<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/NCT03752190</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00193457</org_study_id>
    <nct_id>NCT03752190</nct_id>
  </id_info>
  <brief_title>Comparison of Intramuscular and Intravenous ACTH Stimulation Test in Normal Volunteers</brief_title>
  <official_title>Comparison of Intramuscular and Intravenous ACTH Stimulation Test in Normal Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Johns Hopkins University</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cosyntropin (synthetic ACTH) stimulation test is considered the optimal test for diagnosis of&#xD;
      primary and long-standing secondary adrenal insufficiency.&#xD;
&#xD;
      The standard cosyntropin stimulation test is performed by administering 250 µg cosyntropin&#xD;
      intravenously. Serum cortisol is measured before, and at 30 and 60 minutes after the bolus&#xD;
      injection. Peak cortisol levels below 500 nmol/L (18.1 µg/dL) at 30 or 60 minutes after&#xD;
      cosyntropin administration indicate adrenal insufficiency per recent guidelines, without&#xD;
      specification of how the cosyntropin is administered (intravenously or intramuscularly).&#xD;
      However, the peak stimulated cortisol cutoff value is based on old, fluorometric or&#xD;
      radio-immunological methods that are known to detect significant amounts of glucocorticoids&#xD;
      other than cortisol. For this reason, peak cortisol levels, as determined by older assays,&#xD;
      may set higher thresholds than what might be considered necessary using a newer, more&#xD;
      specific assay.&#xD;
&#xD;
      The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now&#xD;
      replaced worldwide (including Johns Hopkins Hospital) by a new Elecsys® Cortisol assay from&#xD;
      Roche Diagnostics (Cortisol II). The new Cortisol II assay employs a monoclonal as opposed to&#xD;
      a polyclonal capturing antibody, which was used in the old Cortisol I assay. This results in&#xD;
      greater specificity for cortisol. The new Cortisol II assay was shown to have strong&#xD;
      correlation with cortisol levels measured by liquid chromatography-tandem mass spectrometry&#xD;
      (LC-MS/MS) which is considered the gold standard for cortisol measurement.&#xD;
&#xD;
      Previous studies addressing the cortisol cutoff levels for the diagnosis of adrenal&#xD;
      insufficiency with different cortisol assays have been heterogeneous in terms of the dose and&#xD;
      route of administration of cosyntropin used, and the wide variety of subjects being tested&#xD;
      including healthy subjects that are occasionally on oral estrogen therapy and patients with&#xD;
      adrenal insufficiency.&#xD;
&#xD;
      Many clinical centers use intramuscular cosyntropin injections given its convenience, and as&#xD;
      mentioned earlier, many institutions are now using the new Roche Cortisol II assay.&#xD;
&#xD;
      Investigators will conduct a study looking at healthy subjects to establish the expected&#xD;
      range of peak cosyntropin-stimulated cortisol levels with two different cosyntropin&#xD;
      administration modalities. The goal of this study is to compare intravenous (IV) and&#xD;
      intramuscular (IM) administration, and to generate a normal range of post-cosyntropin serum&#xD;
      cortisol measure with the new assay.&#xD;
&#xD;
      The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60&#xD;
      minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Generate&#xD;
      assay-specific normal ACTH stimulation test results&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Investigators will conduct a study looking at healthy subjects to establish the expected&#xD;
      range of peak cosyntropin-stimulated cortisol levels in normal healthy subjects with two&#xD;
      different cosyntropin administration modalities. The goal of this study is to compare&#xD;
      intravenous (IV) and intramuscular (IM) administration, and to generate a normal range of&#xD;
      post-cosyntropin serum cortisol measure with the new assay.&#xD;
&#xD;
      The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60&#xD;
      minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Study the&#xD;
      values obtained using the new Roche Cortisol II assay and establish a new reference range for&#xD;
      cosyntropin-stimulated cortisol levels in healthy subjects for both cosyntropin&#xD;
      administration modalities.&#xD;
&#xD;
      The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now&#xD;
      being replaced worldwide by a new Elecsys® Cortisol assay from Roche Diagnostics (Cortisol&#xD;
      II). The new Cortisol II assay is also a competitive immunoassay, but employs a monoclonal as&#xD;
      opposed to a polyclonal capturing antibody, which was used in the old Cortisol I assay. This&#xD;
      results in greater specificity for cortisol with less interference from other endogenous or&#xD;
      exogenous glucocorticoids. The new Cortisol II assay was shown to have strong correlation&#xD;
      with cortisol levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS)&#xD;
      which is considered the gold standard for cortisol measurement. It has been shown in earlier&#xD;
      studies that Cortisol II assay generates cortisol values that are approximately 20-30% lower&#xD;
      than the older Cortisol I immunoassay with proposed new cortisol cutoff for the diagnosis of&#xD;
      adrenal insufficiency between 350-375 nmol/L (12.7-13.6 µg/dL).&#xD;
&#xD;
      This is a prospective study on healthy subjects. Investigators will perform two cosyntropin&#xD;
      stimulation tests on participants on two separate visits, one using intravenous and another&#xD;
      one using intramuscular cosyntropin (250 µg). Investigators will allow a minimum of one week&#xD;
      and a maximum of 2 months between the two tests.&#xD;
&#xD;
      Blood samples for each of the two tests will be drawn at baseline, before cosyntropin&#xD;
      administration, then at 30 minutes and 60 minutes after cosyntropin administration from&#xD;
      indwelling catheter. A maximum of 5 ml of blood will be drawn at each time point. Serum will&#xD;
      be separated, and samples will be stored at - 80o C after collection until analyzed.&#xD;
&#xD;
      All of the blood samples will be tested to measure cortisol levels using the new Roche&#xD;
      Cortisol II assay. The Cortisol assay kits will be provided from Roche Diagnostics.&#xD;
&#xD;
      Overall study duration will be 18 months. There will be two study visits. Investigators will&#xD;
      allow a minimum of one week and a maximum of 2 months between the two visits.&#xD;
&#xD;
      The study will include 40 healthy subjects between the ages of 18 and 65. Investigators will&#xD;
      exclude subjects with known hypothalamic-pituitary adrenal axis or other endocrine disease,&#xD;
      glucocorticoid use (chronic, current, or within 3 months), pregnancy or oral estrogen use.&#xD;
      Women will be studied during the same menstrual cycle phase for each of the 2 tests.&#xD;
      Participants will be recruited by word of mouth and adds placed within the medical school&#xD;
      campus. Participants will provide written informed consent.&#xD;
&#xD;
      Study Statistics&#xD;
&#xD;
        1. Primary outcome variable.&#xD;
&#xD;
             1. Comparison between peak cosyntropin-stimulated cortisol levels measured using IV&#xD;
                and IM cosyntropin administration in the same subjects&#xD;
&#xD;
             2. Establishing new reference range for expected peak cosyntropin-stimulated cortisol&#xD;
                levels using the new Cortisol II assay for both cosyntropin administration&#xD;
                modalities.&#xD;
&#xD;
        2. Secondary outcome variables.&#xD;
&#xD;
        3. Statistical plan including sample size justification and interim data analysis.&#xD;
&#xD;
      To test the hypothesis that the cortisol levels after IM administration of cosyntropin is&#xD;
      slightly lower than IV administration, the investigator assume that 1) proportional&#xD;
      analytical variability (constant CV) for both methods; 2) a difference &gt; 50% of analytical&#xD;
      variability is clinically meaningful (i.e., an effect size of 0.5). A sample size of 30&#xD;
      subjects will provide 85% power at a significance level of 5% using one-sided paired t-test.&#xD;
      When the two time point data are analyzed together, the power will be higher.&#xD;
&#xD;
      For correlation estimation, the sample size of 30 produces a two-sided 95% confidence&#xD;
      interval with a width &lt; 0.153, assuming the sample correlation is &gt;0.900.&#xD;
&#xD;
      With the proposed 40 healthy subjects, the distance of the reference range (defined as 95&#xD;
      percentile of the reference population) from the upper-bound of the estimated 95% confidence&#xD;
      interval will be &lt; 22%.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Change in personnel leading to inability to conduct study.&#xD;
  </why_stopped>
  <start_date type="Anticipated">July 2019</start_date>
  <completion_date type="Anticipated">December 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>peak serum cortisol</measure>
    <time_frame>60 minutes</time_frame>
    <description>We will obtain peak serum cortisol level in nmol/L form each participant and determine the average</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Adrenal Insufficiency</condition>
  <arm_group>
    <arm_group_label>Intravenous and intramuscular administration</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive intravenous and intramuscular ACTH on different days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cosyntropin</intervention_name>
    <description>intramuscular and intravenous administration</description>
    <arm_group_label>Intravenous and intramuscular administration</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - Healthy volunteers&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        - Know history of pituitary or adrenal disease. Current or recent use of glucocorticoids,&#xD;
        and use of oral estrogen, pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>November 21, 2018</study_first_submitted>
  <study_first_submitted_qc>November 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 23, 2018</study_first_posted>
  <last_update_submitted>May 8, 2019</last_update_submitted>
  <last_update_submitted_qc>May 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2019</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>
  </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>
  </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/NCT03752190
org study id: IRB00193457
nct id: NCT03752190
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Cosyntropin (synthetic ACTH) stimulation test is considered the optimal test for diagnosis of
      primary and long-standing secondary adrenal insufficiency.

      The standard cosyntropin stimulation test is performed by administering 250 µg cosyntropin
      intravenously. Serum cortisol is measured before, and at 30 and 60 minutes after the bolus
      injection. Peak cortisol levels below 500 nmol/L (18.1 µg/dL) at 30 or 60 minutes after
      cosyntropin administration indicate adrenal insufficiency per recent guidelines, without
      specification of how the cosyntropin is administered (intravenously or intramuscularly).
      However, the peak stimulated cortisol cutoff value is based on old, fluorometric or
      radio-immunological methods that are known to detect significant amounts of glucocorticoids
      other than cortisol. For this reason, peak cortisol levels, as determined by older assays,
      may set higher thresholds than what might be considered necessary using a newer, more
      specific assay.

      The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now
      replaced worldwide (including Johns Hopkins Hospital) by a new Elecsys® Cortisol assay from
      Roche Diagnostics (Cortisol II). The new Cortisol II assay employs a monoclonal as opposed to
      a polyclonal capturing antibody, which was used in the old Cortisol I assay. This results in
      greater specificity for cortisol. The new Cortisol II assay was shown to have strong
      correlation with cortisol levels measured by liquid chromatography-tandem mass spectrometry
      (LC-MS/MS) which is considered the gold standard for cortisol measurement.

      Previous studies addressing the cortisol cutoff levels for the diagnosis of adrenal
      insufficiency with different cortisol assays have been heterogeneous in terms of the dose and
      route of administration of cosyntropin used, and the wide variety of subjects being tested
      including healthy subjects that are occasionally on oral estrogen therapy and patients with
      adrenal insufficiency.

      Many clinical centers use intramuscular cosyntropin injections given its convenience, and as
      mentioned earlier, many institutions are now using the new Roche Cortisol II assay.

      Investigators will conduct a study looking at healthy subjects to establish the expected
      range of peak cosyntropin-stimulated cortisol levels with two different cosyntropin
      administration modalities. The goal of this study is to compare intravenous (IV) and
      intramuscular (IM) administration, and to generate a normal range of post-cosyntropin serum
      cortisol measure with the new assay.

      The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60
      minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Generate
      assay-specific normal ACTH stimulation test results
Investigators will conduct a study looking at healthy subjects to establish the expected
      range of peak cosyntropin-stimulated cortisol levels in normal healthy subjects with two
      different cosyntropin administration modalities. The goal of this study is to compare
      intravenous (IV) and intramuscular (IM) administration, and to generate a normal range of
      post-cosyntropin serum cortisol measure with the new assay.

      The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60
      minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Study the
      values obtained using the new Roche Cortisol II assay and establish a new reference range for
      cosyntropin-stimulated cortisol levels in healthy subjects for both cosyntropin
      administration modalities.

      The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now
      being replaced worldwide by a new Elecsys® Cortisol assay from Roche Diagnostics (Cortisol
      II). The new Cortisol II assay is also a competitive immunoassay, but employs a monoclonal as
      opposed to a polyclonal capturing antibody, which was used in the old Cortisol I assay. This
      results in greater specificity for cortisol with less interference from other endogenous or
      exogenous glucocorticoids. The new Cortisol II assay was shown to have strong correlation
      with cortisol levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS)
      which is considered the gold standard for cortisol measurement. It has been shown in earlier
      studies that Cortisol II assay generates cortisol values that are approximately 20-30% lower
      than the older Cortisol I immunoassay with proposed new cortisol cutoff for the diagnosis of
      adrenal insufficiency between 350-375 nmol/L (12.7-13.6 µg/dL).

      This is a prospective study on healthy subjects. Investigators will perform two cosyntropin
      stimulation tests on participants on two separate visits, one using intravenous and another
      one using intramuscular cosyntropin (250 µg). Investigators will allow a minimum of one week
      and a maximum of 2 months between the two tests.

      Blood samples for each of the two tests will be drawn at baseline, before cosyntropin
      administration, then at 30 minutes and 60 minutes after cosyntropin administration from
      indwelling catheter. A maximum of 5 ml of blood will be drawn at each time point. Serum will
      be separated, and samples will be stored at - 80o C after collection until analyzed.

      All of the blood samples will be tested to measure cortisol levels using the new Roche
      Cortisol II assay. The Cortisol assay kits will be provided from Roche Diagnostics.

      Overall study duration will be 18 months. There will be two study visits. Investigators will
      allow a minimum of one week and a maximum of 2 months between the two visits.

      The study will include 40 healthy subjects between the ages of 18 and 65. Investigators will
      exclude subjects with known hypothalamic-pituitary adrenal axis or other endocrine disease,
      glucocorticoid use (chronic, current, or within 3 months), pregnancy or oral estrogen use.
      Women will be studied during the same menstrual cycle phase for each of the 2 tests.
      Participants will be recruited by word of mouth and adds placed within the medical school
      campus. Participants will provide written informed consent.

      Study Statistics

        1. Primary outcome variable.

             1. Comparison between peak cosyntropin-stimulated cortisol levels measured using IV
                and IM cosyntropin administration in the same subjects

             2. Establishing new reference range for expected peak cosyntropin-stimulated cortisol
                levels using the new Cortisol II assay for both cosyntropin administration
                modalities.

        2. Secondary outcome variables.

        3. Statistical plan including sample size justification and interim data analysis.

      To test the hypothesis that the cortisol levels after IM administration of cosyntropin is
      slightly lower than IV administration, the investigator assume that 1) proportional
      analytical variability (constant CV) for both methods; 2) a difference > 50% of analytical
      variability is clinically meaningful (i.e., an effect size of 0.5). A sample size of 30
      subjects will provide 85% power at a significance level of 5% using one-sided paired t-test.
      When the two time point data are analyzed together, the power will be higher.

      For correlation estimation, the sample size of 30 produces a two-sided 95% confidence
      interval with a width < 0.153, assuming the sample correlation is >0.900.

      With the proposed 40 healthy subjects, the distance of the reference range (defined as 95
      percentile of the reference population) from the upper-bound of the estimated 95% confidence
      interval will be < 22%.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: peak serum cortisol
time frame: 60 minutes
description: We will obtain peak serum cortisol level in nmol/L form each participant and determine the average
arm group label: Intravenous and intramuscular administration
arm group type: Experimental
description: Subjects will receive intravenous and intramuscular ACTH on different days
intervention type: Drug
intervention name: Cosyntropin
description: intramuscular and intravenous administration
arm group label: Intravenous and intramuscular administration
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Sponsor
mesh term: Adrenal Insufficiency
mesh term: Cosyntropin
sharing ipd: No