<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/NCT03036670</url>
  </required_header>
  <id_info>
    <org_study_id>PHT/2015/130</org_study_id>
    <nct_id>NCT03036670</nct_id>
  </id_info>
  <brief_title>Eosinophilic Granulomatosis With Polyangiitis Cohort</brief_title>
  <acronym>EGPA Cohort</acronym>
  <official_title>Eosinophilic Granulomatosis With Polyangiitis Cohort</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Portsmouth Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Portsmouth Hospitals NHS Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      EGPA (Eosinophilic Granulomatosis with Polyangiitis, previously Churg-Strauss syndrome) is a&#xD;
      rare vasculitis, characterised by asthma, rhinosinusitis and eosinophilia. There has&#xD;
      previously been confusion around diagnostic criteria, with multiple sets of classification&#xD;
      criteria being used inappropriately for diagnosis. The ERS formed a taskforce to produce&#xD;
      specific diagnostic criteria, and these divided the Churg-Strauss Syndrome cohort into two&#xD;
      groups - vasculitic EGPA and tissular Hypereosinophilic Asthma with Systemic Manifestations&#xD;
      (HASM). It is not known if the groups separated by the diagnostic criteria are also separated&#xD;
      in clinical symptomatology, or if their disease course varies, and this could have&#xD;
      significant impact on management and further research.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background Eosinophilic Granulomatosis with Polyangiitis (EGPA, previously Churg-Strauss&#xD;
      Syndrome) is a rare, idiopathic, ANCA associated vasculitis (AAV), alongside Granulomatosis&#xD;
      with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA). It is an eosinophilic&#xD;
      small/medium vessel vasculitis characterised by asthma, rhinosinusitis and eosinophilia.&#xD;
      Patients can also suffer renal, cardiac, gastrointestinal and neurological involvement. First&#xD;
      described by Churg and Strauss in 1951, exact epidemiology remains difficult because of a&#xD;
      lack of clear diagnostic criteria. It appears to have a prevalence of around 11-13 per&#xD;
      million population with a mean age of 50 years old and represents 10% of diagnosed&#xD;
      vasculitides.&#xD;
&#xD;
      Following Churg and Strauss' original paper, the first attempt to provide diagnostic clarity&#xD;
      was provided by John Lanham in 1984. Lanham listed symptoms seen in a set of patients with&#xD;
      EGPA and suggested which symptoms were required for the disease and which symptoms were&#xD;
      &quot;additional&quot;. The American College of Rheumatology (ACR) in 1990 published a list of 6&#xD;
      symptoms to assist with classification of vasculitides, created by comparing 20 patients with&#xD;
      EGPA with 787 patients with other forms of vasculitis. This was frequently used for diagnosis&#xD;
      despite being intended for classification. In 1994, and revised in 2012, the International&#xD;
      Chapel Hill Consensus Conference produced a nomenclature and definition for vasculitides,&#xD;
      again frequently incorrectly used as diagnostic criteria. Finally, in 2014, diagnostic&#xD;
      criteria were provided by the European Respiratory Society Churg Strauss Syndrome (ERS-CSS)&#xD;
      taskforce; however published literature still uses a variety of criteria.&#xD;
&#xD;
      EGPA is recognised as a Th2 predominant disease with elevated levels of IL-4, IL-5, IL-13 and&#xD;
      IgE according to a number of case control studies and case reports. Association between IL-10&#xD;
      levels and ANCA negative EGPA has been reported. Th17 responses also seem to be elevated with&#xD;
      raised serum IL-25 reported, potentiating Th2 cytokine release. Eosinophil products are&#xD;
      detectable in serum, BAL, urine and biopsies with varying time-courses. Roles of other cells&#xD;
      such as regulatory T cells, memory T cells, dendritic cells, macrophages, ILCs and others are&#xD;
      being investigated.&#xD;
&#xD;
      Previous work within the investigators' unit has demonstrated disturbances in the coagulation&#xD;
      system in patients with asthma. The investigators have demonstrated that, while moderate&#xD;
      asthma appears to favour fibrinolysis, severe asthma is a fibrinogenic condition. Deposition&#xD;
      of fibrin within the airways in fatal asthma has been previously recognised, but a case study&#xD;
      demonstrated strong activation of the coagulation system five days prior to an exacerbation.&#xD;
      Another case study has demonstrated increased activation of the coagulation system in a&#xD;
      patient with active EGPA which normalised on remission, but more in depth work has not been&#xD;
      done.&#xD;
&#xD;
      It has been previously recognised that ANCA positive patients often have a different disease&#xD;
      phenotype to those who are ANCA negative, suffering with more vasculitic symptoms and renal&#xD;
      disease but less cardiac involvement. In 2014 the ERS-CSS taskforce provided diagnostic&#xD;
      criteria for these two main phenotypes - separating the vasculitic phenotype which remains&#xD;
      called Eosinophilic Granulomatosis with Polyangiitis (EGPA), from the ANCA negative tissular&#xD;
      phenotype called Hypereosinophilic Asthma with Systemic Manifestations (HASM). It is&#xD;
      currently unclear if this distinction matches biological endotypes, or whether different&#xD;
      treatment strategies are advisable between the two groups. It is possible that HASM is a&#xD;
      precursor state to full vasculitic EGPA, however the increased incidence of cardiac&#xD;
      manifestations within this group would point away from this, as would the differing&#xD;
      prevalence of genetic markers such as IL-10 promoter activation.&#xD;
&#xD;
      Prior to the advent of corticosteroid use, prognosis of EGPA was poor with a mortality rate&#xD;
      of 50% at 3 months. Treatment primarily consists of immunosuppression with corticosteroids,&#xD;
      with induction therapy using cyclophosphamide in severe cases. Rituximab is approved for use&#xD;
      in GPA and MPA, while case reports demonstrate a good effect in patients with severe,&#xD;
      refractory EGPA, uncontrolled on other therapy. Those who suffer from CSS can be exposed to&#xD;
      prolonged steroid therapy with the majority of patients experiencing side effects of their&#xD;
      medication such as weight gain, osteopaenia, impaired glucose tolerance, cataracts and skin&#xD;
      atrophy. Steroid sparing agents such as azathioprine and mycophenolate are used with variable&#xD;
      effect. Treatment is primarily guided by eosinophil count and symptom scores such as the&#xD;
      Birmingham Vasculitis Activity Score (BVAS) as there are not currently any diagnostic tests&#xD;
      or EGPA-specific biomarkers. Presence of a specific biomarker would allow more accurate&#xD;
      alterations in patients' mediation, as non-specific symptoms can imitate EGPA and prompt&#xD;
      increases in steroid doses.&#xD;
&#xD;
      Research questions Do the ERS-CSS diagnostic criteria divide the PHT cohort into groups with&#xD;
      distinct clinical characteristics? How do the EGPA and HASM groups differ in clinical and&#xD;
      physiological characteristics and how do these change over time?&#xD;
&#xD;
      Potential impact If the investigators confirm that EGPA and HASM represent distinct clinical&#xD;
      entities within our cohort, further research into biological mechanisms and treatment options&#xD;
      is needed, and this work will help to guide further studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 10, 2016</start_date>
  <completion_date type="Actual">January 31, 2017</completion_date>
  <primary_completion_date type="Actual">January 31, 2017</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>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Diagnosis according to various diagnostic criteria</measure>
    <time_frame>From date of diagnosis for 5 years</time_frame>
    <description>The diagnosis of each participant according to different diagnostic or classification criteria (ERS-CSS, Chapel Hill, ACR, Lanham) based on all test results available between the point of diagnosis and 60 months later</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Corticosteroid dose</measure>
    <time_frame>From date of diagnosis for 5 years</time_frame>
    <description>Stable doses (taken for ≥4 weeks) of oral and inhaled corticosteroids at diagnosis and 12 monthly up to 5 years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunosuppressive medication</measure>
    <time_frame>From date of diagnosis for 5 years</time_frame>
    <description>Which additional immunosuppressive medication had been given and when</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comorbid conditions</measure>
    <time_frame>From date of diagnosis for 5 years</time_frame>
    <description>List of comorbidities</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biopsy findings</measure>
    <time_frame>From date of diagnosis for 5 years</time_frame>
    <description>List of Biopsy results</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse rates</measure>
    <time_frame>From date of diagnosis for 5 years</time_frame>
    <description>Rate of relapses or flares</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak disease activity</measure>
    <time_frame>From date of diagnosis for 5 years</time_frame>
    <description>maximum disease activity from diagnosis to 5 years as defined by BVAS score and VDI score</description>
  </secondary_outcome>
  <enrollment type="Actual">50</enrollment>
  <condition>Churg-Strauss Syndrome</condition>
  <eligibility>
    <study_pop>
      <textblock>
        Study participants are adults with Churg-Strauss syndrome under the care of Portsmouth&#xD;
        Hospitals NHS Trust.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or Female, aged 18 years or above.&#xD;
&#xD;
          -  Cared for currently or previously cared for at Portsmouth Hospitals NHS Trust&#xD;
&#xD;
          -  Diagnosed with EGPA/HASM according to clinicians&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        - Medical notes not obtainable&#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>Anoop J Chauhan, PhD FRCP</last_name>
    <role>Principal Investigator</role>
    <affiliation>Portsmouth Hospitals NHS Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Queen Alexandra Hospital</name>
      <address>
        <city>Portsmouth</city>
        <state>Hampshire</state>
        <zip>PO6 3LY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>September 26, 2016</study_first_submitted>
  <study_first_submitted_qc>January 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 30, 2017</study_first_posted>
  <last_update_submitted>April 6, 2023</last_update_submitted>
  <last_update_submitted_qc>April 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2023</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>Granulomatosis with Polyangiitis</mesh_term>
    <mesh_term>Systemic Vasculitis</mesh_term>
    <mesh_term>Churg-Strauss Syndrome</mesh_term>
  </condition_browse>
  <!-- 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/NCT03036670
org study id: PHT/2015/130
nct id: NCT03036670
lead sponsor: 
has dmc: No
EGPA (Eosinophilic Granulomatosis with Polyangiitis, previously Churg-Strauss syndrome) is a
      rare vasculitis, characterised by asthma, rhinosinusitis and eosinophilia. There has
      previously been confusion around diagnostic criteria, with multiple sets of classification
      criteria being used inappropriately for diagnosis. The ERS formed a taskforce to produce
      specific diagnostic criteria, and these divided the Churg-Strauss Syndrome cohort into two
      groups - vasculitic EGPA and tissular Hypereosinophilic Asthma with Systemic Manifestations
      (HASM). It is not known if the groups separated by the diagnostic criteria are also separated
      in clinical symptomatology, or if their disease course varies, and this could have
      significant impact on management and further research.
Background Eosinophilic Granulomatosis with Polyangiitis (EGPA, previously Churg-Strauss
      Syndrome) is a rare, idiopathic, ANCA associated vasculitis (AAV), alongside Granulomatosis
      with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA). It is an eosinophilic
      small/medium vessel vasculitis characterised by asthma, rhinosinusitis and eosinophilia.
      Patients can also suffer renal, cardiac, gastrointestinal and neurological involvement. First
      described by Churg and Strauss in 1951, exact epidemiology remains difficult because of a
      lack of clear diagnostic criteria. It appears to have a prevalence of around 11-13 per
      million population with a mean age of 50 years old and represents 10% of diagnosed
      vasculitides.

      Following Churg and Strauss' original paper, the first attempt to provide diagnostic clarity
      was provided by John Lanham in 1984. Lanham listed symptoms seen in a set of patients with
      EGPA and suggested which symptoms were required for the disease and which symptoms were
      "additional". The American College of Rheumatology (ACR) in 1990 published a list of 6
      symptoms to assist with classification of vasculitides, created by comparing 20 patients with
      EGPA with 787 patients with other forms of vasculitis. This was frequently used for diagnosis
      despite being intended for classification. In 1994, and revised in 2012, the International
      Chapel Hill Consensus Conference produced a nomenclature and definition for vasculitides,
      again frequently incorrectly used as diagnostic criteria. Finally, in 2014, diagnostic
      criteria were provided by the European Respiratory Society Churg Strauss Syndrome (ERS-CSS)
      taskforce; however published literature still uses a variety of criteria.

      EGPA is recognised as a Th2 predominant disease with elevated levels of IL-4, IL-5, IL-13 and
      IgE according to a number of case control studies and case reports. Association between IL-10
      levels and ANCA negative EGPA has been reported. Th17 responses also seem to be elevated with
      raised serum IL-25 reported, potentiating Th2 cytokine release. Eosinophil products are
      detectable in serum, BAL, urine and biopsies with varying time-courses. Roles of other cells
      such as regulatory T cells, memory T cells, dendritic cells, macrophages, ILCs and others are
      being investigated.

      Previous work within the investigators' unit has demonstrated disturbances in the coagulation
      system in patients with asthma. The investigators have demonstrated that, while moderate
      asthma appears to favour fibrinolysis, severe asthma is a fibrinogenic condition. Deposition
      of fibrin within the airways in fatal asthma has been previously recognised, but a case study
      demonstrated strong activation of the coagulation system five days prior to an exacerbation.
      Another case study has demonstrated increased activation of the coagulation system in a
      patient with active EGPA which normalised on remission, but more in depth work has not been
      done.

      It has been previously recognised that ANCA positive patients often have a different disease
      phenotype to those who are ANCA negative, suffering with more vasculitic symptoms and renal
      disease but less cardiac involvement. In 2014 the ERS-CSS taskforce provided diagnostic
      criteria for these two main phenotypes - separating the vasculitic phenotype which remains
      called Eosinophilic Granulomatosis with Polyangiitis (EGPA), from the ANCA negative tissular
      phenotype called Hypereosinophilic Asthma with Systemic Manifestations (HASM). It is
      currently unclear if this distinction matches biological endotypes, or whether different
      treatment strategies are advisable between the two groups. It is possible that HASM is a
      precursor state to full vasculitic EGPA, however the increased incidence of cardiac
      manifestations within this group would point away from this, as would the differing
      prevalence of genetic markers such as IL-10 promoter activation.

      Prior to the advent of corticosteroid use, prognosis of EGPA was poor with a mortality rate
      of 50% at 3 months. Treatment primarily consists of immunosuppression with corticosteroids,
      with induction therapy using cyclophosphamide in severe cases. Rituximab is approved for use
      in GPA and MPA, while case reports demonstrate a good effect in patients with severe,
      refractory EGPA, uncontrolled on other therapy. Those who suffer from CSS can be exposed to
      prolonged steroid therapy with the majority of patients experiencing side effects of their
      medication such as weight gain, osteopaenia, impaired glucose tolerance, cataracts and skin
      atrophy. Steroid sparing agents such as azathioprine and mycophenolate are used with variable
      effect. Treatment is primarily guided by eosinophil count and symptom scores such as the
      Birmingham Vasculitis Activity Score (BVAS) as there are not currently any diagnostic tests
      or EGPA-specific biomarkers. Presence of a specific biomarker would allow more accurate
      alterations in patients' mediation, as non-specific symptoms can imitate EGPA and prompt
      increases in steroid doses.

      Research questions Do the ERS-CSS diagnostic criteria divide the PHT cohort into groups with
      distinct clinical characteristics? How do the EGPA and HASM groups differ in clinical and
      physiological characteristics and how do these change over time?

      Potential impact If the investigators confirm that EGPA and HASM represent distinct clinical
      entities within our cohort, further research into biological mechanisms and treatment options
      is needed, and this work will help to guide further studies.
observational model: Cohort
time perspective: Retrospective
measure: Diagnosis according to various diagnostic criteria
time frame: From date of diagnosis for 5 years
description: The diagnosis of each participant according to different diagnostic or classification criteria (ERS-CSS, Chapel Hill, ACR, Lanham) based on all test results available between the point of diagnosis and 60 months later
measure: Corticosteroid dose
time frame: From date of diagnosis for 5 years
description: Stable doses (taken for ≥4 weeks) of oral and inhaled corticosteroids at diagnosis and 12 monthly up to 5 years
measure: Immunosuppressive medication
time frame: From date of diagnosis for 5 years
description: Which additional immunosuppressive medication had been given and when
measure: Comorbid conditions
time frame: From date of diagnosis for 5 years
description: List of comorbidities
measure: Biopsy findings
time frame: From date of diagnosis for 5 years
description: List of Biopsy results
measure: Relapse rates
time frame: From date of diagnosis for 5 years
description: Rate of relapses or flares
measure: Peak disease activity
time frame: From date of diagnosis for 5 years
description: maximum disease activity from diagnosis to 5 years as defined by BVAS score and VDI score
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anoop J Chauhan, PhD FRCP
role: Principal Investigator
affiliation: Portsmouth Hospitals NHS Trust
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Granulomatosis with Polyangiitis
mesh term: Systemic Vasculitis
mesh term: Churg-Strauss Syndrome