<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/NCT03294876</url>
  </required_header>
  <id_info>
    <org_study_id>AC17080</org_study_id>
    <nct_id>NCT03294876</nct_id>
  </id_info>
  <brief_title>Rheumatoid Arthritis Adrenal Recovery Study</brief_title>
  <acronym>RAAR</acronym>
  <official_title>Investigating Recovery of the Hypothalamus-pituitary-adrenal Axis in Patients With Rheumatoid Arthritis Following Exposure to Prednisolone</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Edinburgh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Edinburgh</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>
      Cortisol is a naturally occurring stress hormone, made by the adrenal glands in response to&#xD;
      hormones produced by the pituitary and hypothalamus. Man-made forms of cortisol ('steroids',&#xD;
      for example prednisolone) have been used for the treatment of rheumatoid arthritis since the&#xD;
      1950s; they are very effective at reducing inflammation.&#xD;
&#xD;
      A normal response to taking steroid treatment is that the body needs to make less cortisol.&#xD;
      Following treatment with steroids, the system responsible for making cortisol can be slow to&#xD;
      wake up. If someone does not make enough cortisol, they are less able to deal with stress and&#xD;
      are at increased risk of becoming unwell, or suffering a potentially fatal adrenal crisis. It&#xD;
      is not clear how common failure of recovery of the adrenal axis is, how long it can last for&#xD;
      or, if any factors might predict which patients are most at risk.&#xD;
&#xD;
      This study aims to improve our understanding of hypothalamus-pituitary-adrenal (HPA) axis&#xD;
      recovery in patients with rheumatoid arthritis treated with prednisolone. The investigators&#xD;
      will also test potential predictive biomarkers of recovery.&#xD;
&#xD;
      The study will be conducted in hospital and a clinical research facility. Participants will&#xD;
      undergo two visits for blood tests and will also be asked to supply three samples of saliva&#xD;
      on six days over the three weeks of the study.&#xD;
&#xD;
      A better understanding of the physiology of HPA axis recovery should inform the development&#xD;
      of tools which would allow prediction of patients at risk following withdrawal of steroid&#xD;
      treatment. Such tools would be useful to improve patient safety.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cortisol is a naturally occurring stress hormone. It is made by the adrenal glands in&#xD;
      response to hormones produced by the pituitary and hypothalamus. Man-made forms of cortisol&#xD;
      ('steroids', for example prednisolone) have been used for the treatment of rheumatoid&#xD;
      arthritis since the 1950s; they are very effective at reducing inflammation. Steroids are&#xD;
      prescribed for a wide variety of inflammatory conditions. The British prevalence of chronic&#xD;
      (greater than 3 months) steroid prescription is 1%.&#xD;
&#xD;
      A normal response to taking steroid treatment is that the body needs to make less cortisol.&#xD;
      Following treatment with steroids, the system responsible for making cortisol (known as the&#xD;
      hypothalamic pituitary adrenal axis (HPA axis)) can be slow to re-establish production. If&#xD;
      someone does not make enough cortisol, they are less able to deal with stress and are at&#xD;
      increased risk of becoming unwell, or suffering a potentially fatal adrenal crisis. The&#xD;
      prevalence of inadequate cortisol production following treatment with steroids is between&#xD;
      10-30% of patients; its duration and whether any patient factors might predict which patients&#xD;
      are at risk is unclear. Generally studies have been small in size and do not report&#xD;
      sufficient information to determine if any potential factors maybe useful predictors; for&#xD;
      example age, sex, length of treatment, length of time off treatment, other medications.&#xD;
&#xD;
      Rheumatoid arthritis (RA) has a prevalence of 1%. Patients are usually treated with a 13 week&#xD;
      course of prednisolone in a reducing dose (treatment regimen known as COBRA-light) at&#xD;
      diagnosis. 1-2 patients present each week to the rheumatology department in Edinburgh with a&#xD;
      new diagnosis of RA. At the end of the initial COBRA-light treatment, the adrenal axis is not&#xD;
      routinely assessed in these patients. It is assumed that the slow reducing dosage of steroids&#xD;
      reduces the risk of ongoing adrenal insufficiency. It should be noted that the meta-analysis&#xD;
      of Joseph et al. demonstrated weaning had little impact upon the recovery of the HPA axis.&#xD;
      These patients are thus potentially at risk of the morbidity and mortality associated with an&#xD;
      underactive HPA axis.&#xD;
&#xD;
      This study aims to improve our understanding of HPA axis recovery in patients with rheumatoid&#xD;
      arthritis following treatment with prednisolone. The investigators will also test two novel&#xD;
      potential predictive biomarkers of recovery.&#xD;
&#xD;
      A better understanding of the physiology of HPA axis recovery should inform the development&#xD;
      of tools which would allow prediction of patients at risk following withdrawal of steroid&#xD;
      treatment. Such tools would be useful to improve patient safety and wellbeing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 10, 2018</start_date>
  <completion_date type="Anticipated">August 1, 2020</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Synacthen test 1</measure>
    <time_frame>Day 1</time_frame>
    <description>Short synacthen test the after withdrawal of prednisone</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Synacthen test 2</measure>
    <time_frame>Day 21</time_frame>
    <description>Short synacthen test 21 days after withdrawal of prednisone</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cortisol awakening curve</measure>
    <time_frame>2 days in each of weeks 1, 2 and 3</time_frame>
    <description>Salivary cortisol at waking, and 30 mins and 45 mins after waking</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Single Nucleotide Polymorphism</measure>
    <time_frame>Assessed at day 0</time_frame>
    <description>Assessment of an SNP as a predictor of prolonged HPA axis suppression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>Assessed at day 21</time_frame>
    <description>SF-36 (Short Form Survey) assessed quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolite panel</measure>
    <time_frame>Day 0</time_frame>
    <description>Assessment of a panel of metabolites which might predict HPA suppression</description>
  </secondary_outcome>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <condition>Adrenal Insufficiency</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood Blood for DNA Saliva&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients recruited following 13 week weaning dose of prednisone for treatment of early&#xD;
        arthritis&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Rheumatoid arthritis&#xD;
&#xD;
          -  Treatment with prednisone via COBRA light regime&#xD;
&#xD;
          -  Age over 18&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Adrenal or pituitary disease&#xD;
&#xD;
          -  Alcohol intake over 21 units/week&#xD;
&#xD;
          -  Shift work (night shifts)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas JG Chambers, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Edinburgh</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Thomas JG Chambers, PhD</last_name>
    <phone>0131 537 3072</phone>
    <email>tom.chambers@ed.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mark Strachan, MD</last_name>
    <phone>0131 537 3072</phone>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Metabolic Unit, Western General Hospital, NHS Lothian, Crewe Road</name>
      <address>
        <city>Edinburgh</city>
        <state>Scotland</state>
        <zip>EH4 2XU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Thomas JG Chambers, PhD</last_name>
      <phone>0131 537 3072</phone>
      <email>tom.chambers@ed.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Mark Strachan, MD</last_name>
    </contact_backup>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>September 22, 2017</study_first_submitted>
  <study_first_submitted_qc>September 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>October 10, 2018</last_update_submitted>
  <last_update_submitted_qc>October 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Glucocorticoid</keyword>
  <keyword>HPA axis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
    <mesh_term>Adrenal Insufficiency</mesh_term>
  </condition_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/NCT03294876
org study id: AC17080
nct id: NCT03294876
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Cortisol is a naturally occurring stress hormone, made by the adrenal glands in response to
      hormones produced by the pituitary and hypothalamus. Man-made forms of cortisol ('steroids',
      for example prednisolone) have been used for the treatment of rheumatoid arthritis since the
      1950s; they are very effective at reducing inflammation.

      A normal response to taking steroid treatment is that the body needs to make less cortisol.
      Following treatment with steroids, the system responsible for making cortisol can be slow to
      wake up. If someone does not make enough cortisol, they are less able to deal with stress and
      are at increased risk of becoming unwell, or suffering a potentially fatal adrenal crisis. It
      is not clear how common failure of recovery of the adrenal axis is, how long it can last for
      or, if any factors might predict which patients are most at risk.

      This study aims to improve our understanding of hypothalamus-pituitary-adrenal (HPA) axis
      recovery in patients with rheumatoid arthritis treated with prednisolone. The investigators
      will also test potential predictive biomarkers of recovery.

      The study will be conducted in hospital and a clinical research facility. Participants will
      undergo two visits for blood tests and will also be asked to supply three samples of saliva
      on six days over the three weeks of the study.

      A better understanding of the physiology of HPA axis recovery should inform the development
      of tools which would allow prediction of patients at risk following withdrawal of steroid
      treatment. Such tools would be useful to improve patient safety.
Cortisol is a naturally occurring stress hormone. It is made by the adrenal glands in
      response to hormones produced by the pituitary and hypothalamus. Man-made forms of cortisol
      ('steroids', for example prednisolone) have been used for the treatment of rheumatoid
      arthritis since the 1950s; they are very effective at reducing inflammation. Steroids are
      prescribed for a wide variety of inflammatory conditions. The British prevalence of chronic
      (greater than 3 months) steroid prescription is 1%.

      A normal response to taking steroid treatment is that the body needs to make less cortisol.
      Following treatment with steroids, the system responsible for making cortisol (known as the
      hypothalamic pituitary adrenal axis (HPA axis)) can be slow to re-establish production. If
      someone does not make enough cortisol, they are less able to deal with stress and are at
      increased risk of becoming unwell, or suffering a potentially fatal adrenal crisis. The
      prevalence of inadequate cortisol production following treatment with steroids is between
      10-30% of patients; its duration and whether any patient factors might predict which patients
      are at risk is unclear. Generally studies have been small in size and do not report
      sufficient information to determine if any potential factors maybe useful predictors; for
      example age, sex, length of treatment, length of time off treatment, other medications.

      Rheumatoid arthritis (RA) has a prevalence of 1%. Patients are usually treated with a 13 week
      course of prednisolone in a reducing dose (treatment regimen known as COBRA-light) at
      diagnosis. 1-2 patients present each week to the rheumatology department in Edinburgh with a
      new diagnosis of RA. At the end of the initial COBRA-light treatment, the adrenal axis is not
      routinely assessed in these patients. It is assumed that the slow reducing dosage of steroids
      reduces the risk of ongoing adrenal insufficiency. It should be noted that the meta-analysis
      of Joseph et al. demonstrated weaning had little impact upon the recovery of the HPA axis.
      These patients are thus potentially at risk of the morbidity and mortality associated with an
      underactive HPA axis.

      This study aims to improve our understanding of HPA axis recovery in patients with rheumatoid
      arthritis following treatment with prednisolone. The investigators will also test two novel
      potential predictive biomarkers of recovery.

      A better understanding of the physiology of HPA axis recovery should inform the development
      of tools which would allow prediction of patients at risk following withdrawal of steroid
      treatment. Such tools would be useful to improve patient safety and wellbeing.
observational model: Cohort
time perspective: Prospective
measure: Synacthen test 1
time frame: Day 1
description: Short synacthen test the after withdrawal of prednisone
measure: Synacthen test 2
time frame: Day 21
description: Short synacthen test 21 days after withdrawal of prednisone
measure: Cortisol awakening curve
time frame: 2 days in each of weeks 1, 2 and 3
description: Salivary cortisol at waking, and 30 mins and 45 mins after waking
measure: Single Nucleotide Polymorphism
time frame: Assessed at day 0
description: Assessment of an SNP as a predictor of prolonged HPA axis suppression
measure: Quality of life
time frame: Assessed at day 21
description: SF-36 (Short Form Survey) assessed quality of life
measure: Metabolite panel
time frame: Day 0
description: Assessment of a panel of metabolites which might predict HPA suppression
Blood Blood for DNA Saliva
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Thomas JG Chambers, PhD
role: Principal Investigator
affiliation: University of Edinburgh
last name: Thomas JG Chambers, PhD
phone: 0131 537 3072
email: tom.chambers@ed.ac.uk
last name: Mark Strachan, MD
phone: 0131 537 3072
facility: 
status: Recruiting
contact: 
contact backup: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
mesh term: Adrenal Insufficiency
sharing ipd: No