy on how the body uses&#xD;
      and breaks down (metabolises) steroids. This will be done by several different research&#xD;
      methods: by measuring markers of steroid action and metabolism in blood, urine and within the&#xD;
      fat tissue under the skin in the abdomen. These results will be compared in the same patient&#xD;
      while on their usual hydrocortisone and after switching to modified release hydrocortisone&#xD;
      for 12 weeks, and to results from a normal healthy control group who are not on steroid&#xD;
      replacement.&#xD;
&#xD;
      This will be the first study to assess the impact of this new modified release hydrocortisone&#xD;
      in relation to tissue steroid metabolism. The results will potentially help us to improve the&#xD;
      treatment of patients with steroid deficiency and reduce the side effects seen in these&#xD;
      patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a prospective, cross-over study. This study cannot be blinded or placebo controlled&#xD;
      due to the risk of adrenal crisis in the study population with primary and secondary adrenal&#xD;
      insufficiency.&#xD;
&#xD;
      The aim of study is to assess the effect of immediate release and modified release&#xD;
      hydrocortisone therapy on corticosteroid metabolism and 11-HSD1 in vivo (by assessment of&#xD;
      urine metabolites and liver/ adipose tissue metabolism) by using several translational&#xD;
      research approaches. This will also be compared to normal healthy controls to assess which&#xD;
      treatment protocol is most physiological.&#xD;
&#xD;
      Study Objectives&#xD;
&#xD;
        -  To assess the effect of changing to modified release hydrocortisone therapy on global&#xD;
           corticosteroid metabolism as assessed by urinary steroid metabolite profiles.&#xD;
&#xD;
        -  To assess the effect of changing to modified release hydrocortisone therapy on adipose&#xD;
           tissue corticosteroid metabolism and action&#xD;
&#xD;
        -  To assess the effect of changing to modified release hydrocortisone on hepatic&#xD;
           corticosteroid metabolism.&#xD;
&#xD;
        -  To assess the effect of changing to modified release hydrocortisone therapy on patient&#xD;
           quality of life (QoL) as assessed through validated QoL questionnaires.&#xD;
&#xD;
        -  To compare results to normal healthy controls to assess which treatment protocol is most&#xD;
           physiological.&#xD;
&#xD;
        -  To assess potential biomarkers for adequacy of hydrocortisone replacement therapy.&#xD;
&#xD;
      Patients will switch from their usual conventional immediate release hydrocortisone to daily&#xD;
      dose equivalent of modified release hydrocortisone (Plenadren®) for 12 weeks.Other hormone&#xD;
      replacement therapy regimens will not be adjusted during the study period.&#xD;
&#xD;
      Research laboratory measurements will be performed at baseline and 12 weeks of modified&#xD;
      release hydrocortisone. At the end of the intervention treatment period, the patients will be&#xD;
      shifted to their usual hydrocortisone treatment and will be followed at the outpatient clinic&#xD;
      according to the directives of the clinic.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date type="Actual">September 5, 2017</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">September 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Global corticosteroid metabolism</measure>
    <time_frame>At baseline and after 12 weeks of Plenadren(intervention) treatment</time_frame>
    <description>Urinary steroid metabolite profiles.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adipose tissue corticosteroid metabolism</measure>
    <time_frame>At baseline and after 12 weeks of Plenadren(intervention) treatment</time_frame>
    <description>Cortisol generation profile using adipose tissue microdialysis catheter</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hepatic corticosteroid metabolism</measure>
    <time_frame>At baseline and after 12 weeks of Plenadren(intervention) treatment</time_frame>
    <description>Serum Cortisol generation profile</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quality of Life questionnaires</measure>
    <time_frame>At baseline and after 12 weeks of Plenadren(intervention) treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Potential biomarkers for adequacy of hydrocortisone replacement</measure>
    <time_frame>At baseline and after 12 weeks of Plenadren(intervention) treatment</time_frame>
    <description>Gene and protein expression of adipose tissue samples</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Adrenal Insufficiency</condition>
  <arm_group>
    <arm_group_label>Conventional immediate release hydrocortisone</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Modified release Hydrocortisone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>12 weeks of modified release hydrocortisone (Plenadren)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Same research laboratory measurements performed in a healthy control group for comparison to patient group</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Modified release hydrocortisone</intervention_name>
    <description>Patients will switch from their usual conventional immediate release hydrocortisone to daily dose equivalent of modified release hydrocortisone (Plenadren®)</description>
    <arm_group_label>Modified release Hydrocortisone</arm_group_label>
    <other_name>Plenadren</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female patients ≥ 18years of age with Primary Adrenal Insufficiency (Addison's&#xD;
             disease) confirmed on biochemical testing.&#xD;
&#xD;
          -  Male or female patients ≥ 18years of age with ACTH deficiency defined by a stimulated&#xD;
             peak cortisol in response to insulin-induced hypoglycaemia or short synacthen testing&#xD;
             &lt;400 nmol/l, with known organic pituitary disease, and no adjustment in hormone&#xD;
             replacement for at least 3 months prior to study entry.&#xD;
&#xD;
          -  Signed informed consent to participate in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Patients with acute medical or surgical illness&#xD;
&#xD;
          -  Patients with advanced cardiac/pulmonary disease&#xD;
&#xD;
          -  Patients with a terminal illness&#xD;
&#xD;
          -  Patients on glucocorticoids for purposes other than ACTH deficiency&#xD;
&#xD;
          -  Patients on agents that interfere with corticosteroid metabolism&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark Sherlock</last_name>
    <role>Principal Investigator</role>
    <affiliation>Adelaide and Meath Hospital incorporating the national childrens hospital, Tallaght, Dublin, Ireland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Adelaide and Meath Hospital incorporating the National Childrens Hospital</name>
      <address>
        <city>Dublin</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ireland</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>September 12, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>September 12, 2017</last_update_submitted>
  <last_update_submitted_qc>September 12, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Adelaide and Meath Hospital, incorporating The National Children's Hospital</investigator_affiliation>
    <investigator_full_name>Dr Mark Sherlock</investigator_full_name>
    <investigator_title>Consultant Endocrinologist</investigator_title>
  </responsible_party>
  <keyword>cortisol</keyword>
  <keyword>adrenal insufficiency</keyword>
  <keyword>hypopituitarism</keyword>
  <keyword>hydrocortisone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adrenal Insufficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydrocortisone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03282487
org study id: 2016/09/05
nct id: NCT03282487
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Global corticosteroid metabolism
time frame: At baseline and after 12 weeks of Plenadren(intervention) treatment
description: Urinary steroid metabolite profiles.
measure: Adipose tissue corticosteroid metabolism
time frame: At baseline and after 12 weeks of Plenadren(intervention) treatment
description: Cortisol generation profile using adipose tissue microdialysis catheter
measure: Hepatic corticosteroid metabolism
time frame: At baseline and after 12 weeks of Plenadren(intervention) treatment
description: Serum Cortisol generation profile
measure: Quality of Life questionnaires
time frame: At baseline and after 12 weeks of Plenadren(intervention) treatment
measure: Potential biomarkers for adequacy of hydrocortisone replacement
time frame: At baseline and after 12 weeks of Plenadren(intervention) treatment
description: Gene and protein expression of adipose tissue samples
arm group label: Conventional immediate release hydrocortisone
arm group type: No Intervention
arm group label: Modified release Hydrocortisone
arm group type: Active Comparator
description: 12 weeks of modified release hydrocortisone (Plenadren)
arm group label: Healthy control group
arm group type: No Intervention
description: Same research laboratory measurements performed in a healthy control group for comparison to patient group
intervention type: Drug
intervention name: Modified release hydrocortisone
description: Patients will switch from their usual conventional immediate release hydrocortisone to daily dose equivalent of modified release hydrocortisone (Plenadren®)
arm group label: Modified release Hydrocortisone
other name: Plenadren
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Mark Sherlock
role: Principal Investigator
affiliation: Adelaide and Meath Hospital incorporating the national childrens hospital, Tallaght, Dublin, Ireland
facility: 
country: Ireland
responsible party type: Principal Investigator
investigator affiliation: The Adelaide and Meath Hospital, incorporating The National Children's Hospital
investigator full name: Dr Mark Sherlock
investigator title: Consultant Endocrinologist
mesh term: Adrenal Insufficiency
mesh term: Hydrocortisone
sharing ipd: Undecided