<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/NCT03793114</url>
  </required_header>
  <id_info>
    <org_study_id>2018/751/REK sør-øst A (REK)</org_study_id>
    <nct_id>NCT03793114</nct_id>
  </id_info>
  <brief_title>Screening and Stimulation Testing for Residual Secretion of Adrenal Steroid Hormones in Autoimmune Addison's Disease</brief_title>
  <official_title>Residual Secretion of Adrenal Steroid Hormones in Addison's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Bergen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Charite University, Berlin, Germany</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Bergen</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>
      In autoimmune adrenal insufficiency, or Addison's disease (AD), the immune system attacks the&#xD;
      adrenal cortex. As a result, the adrenal cells producing hormones such as cortisol and&#xD;
      aldosterone are destroyed, leaving the body with insufficient levels to meet its needs. The&#xD;
      common perception is that upon diagnosis of Addison's disease, basically all adrenal hormone&#xD;
      production has ceased.&#xD;
&#xD;
      There have, however, been found a few individuals who preserve some residual secretion of&#xD;
      cortisol even years after diagnosis. The objectives of this study is to find out how common&#xD;
      it is, and to explore if residual function have impact on patient outcome. That is, do&#xD;
      patients with and without residual function differ when it comes to quality of life, working&#xD;
      ability, medication dosages, and risk of adrenal crisis?&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Autoimmune destruction of the adrenal cortex is the main cause of primary adrenal&#xD;
      insufficiency (Addison's disease, AD). Autoimmune AD (AAD) becomes clinically manifest when&#xD;
      90 % of cortex of adrenal gland is destroyed. Current dogma says that adrenal insufficiency&#xD;
      ultimately is complete, that is the adrenal cortex stops producing steroids altogether.&#xD;
      However, several case reports indicate that there might be a subgroup of patients that retain&#xD;
      some steroid production, even years after the diagnosis. This ability could be beneficial as&#xD;
      it could protect against adrenal crises, ease medication, and leave the patient with better&#xD;
      quality of life.&#xD;
&#xD;
      The objective of the study is to systematically assess to what extent patients with AAD have&#xD;
      residual adrenocortical function, and to characterize this subgroup.&#xD;
&#xD;
      The study will be an open non-randomized three-stage multicenter clinical trial comprising&#xD;
      patients from the Norwegian Registry for organ-specific autoimmune disease (ROAS), the&#xD;
      Swedish Addison registry, and Germany. In stage 1, patients will be asked to fill out&#xD;
      questionnaires and deliver medication-fasting samples for analyses of adrenal steroids. In&#xD;
      addition, patients with congenital adrenal hyperplasia (CAH) and bilaterally adrenalectomized&#xD;
      will serve as negative controls for adrenal steroids. In stage 2, AAD patients with residual&#xD;
      steroid production will be invited to a cosyntropin stimulation test to estimate the maximum&#xD;
      steroid output from the adrenal glands. Twenty patients with no sign of residual function&#xD;
      will also be tested as a control group. In stage 3, AAD patients with confirmed residual&#xD;
      function will be invited to go through a 30-hour ambulatory sampling of interstitial fluid&#xD;
      for investigation of diurnal variation in adrenocortical hormone levels. Also, newly&#xD;
      diagnosed AAD patients will be invited to repeated cosyntropin testing as a means of&#xD;
      delineating the natural progression of adrenocortical failure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 26, 2018</start_date>
  <completion_date type="Anticipated">April 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Screening</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The percentage of included patients with residual secretion of cortisol and aldosterone.</measure>
    <time_frame>1 day</time_frame>
    <description>Percentage of included patients with detectable levels of adrenal steroid hormones.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting adrenocorticotropic hormone (ACTH)-stimulated levels of metanephrines</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in hair samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol precursors</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol precursors</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol precursors</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in hair samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol metabolites</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol metabolites</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of cortisol metabolites</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in hair samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of aldosterone</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of aldosterone</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of aldosterone precursors</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of aldosterone precursors</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of aldosterone metabolites</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of aldosterone metabolites</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of renin in patients with and without residual function.</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of renin in patients with and without residual function.</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of ACTH in patients with and without residual function.</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of ACTH in patients with and without residual function.</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of metanephrines in patients with and without residual function</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting basal levels of metanephrines in patients with and without residual function</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting ACTH-stimulated levels of cortisol</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting ACTH-stimulated levels of cortisol precursors</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting ACTH-stimulated levels of cortisol metabolites</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting ACTH-stimulated levels of aldosterone</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting ACTH-stimulated levels of aldosterone precursors</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication-fasting ACTH-stimulated levels of aldosterone metabolites</measure>
    <time_frame>1 day</time_frame>
    <description>Levels in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cortisol replacement doses, including stress doses in patients with and without residual function.</measure>
    <time_frame>1 day</time_frame>
    <description>Total daily dosage</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cortisol stress doses in patients with and without residual function.</measure>
    <time_frame>1 day</time_frame>
    <description>No. stress doses the last week</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fludrocortisone replacement doses in patients with and without residual function.</measure>
    <time_frame>1 day</time_frame>
    <description>Total daily dosage.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In patients with and without residual function: disease-specific quality-of-life</measure>
    <time_frame>1 day</time_frame>
    <description>Total score ranging from 30 to 120 in disease-specific quality-of-life questionnaire, Addison Quality of Life (AddiQoL). For every question, scoring is translated in points (1 = 1 point, 2 and 3 = 2 points, 4 and 5 = 3 points, 6 = 4 points) and the algebraic sum of points is calculated. A higher score reflects better health-related quality-of-life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In patients with and without residual function, generic health-related quality of life by the Short Form (36) Health Survey</measure>
    <time_frame>1 day</time_frame>
    <description>The Short Form (36) Health Survey is a generic tool comprising 36 items evaluating patient reported quality of life concerning eight domains (physical functioning, role functioning physical, bodily pain, general health perception, vitality, social functioning, role functioning emotional, and mental health and general perception of change in health). Scores are expressed on a 0-100 scale with higher scores associated with better quality of life. The result of each domain is presented separately.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of adrenal crises pr. 100 patient years</measure>
    <time_frame>1 day</time_frame>
    <description>Number of crises pr. 100 patient years for all included patients as well as in patients with versus without residual adrenal function</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Adrenocortical hormones in congenital adrenal hyperplasia (CAH) controls</measure>
    <time_frame>1 day</time_frame>
    <description>Presence or absence of adrenocortical hormones in congenital adrenal hyperplasia (CAH) controls in a medication fasting morning baseline blood sample</description>
  </other_outcome>
  <other_outcome>
    <measure>Adrenocortical hormones in bilaterally adrenalectomized controls</measure>
    <time_frame>1 day</time_frame>
    <description>Presence or absence of adrenocortical hormones in bilaterally adrenalectomized controls in a medication fasting morning baseline blood sample</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in response to cosyntropin testing</measure>
    <time_frame>4 days</time_frame>
    <description>Response to cosyntropin testing at 3, 6, 12, and 24 months after diagnosis</description>
  </other_outcome>
  <other_outcome>
    <measure>Diurnal variation in adrenocortical hormone secretion</measure>
    <time_frame>2 days</time_frame>
    <description>Variation in endogenous adrenocortical hormone secretion during 30 hour continuous sampling</description>
  </other_outcome>
  <number_of_arms>8</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Primary Adrenal Insufficiency</condition>
  <arm_group>
    <arm_group_label>Detectable levels of adrenal hormones</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with detectable serum levels of adrenal hormones will go through cosyntropin stimulation testing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls with undetectable hormone levels</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Twenty patients without detectable serum levels of adrenal hormones will serve as controls in cosyntropin stimulation testing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Undetectable levels of adrenal hormones</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients without detectable serum levels of adrenal hormones. Cosyntropin stimulation testing will not be performed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Congenital adrenal hyperplasia (CAH) control group</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Mapping adrenal steroid profile in patients with congenital adrenal hyperplasia (CAH) with confirmed total deficiency of 21-hydroxylase.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bilaterally adrenalectomized control group</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Mapping adrenal steroid profile in patients who are bilaterally adrenalectomized.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Diurnal variation in residual adrenocortical hormone levels</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with detectable serum levels of adrenal hormones will go through a 30-hour ambulatory sampling of interstitial fluid for mapping of any diurnal variation in endogenous adrenocortical secretion.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Repeated cosyntropin testing in newly diagnosed patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Newly diagnosed patients will be invited to go through repeated cosyntropin testing to delineate the natural progression of adrenocortical failure.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cardiovascular and inflammatory biomarkers</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Compare cardiovascular and inflammatory biomarker profiles in patients with and without residual production of adrenocortical steroids</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Cosyntropin stimulation test</intervention_name>
    <description>Blood samples are taken before (0 min), and 30 and 60 min after intravenously administration of 250 µg cosyntropin (tetracosactide acetate) with the patient placed in the recumbent position. The test will be performed non-fasting (but medication-fasting) between 08:00 and 10:00 a.m.</description>
    <arm_group_label>Controls with undetectable hormone levels</arm_group_label>
    <arm_group_label>Detectable levels of adrenal hormones</arm_group_label>
    <arm_group_label>Repeated cosyntropin testing in newly diagnosed patients</arm_group_label>
    <other_name>Synacthen stimulation test</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Baseline blood tests</intervention_name>
    <description>Medication-fasting morning levels of adrenocortical hormones.</description>
    <arm_group_label>Bilaterally adrenalectomized control group</arm_group_label>
    <arm_group_label>Congenital adrenal hyperplasia (CAH) control group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>30-hour ambulatory sampling of intestinal fluid</intervention_name>
    <description>30-hour ambulatory sampling of intestinal fluid for analysis of adrenocortical hormones.</description>
    <arm_group_label>Diurnal variation in residual adrenocortical hormone levels</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Blood test</intervention_name>
    <description>Cardiovascular and inflammatory biomarker profiles</description>
    <arm_group_label>Cardiovascular and inflammatory biomarkers</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women with AAD, age 18-70 years old. This requires documented adrenal&#xD;
             insufficiency and a positive test for 21-hydroxylase autoantibodies (biomarker for&#xD;
             autoimmune cause) on at least one occasion.&#xD;
&#xD;
          -  Provided written informed consent&#xD;
&#xD;
          -  In case of concomitant endocrine/autoimmune diseases, the patients should be on stable&#xD;
             adequate treatment at least the last 3 months prior to the study period.&#xD;
&#xD;
          -  For Norwegian AD patients: enrolled in ROAS&#xD;
&#xD;
          -  For Swedish AD patients: enrolled in the Swedish Addison registry&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Antihypertensive treatment, with the exception of doxazosin, verapamil, and&#xD;
             moxonidine.&#xD;
&#xD;
          -  Active malignant disease, severe heart, kidney or liver failure.&#xD;
&#xD;
          -  Diabetes mellitus type 1.&#xD;
&#xD;
          -  Pregnancy or breast feeding.&#xD;
&#xD;
          -  Pharmacological treatment with glucocorticoids (except their usual cortisone or&#xD;
             hydrocortisone replacement therapy) or drugs that interfere with cortisol and&#xD;
             catecholamine metabolism (antiepileptics, rifampicin, St. Johns wart).&#xD;
&#xD;
          -  Use of other glucocorticoid replacement medication than cortisone acetate or&#xD;
             hydrocortisone.&#xD;
&#xD;
          -  Intake of grapefruit, grapefruit juice, or and liquorice juice the last week before or&#xD;
             during the study period.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eystein S Husebye, M.D, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Bergen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Endokrinologie in Charlottenburg</name>
      <address>
        <city>Berlin</city>
        <zip>10627</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Haukeland University Hospital</name>
      <address>
        <city>Bergen</city>
        <zip>5021</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karolinska Institutet</name>
      <address>
        <city>Stockholm</city>
        <zip>171 77</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Norway</country>
    <country>Sweden</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>November 6, 2018</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 4, 2019</study_first_posted>
  <last_update_submitted>November 3, 2022</last_update_submitted>
  <last_update_submitted_qc>November 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adrenal Insufficiency</mesh_term>
    <mesh_term>Addison Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cosyntropin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Upon informed and signed content, biological samples will be stored in the biobank for research on endocrine disorders. Any new analyses will not be performed without approval from the Regional committee for medical and health research ethics.</ipd_description>
  </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/NCT03793114
org study id: 2018/751/REK sør-øst A (REK)
nct id: NCT03793114
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In autoimmune adrenal insufficiency, or Addison's disease (AD), the immune system attacks the
      adrenal cortex. As a result, the adrenal cells producing hormones such as cortisol and
      aldosterone are destroyed, leaving the body with insufficient levels to meet its needs. The
      common perception is that upon diagnosis of Addison's disease, basically all adrenal hormone
      production has ceased.

      There have, however, been found a few individuals who preserve some residual secretion of
      cortisol even years after diagnosis. The objectives of this study is to find out how common
      it is, and to explore if residual function have impact on patient outcome. That is, do
      patients with and without residual function differ when it comes to quality of life, working
      ability, medication dosages, and risk of adrenal crisis?
Autoimmune destruction of the adrenal cortex is the main cause of primary adrenal
      insufficiency (Addison's disease, AD). Autoimmune AD (AAD) becomes clinically manifest when
      90 % of cortex of adrenal gland is destroyed. Current dogma says that adrenal insufficiency
      ultimately is complete, that is the adrenal cortex stops producing steroids altogether.
      However, several case reports indicate that there might be a subgroup of patients that retain
      some steroid production, even years after the diagnosis. This ability could be beneficial as
      it could protect against adrenal crises, ease medication, and leave the patient with better
      quality of life.

      The objective of the study is to systematically assess to what extent patients with AAD have
      residual adrenocortical function, and to characterize this subgroup.

      The study will be an open non-randomized three-stage multicenter clinical trial comprising
      patients from the Norwegian Registry for organ-specific autoimmune disease (ROAS), the
      Swedish Addison registry, and Germany. In stage 1, patients will be asked to fill out
      questionnaires and deliver medication-fasting samples for analyses of adrenal steroids. In
      addition, patients with congenital adrenal hyperplasia (CAH) and bilaterally adrenalectomized
      will serve as negative controls for adrenal steroids. In stage 2, AAD patients with residual
      steroid production will be invited to a cosyntropin stimulation test to estimate the maximum
      steroid output from the adrenal glands. Twenty patients with no sign of residual function
      will also be tested as a control group. In stage 3, AAD patients with confirmed residual
      function will be invited to go through a 30-hour ambulatory sampling of interstitial fluid
      for investigation of diurnal variation in adrenocortical hormone levels. Also, newly
      diagnosed AAD patients will be invited to repeated cosyntropin testing as a means of
      delineating the natural progression of adrenocortical failure.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Screening
masking: None (Open Label)
measure: The percentage of included patients with residual secretion of cortisol and aldosterone.
time frame: 1 day
description: Percentage of included patients with detectable levels of adrenal steroid hormones.
measure: Medication-fasting adrenocorticotropic hormone (ACTH)-stimulated levels of metanephrines
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of cortisol
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of cortisol
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of cortisol
time frame: 1 day
description: Levels in hair samples
measure: Medication-fasting basal levels of cortisol precursors
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of cortisol precursors
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of cortisol precursors
time frame: 1 day
description: Levels in hair samples
measure: Medication-fasting basal levels of cortisol metabolites
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of cortisol metabolites
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of cortisol metabolites
time frame: 1 day
description: Levels in hair samples
measure: Medication-fasting basal levels of aldosterone
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of aldosterone
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of aldosterone precursors
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of aldosterone precursors
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of aldosterone metabolites
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of aldosterone metabolites
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of renin in patients with and without residual function.
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of renin in patients with and without residual function.
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of ACTH in patients with and without residual function.
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of ACTH in patients with and without residual function.
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting basal levels of metanephrines in patients with and without residual function
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting basal levels of metanephrines in patients with and without residual function
time frame: 1 day
description: Levels in urine samples
measure: Medication-fasting ACTH-stimulated levels of cortisol
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting ACTH-stimulated levels of cortisol precursors
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting ACTH-stimulated levels of cortisol metabolites
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting ACTH-stimulated levels of aldosterone
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting ACTH-stimulated levels of aldosterone precursors
time frame: 1 day
description: Levels in blood samples
measure: Medication-fasting ACTH-stimulated levels of aldosterone metabolites
time frame: 1 day
description: Levels in blood samples
measure: Cortisol replacement doses, including stress doses in patients with and without residual function.
time frame: 1 day
description: Total daily dosage
measure: Cortisol stress doses in patients with and without residual function.
time frame: 1 day
description: No. stress doses the last week
measure: Fludrocortisone replacement doses in patients with and without residual function.
time frame: 1 day
description: Total daily dosage.
measure: In patients with and without residual function: disease-specific quality-of-life
time frame: 1 day
description: Total score ranging from 30 to 120 in disease-specific quality-of-life questionnaire, Addison Quality of Life (AddiQoL). For every question, scoring is translated in points (1 = 1 point, 2 and 3 = 2 points, 4 and 5 = 3 points, 6 = 4 points) and the algebraic sum of points is calculated. A higher score reflects better health-related quality-of-life.
measure: In patients with and without residual function, generic health-related quality of life by the Short Form (36) Health Survey
time frame: 1 day
description: The Short Form (36) Health Survey is a generic tool comprising 36 items evaluating patient reported quality of life concerning eight domains (physical functioning, role functioning physical, bodily pain, general health perception, vitality, social functioning, role functioning emotional, and mental health and general perception of change in health). Scores are expressed on a 0-100 scale with higher scores associated with better quality of life. The result of each domain is presented separately.
measure: Number of adrenal crises pr. 100 patient years
time frame: 1 day
description: Number of crises pr. 100 patient years for all included patients as well as in patients with versus without residual adrenal function
measure: Adrenocortical hormones in congenital adrenal hyperplasia (CAH) controls
time frame: 1 day
description: Presence or absence of adrenocortical hormones in congenital adrenal hyperplasia (CAH) controls in a medication fasting morning baseline blood sample
measure: Adrenocortical hormones in bilaterally adrenalectomized controls
time frame: 1 day
description: Presence or absence of adrenocortical hormones in bilaterally adrenalectomized controls in a medication fasting morning baseline blood sample
measure: Change in response to cosyntropin testing
time frame: 4 days
description: Response to cosyntropin testing at 3, 6, 12, and 24 months after diagnosis
measure: Diurnal variation in adrenocortical hormone secretion
time frame: 2 days
description: Variation in endogenous adrenocortical hormone secretion during 30 hour continuous sampling
arm group label: Detectable levels of adrenal hormones
arm group type: Experimental
description: Patients with detectable serum levels of adrenal hormones will go through cosyntropin stimulation testing.
arm group label: Controls with undetectable hormone levels
arm group type: Active Comparator
description: Twenty patients without detectable serum levels of adrenal hormones will serve as controls in cosyntropin stimulation testing.
arm group label: Undetectable levels of adrenal hormones
arm group type: No Intervention
description: Patients without detectable serum levels of adrenal hormones. Cosyntropin stimulation testing will not be performed.
arm group label: Congenital adrenal hyperplasia (CAH) control group
arm group type: Other
description: Mapping adrenal steroid profile in patients with congenital adrenal hyperplasia (CAH) with confirmed total deficiency of 21-hydroxylase.
arm group label: Bilaterally adrenalectomized control group
arm group type: Other
description: Mapping adrenal steroid profile in patients who are bilaterally adrenalectomized.
arm group label: Diurnal variation in residual adrenocortical hormone levels
arm group type: Experimental
description: Patients with detectable serum levels of adrenal hormones will go through a 30-hour ambulatory sampling of interstitial fluid for mapping of any diurnal variation in endogenous adrenocortical secretion.
arm group label: Repeated cosyntropin testing in newly diagnosed patients
arm group type: Experimental
description: Newly diagnosed patients will be invited to go through repeated cosyntropin testing to delineate the natural progression of adrenocortical failure.
arm group label: Cardiovascular and inflammatory biomarkers
arm group type: Active Comparator
description: Compare cardiovascular and inflammatory biomarker profiles in patients with and without residual production of adrenocortical steroids
intervention type: Diagnostic Test
intervention name: Cosyntropin stimulation test
description: Blood samples are taken before (0 min), and 30 and 60 min after intravenously administration of 250 µg cosyntropin (tetracosactide acetate) with the patient placed in the recumbent position. The test will be performed non-fasting (but medication-fasting) between 08:00 and 10:00 a.m.
arm group label: Controls with undetectable hormone levels
arm group label: Detectable levels of adrenal hormones
arm group label: Repeated cosyntropin testing in newly diagnosed patients
other name: Synacthen stimulation test
intervention type: Diagnostic Test
intervention name: Baseline blood tests
description: Medication-fasting morning levels of adrenocortical hormones.
arm group label: Bilaterally adrenalectomized control group
arm group label: Congenital adrenal hyperplasia (CAH) control group
intervention type: Device
intervention name: 30-hour ambulatory sampling of intestinal fluid
description: 30-hour ambulatory sampling of intestinal fluid for analysis of adrenocortical hormones.
arm group label: Diurnal variation in residual adrenocortical hormone levels
intervention type: Other
intervention name: Blood test
description: Cardiovascular and inflammatory biomarker profiles
arm group label: Cardiovascular and inflammatory biomarkers
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Eystein S Husebye, M.D, Prof
role: Principal Investigator
affiliation: University of Bergen
facility: 
facility: 
facility: 
country: Germany
country: Norway
country: Sweden
responsible party type: Sponsor
mesh term: Adrenal Insufficiency
mesh term: Addison Disease
mesh term: Cosyntropin
sharing ipd: No
ipd description: Upon informed and signed content, biological samples will be stored in the biobank for research on endocrine disorders. Any new analyses will not be performed without approval from the Regional committee for medical and health research ethics.