<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/NCT01705795</url>
  </required_header>
  <id_info>
    <org_study_id>191/11</org_study_id>
    <nct_id>NCT01705795</nct_id>
  </id_info>
  <brief_title>Anti-IL-5 Therapy in Bullous Pemphigoid (BP)</brief_title>
  <official_title>Anti-IL-5 Therapy in Bullous Pemphigoid. Randomized, Placebo-controlled, Double-blind Study Evaluating the Effect of Anti-IL-5 Therapy in Patients With Bullous Pemphigoid.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Randomized, placebo-controlled, double-blind study evaluating the effect of anti-IL-5-therapy&#xD;
      in patients with bullous pemphigoid. The primary study objective is to determine the efficacy&#xD;
      of an anti-IL-5 monoclonal antibody therapy, administered as 750mg mepolizumab, in patients&#xD;
      with bullous pemphigoid.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease. It&#xD;
      characteristically affects the elderly (&gt;70 years) with an annual incidence of 5 to 35 per&#xD;
      million. This is comparable with the incidence of eosinophilic esophagitis that we determined&#xD;
      with approximately 14 per million. Eosinophilic esophagitis has been recognized as an&#xD;
      emerging medical problem and, consequently, several studies with anti-IL-5-antibodies have&#xD;
      been performed and are still ongoing. It should be noted, however, that, in contrast to&#xD;
      eosinophilic esophagitis, the incidence of BP is dramatically increasing with an average of&#xD;
      17% per year. Moreover, with the increase of the proportion of the elderly in the&#xD;
      industrialized world, the medical problems associated with BP will even be more visible in&#xD;
      the near future. For instance, patients with BP have an increased mortality risk of 2.3. In&#xD;
      the US, an increase in mortality of BP patients has been noticed from 1979 to 2002. Taken&#xD;
      together, BP is a frequent disease that affects mostly the elderly.&#xD;
&#xD;
      BP often starts with extremely pruritic skin lesions resembling eczema or urticaria before&#xD;
      vesicles and blisters arise. In 10-30% of patients, BP also involves the oral mucosa. Disease&#xD;
      severity can be determined by means of the autoimmune bullous skin disorder intensity score&#xD;
      (ABSIS) that evaluates the involved area as well as the disease activity. The disease is due&#xD;
      to an autoimmune response to structural components of junctional adhesion complexes leading&#xD;
      to the damage of the dermal-epidermal junction with subepidermal blister formation.&#xD;
      Specifically, autoreactive B and T cell responses against the hemidesmosomal antigens BP180&#xD;
      and BP230 have been identified. Serum levels of autoantibodies to BP180 reflect the disease&#xD;
      severity and activity. The T cells are memory CD4+ cells producing both Th1 and Th2&#xD;
      cytokines, mostly IL-4, IL-5 and IL-13. IL-5 as well as eotaxin are abundantly found in&#xD;
      blister fluids. The production of IL-5 is indeed associated with blood eosinophilia and&#xD;
      significant eosinophil infiltration in the skin of BP patients. Eosinophils are thought to be&#xD;
      critically implicated in blister formation by releasing toxic granule proteins (ESP, MBP) and&#xD;
      proteolytic enzymes.&#xD;
&#xD;
      Systemic corticosteroids have been widely used for the treatment of BP. Nevertheless, the use&#xD;
      of steroids is limited by their side effects. in therapy-resistant cases, immunosuppressive&#xD;
      drugs such as azathioprine, chlorambucil, cyclophosphamide, cyclosporine, methotrexate,&#xD;
      mycophenolate mofetil are employed, but their corticosteroid-sparing effect and overall&#xD;
      benefit in BP is highly disputed. 70% of the relapses are usually observed within three&#xD;
      months, 85% within 6 months after stopping therapy.&#xD;
&#xD;
      Since eosinophils are characteristically found in the skin at early stages of the disease&#xD;
      before blisters occur and contribute to tissue damage, targeting eosinophils by reducing&#xD;
      their number and activation might thus be a promising alternative therapeutic approach.&#xD;
      Anti-IL-5 antibody therapy has been shown to be effective in depleting eosinophils, e.g. in&#xD;
      diseases such as eosinophilic esophagitis and hypereosinophilic syndrome.&#xD;
&#xD;
      Objective&#xD;
&#xD;
      To determine the safety and efficacy of mepolizumab in patients with bullous pemphigoid.&#xD;
&#xD;
      Methods&#xD;
&#xD;
      clinical trial with 750 mg mepolizumab over three months, evaluate time period from start of&#xD;
      therapy until relapse, ABSIS-Score, Pruritus Score, Antibody levels, immuno pathological&#xD;
      evaluation of skin biopsy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 13, 2013</start_date>
  <completion_date type="Actual">January 31, 2017</completion_date>
  <primary_completion_date type="Actual">January 31, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time period (in days) from start of therapy until relapse, mepolizumab vs placebo</measure>
    <time_frame>Before, at 3-9 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes of BP severity score over time (ABSIS)</measure>
    <time_frame>At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes of pruritus score (visual analog scale)</measure>
    <time_frame>At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes of BP-antibody titers over time</measure>
    <time_frame>At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with AE, severity of AE</measure>
    <time_frame>At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Pemphigoid, Bullous</condition>
  <arm_group>
    <arm_group_label>Mepolizumab</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Mepolizumab 750 mg four times one month apart.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo (saline) four times one month apart</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mepolizumab (a-IL-5 antibody)</intervention_name>
    <description>750mg mepolizumab four times over four months</description>
    <arm_group_label>Mepolizumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Nacl four times over four months</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men, women &gt;18 years&#xD;
&#xD;
          -  Active BP (diagnosed by typical clinical picture and skin biopsy)&#xD;
&#xD;
          -  Must give written informed consent&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Patients with other skin disease&#xD;
&#xD;
          -  Patients with severe diseases of other organ systems&#xD;
&#xD;
          -  Systemic treatment for BP&#xD;
&#xD;
          -  Topical therapy with corticosteroids and other anti-inflammatory substances&#xD;
&#xD;
          -  For female patients, unless postmenopausal or surgically sterile, unwillingness to&#xD;
             practice effective contraception (defined as methods with &lt;1% failure rate)&#xD;
&#xD;
          -  Female patients who are currently pregnant or breast-feeding&#xD;
&#xD;
          -  Current abuse of alcohol and/or drugs&#xD;
&#xD;
          -  History of or a new diagnosis or treatment of an invasive malignancy within 5 years of&#xD;
             enrollment. Patients with a history of treated squamous cell and/or basal cell&#xD;
             carcinomas limited to the skin are not excluded.&#xD;
&#xD;
          -  History of recurrent clinically significant infection&#xD;
&#xD;
          -  Congenital or acquired immunodeficiency syndrome&#xD;
&#xD;
          -  Current enrollment in any other investigational drug study&#xD;
&#xD;
          -  Previous participation in this study or previous studies with mepolizumab&#xD;
&#xD;
          -  Hypersensitivity to mepolizumab or its constituents&#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>Dagmar Simon</last_name>
    <role>Principal Investigator</role>
    <affiliation>Inselspital, Bern University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dep. of Dermatology, Bern University Hospital</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>October 5, 2012</study_first_submitted>
  <study_first_submitted_qc>October 11, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 12, 2012</study_first_posted>
  <last_update_submitted>February 27, 2017</last_update_submitted>
  <last_update_submitted_qc>February 27, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2017</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>Pemphigoid, Bullous</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Antibodies</mesh_term>
  </intervention_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/NCT01705795
org study id: 191/11
nct id: NCT01705795
lead sponsor: 
has dmc: Yes
Randomized, placebo-controlled, double-blind study evaluating the effect of anti-IL-5-therapy
      in patients with bullous pemphigoid. The primary study objective is to determine the efficacy
      of an anti-IL-5 monoclonal antibody therapy, administered as 750mg mepolizumab, in patients
      with bullous pemphigoid.
Background

      Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease. It
      characteristically affects the elderly (>70 years) with an annual incidence of 5 to 35 per
      million. This is comparable with the incidence of eosinophilic esophagitis that we determined
      with approximately 14 per million. Eosinophilic esophagitis has been recognized as an
      emerging medical problem and, consequently, several studies with anti-IL-5-antibodies have
      been performed and are still ongoing. It should be noted, however, that, in contrast to
      eosinophilic esophagitis, the incidence of BP is dramatically increasing with an average of
      17% per year. Moreover, with the increase of the proportion of the elderly in the
      industrialized world, the medical problems associated with BP will even be more visible in
      the near future. For instance, patients with BP have an increased mortality risk of 2.3. In
      the US, an increase in mortality of BP patients has been noticed from 1979 to 2002. Taken
      together, BP is a frequent disease that affects mostly the elderly.

      BP often starts with extremely pruritic skin lesions resembling eczema or urticaria before
      vesicles and blisters arise. In 10-30% of patients, BP also involves the oral mucosa. Disease
      severity can be determined by means of the autoimmune bullous skin disorder intensity score
      (ABSIS) that evaluates the involved area as well as the disease activity. The disease is due
      to an autoimmune response to structural components of junctional adhesion complexes leading
      to the damage of the dermal-epidermal junction with subepidermal blister formation.
      Specifically, autoreactive B and T cell responses against the hemidesmosomal antigens BP180
      and BP230 have been identified. Serum levels of autoantibodies to BP180 reflect the disease
      severity and activity. The T cells are memory CD4+ cells producing both Th1 and Th2
      cytokines, mostly IL-4, IL-5 and IL-13. IL-5 as well as eotaxin are abundantly found in
      blister fluids. The production of IL-5 is indeed associated with blood eosinophilia and
      significant eosinophil infiltration in the skin of BP patients. Eosinophils are thought to be
      critically implicated in blister formation by releasing toxic granule proteins (ESP, MBP) and
      proteolytic enzymes.

      Systemic corticosteroids have been widely used for the treatment of BP. Nevertheless, the use
      of steroids is limited by their side effects. in therapy-resistant cases, immunosuppressive
      drugs such as azathioprine, chlorambucil, cyclophosphamide, cyclosporine, methotrexate,
      mycophenolate mofetil are employed, but their corticosteroid-sparing effect and overall
      benefit in BP is highly disputed. 70% of the relapses are usually observed within three
      months, 85% within 6 months after stopping therapy.

      Since eosinophils are characteristically found in the skin at early stages of the disease
      before blisters occur and contribute to tissue damage, targeting eosinophils by reducing
      their number and activation might thus be a promising alternative therapeutic approach.
      Anti-IL-5 antibody therapy has been shown to be effective in depleting eosinophils, e.g. in
      diseases such as eosinophilic esophagitis and hypereosinophilic syndrome.

      Objective

      To determine the safety and efficacy of mepolizumab in patients with bullous pemphigoid.

      Methods

      clinical trial with 750 mg mepolizumab over three months, evaluate time period from start of
      therapy until relapse, ABSIS-Score, Pruritus Score, Antibody levels, immuno pathological
      evaluation of skin biopsy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Time period (in days) from start of therapy until relapse, mepolizumab vs placebo
time frame: Before, at 3-9 months
measure: Changes of BP severity score over time (ABSIS)
time frame: At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)
measure: Changes of pruritus score (visual analog scale)
time frame: At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)
measure: Changes of BP-antibody titers over time
time frame: At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)
measure: Number of patients with AE, severity of AE
time frame: At baseline, during therapy (expected to be ca. 4 months), follow up (expected to be ca. 9 months)
arm group label: Mepolizumab
arm group type: Active Comparator
description: Mepolizumab 750 mg four times one month apart.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo (saline) four times one month apart
intervention type: Drug
intervention name: Mepolizumab (a-IL-5 antibody)
description: 750mg mepolizumab four times over four months
arm group label: Mepolizumab
intervention type: Drug
intervention name: Placebo
description: Nacl four times over four months
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dagmar Simon
role: Principal Investigator
affiliation: Inselspital, Bern University Hospital
facility: 
country: Switzerland
responsible party type: Sponsor
mesh term: Pemphigoid, Bullous
mesh term: Antibodies