<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/NCT03295383</url>
  </required_header>
  <id_info>
    <org_study_id>2015/208/HP</org_study_id>
    <nct_id>NCT03295383</nct_id>
  </id_info>
  <brief_title>Randomized Clinical Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid</brief_title>
  <acronym>RITUX-MMP</acronym>
  <official_title>Randomized Double Blind Double Dummy Control Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Rouen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Rouen</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Mucous membrane pemphigoid (MMP) describes a group of chronic auto-immune bullous diseases&#xD;
      (AIBD) of the basement membrane zone (BMZ), characterized by predominant or exclusive mucosal&#xD;
      involvement, including oral, naso-pharyngeal, laryngo-tracheal, genital, oesophageal, anal&#xD;
      and ocular mucous membranes. Circulating autoantibodies are directed against various antigens&#xD;
      of the BMZ: BP180, laminin 332 and type 7 collagen. MMP is a rare disease with an incidence&#xD;
      of 1.8 new cases/million inhabitants/year in France.&#xD;
&#xD;
      Scar formation which is secondary to initial inflammation, is a characteristic feature of&#xD;
      MMP, leading to major disability (e.g blindness and oesophageal, anal, vaginal stenosis) and&#xD;
      life-threatening situations (e.g. laryngeal stenosis leading to respiratory failure).&#xD;
&#xD;
      Dapsone is the first line treatment of mild/moderate forms of MMP. Dapsone is used both as&#xD;
      initial treatment, and as maintenance therapy. However, severe forms of MMP can rapidly&#xD;
      worsen leading to blindness, aphagia due to esophageal stenosis, respiratory failure due to&#xD;
      tracheal or laryngeal stenosis, and urinary and sexual dysfunctions due to genital&#xD;
      involvement. These patients are usually treated using immunosuppressive drugs. Indeed,&#xD;
      corticosteroids (CS) are not recommended in MMP.&#xD;
&#xD;
      Cyclophosphamide was considered as the most effective immunosuppressant in severe forms of&#xD;
      MMP, before the use of rituximab, an anti-CD20 monoclonal antibody (MAb).&#xD;
&#xD;
      Two series from our group have assessed the advantages and disadvantages of IV pulse and oral&#xD;
      administration of cyclophosphamide in MMP. Oral administration seems more rapidly effective&#xD;
      with 54% of complete remission (CR) after a median time of 24 weeks (16-52 weeks).&#xD;
&#xD;
      The results of 41 patients with severe types of MMP (including a French series of 20&#xD;
      patients) treated with rituximab have been published. Rate of CR after one and two cycles&#xD;
      were 66% and 90%, respectively. Clinical improvement was rapid, since a decrease in disease&#xD;
      activity was observed after 4 weeks of treatment in 64% of patients.&#xD;
&#xD;
      Our results and those of the literature suggest that rituximab might be more effective than&#xD;
      cyclophosphamide, which has been considered as the gold standard of treatment in severe forms&#xD;
      of disease, up to now.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 11, 2019</start_date>
  <completion_date type="Anticipated">November 2, 2023</completion_date>
  <primary_completion_date type="Anticipated">November 2, 2022</primary_completion_date>
  <phase>Phase 3</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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients achieving CR or Partial Remission (PR)</measure>
    <time_frame>Month 12</time_frame>
    <description>Complete remission: absence of any inflammatory lesion, blister or erosion, and, absence of new fibrosing lesions, and/or absence of worsening of established fibrosing lesions Partial remission: presence of transient new inflammatory lesions, blisters or erosions that heal within one week without treatment and, absence of new fibrosing lesions, and/or absence of worsening of established fibrosing lesions. (Murrell D et al. 2015)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean evolution of MMP DAI activity score</measure>
    <time_frame>Month 24</time_frame>
    <description>MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 &quot;activity&quot; and &quot;damage&quot; sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean evolution of MMP DAI activity score</measure>
    <time_frame>Month 6</time_frame>
    <description>MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 &quot;activity&quot; and &quot;damage&quot; sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of MMP DAI activity score</measure>
    <time_frame>Month 12</time_frame>
    <description>MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 &quot;activity&quot; and &quot;damage&quot; sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of flares / relapses</measure>
    <time_frame>Month 24</time_frame>
    <description>relapse / flare is defined as &quot;the reappearance of at least 3 new lesions a month (blisters, erosions) that do not heal within one week, or the extension of established lesions in a patient who has achieved disease control.&quot; (Murrell D et al. 2015).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of quality of life score (TAB QOL)</measure>
    <time_frame>Month 12</time_frame>
    <description>ABQOL score is a quality of life questionnaires specifically developed for patients with autoimmune blistering disorders to assess quality of life (ABQOL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of quality of life score AB QOL</measure>
    <time_frame>Month 12</time_frame>
    <description>TAB QOL score is a quality of life questionnaires specifically developed for patients with autoimmune blistering disorders to assess evolution under treatment (TAB QOL)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">130</enrollment>
  <condition>Severe Forms of Mucous Membrane Pemphigoid</condition>
  <arm_group>
    <arm_group_label>Rituximab treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rituximab at a dose of 1000 mg (or matching placebo) will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197&#xD;
cyclophosphamide placebo will be administered orally once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyclophosphamide treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>cyclophosphamide will be administered orally once daily at the following initial doses:&#xD;
patients younger than 75 years: 1.5 mg/kg/day, orally. patients older than 75 years: 1 mg/kg/day, orally.&#xD;
Rituximab placebo (NaCl 0.9 %) will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab 1g IV</intervention_name>
    <description>Rituximab at a dose of 1000 mg will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197</description>
    <arm_group_label>Rituximab treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide 50Mg Oral Tablet</intervention_name>
    <description>cyclophosphamide will be administered orally once daily at the following initial doses:&#xD;
patients younger than 75 years: 1.5 mg/kg/day, orally.&#xD;
patients older than 75 years: 1 mg/kg/day, orally.</description>
    <arm_group_label>Cyclophosphamide treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo of Rituximab</intervention_name>
    <description>Rituximab placebo will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab administration on Day 182 and Day 197</description>
    <arm_group_label>Cyclophosphamide treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>cyclophosphamide placebo will be administered orally once daily</description>
    <arm_group_label>Rituximab treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female patients aged ≥18 years old and ≤ 80 years old with a newly diagnosed&#xD;
             or previously diagnosed severe MMP diagnosed according to the International MMP&#xD;
             Consensus (Chan 2002) on the following criteria:&#xD;
&#xD;
             Clinical features: Blisters or erosions predominantly affecting any or all mucous&#xD;
             membranes (oral, nasal, pharyngeal, laryngeal, anal, genital, or esophageal,) with or&#xD;
             without clinically observable scarring. Ocular involvement includes conjunctival&#xD;
             inflammation, shortening of fornices, symblepharon, ankyloblepharon, entropion,&#xD;
             trichiasis and corneal neovascularisation.&#xD;
&#xD;
             Patients with skin involvement must not have more than 2 out of the 4 clinical&#xD;
             criteria for bullous pemphigoid (BP) proposed by the French group (Vaillant L et&#xD;
             al,1998; Joly P et al. 2004) Direct Immunofluorescence (DIF): Linear deposits of IgG,&#xD;
             IgA and/or C3 on the BMZ by DIF of patient's skin or mucous membrane Histology: Sub&#xD;
             epithelial blister with or without significant leukocyte infiltrate by standard&#xD;
             histology of skin or mucosal lesions, when the skin or mucosal biopsy is possible and&#xD;
             appropriate.&#xD;
&#xD;
          2. MMP is defined as &quot;severe&quot; in patients with:&#xD;
&#xD;
             Sight-threatening ocular disease, and/or Potentially life-threatening laryngeal,&#xD;
             tracheal or oesophageal stenosis, and/or Involvement of a mucosal site where there is&#xD;
             a risk of scarring stenosis (larynx, trachea, esophagus, anus, foreskin, vagina…)&#xD;
             and/or More than one mucosal site involved and/or Mucosal involvement (including&#xD;
             exclusive but severe oral involvement defined as an oral MMP DAI score &gt; 10), and/or&#xD;
             Skin involvement, which have not achieved control of disease activity despite a one&#xD;
             month treatment with dapsone at the maximum dose tolerated or for patients with&#xD;
             sight-threatening ocular disease, and/or potentially life-threatening laryngeal,&#xD;
             tracheal or oesophageal stenosis, without previous treatment by dapsone&#xD;
&#xD;
          3. Patient having read and understood the information letter and signed the Informed&#xD;
             Consent Form&#xD;
&#xD;
          4. Patient with updated vaccinations. It is recommended that a patient's vaccination&#xD;
             record and the need for immunization prior to study entry be carefully investigated.&#xD;
&#xD;
          5. For women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhoea)&#xD;
             or surgically sterile (absence of ovaries and/or uterus) and who do not plan on having&#xD;
             children anymore: agreement to remain abstinent or use two adequate methods of&#xD;
             contraception, including at least one method with a failure rate of &lt;1% per year,&#xD;
             during the treatment period and for at least 12 months after the last dose of study&#xD;
             treatment.&#xD;
&#xD;
             Abstinence is acceptable only if it is in line with the preferred and usual lifestyle&#xD;
             of the patient.&#xD;
&#xD;
             Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation&#xD;
             methods) and withdrawal are not acceptable methods of contraception.&#xD;
&#xD;
             Barrier methods must always be supplemented with the use of a spermicide.&#xD;
&#xD;
             For men: Surgical sterility or agreement to remain abstinent or use a condom during&#xD;
             the treatment period and for at least 12 months after the last dose of study treatment&#xD;
             and agreement to refrain from donating sperm during this same period.&#xD;
&#xD;
             Abstinence is only acceptable if it is in line with the preferred and usual lifestyle&#xD;
             of the patient.&#xD;
&#xD;
             Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation&#xD;
             methods) and withdrawal are not acceptable methods of contraception.&#xD;
&#xD;
          6. Patient agreement to avoid excessive exposure to sunlight during study participation&#xD;
&#xD;
          7. Patient able to comply with the study protocol, in the investigator's judgment&#xD;
&#xD;
          8. Patient affiliated with, or beneficiary of a social security category&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient &lt; 18 years old or &gt; 80 years old&#xD;
&#xD;
          2. Non-consenting patient or patient who cannot be followed regularly&#xD;
&#xD;
          3. Patients with only MMP sequelae (stenosis, fibrosis, without inflammation or disease&#xD;
             activity)&#xD;
&#xD;
          4. Patients with Brunsting Perry pemphigoid and exclusive skin lesions without mucosal&#xD;
             involvement&#xD;
&#xD;
          5. Karnofsky index &lt; 50% (see Appendix 3)&#xD;
&#xD;
          6. Unstable angina or advanced ischemic cardiopathy (extensive myocardial infarction&#xD;
             within the last 3 months or post-infarction heart failure)&#xD;
&#xD;
          7. Severe heart failure (NYHA Class III or IV) or severe uncontrolled cardiac disease&#xD;
&#xD;
          8. Uncontrolled cardiac rhythm disorders&#xD;
&#xD;
          9. Severe bronchial obstruction&#xD;
&#xD;
         10. Past history of malignant disease in the previous 10 years, or current progressive&#xD;
             malignant disease, except basal cell carcinoma, and squamous cell carcinoma of the&#xD;
             skin that have been treated or excised and cured, in situ cervix carcinoma, or any&#xD;
             situation in which the oncologist in charge of the patient considers that risk of&#xD;
             evolution of severe localisation(s) of MMP is higher than oncologic risk of&#xD;
             cyclophosphamide and rituximab.&#xD;
&#xD;
         11. Anemia (haemoglobin &lt; 10 g/ dL ), neutropenia (&lt;1000/mm3), lymphopenia (&lt;900/mm3),&#xD;
             thrombopenia (&lt;100 000/mm3)&#xD;
&#xD;
         12. Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core,&#xD;
             antibody (HBcAb), or hepatitis C virus (HCV) serology at screening&#xD;
&#xD;
         13. Liver insufficiency, major renal insufficiency (creatinin clearance ≤ 30 ml/min)&#xD;
&#xD;
         14. Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24&#xD;
             weeks prior to screening&#xD;
&#xD;
         15. Patients with positive blood test for HIV&#xD;
&#xD;
         16. Inherited or acquired severe immune deficiency&#xD;
&#xD;
         17. Known active infection of any kind (excluding fungal infections of nail), or recent&#xD;
             episode of infection, which has required oral antibiotic treatment within 2 weeks&#xD;
             prior to enrollment in the trial&#xD;
&#xD;
         18. Infection having required hospitalization, or IV antibiotic treatment within 4 weeks&#xD;
             prior to enrollment&#xD;
&#xD;
         19. Past history of severe infection such as fasciitis, osteomyelitis septic arthritis&#xD;
             during the year prior to enrollment. Entry into this study may be reconsidered once&#xD;
             the infection has fully resolved&#xD;
&#xD;
         20. Evidence of any new or uncontrolled concomitant disease that, in the investigator's&#xD;
             judgment, would preclude patient participation, including but not limited to nervous&#xD;
             system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders&#xD;
&#xD;
         21. Any concomitant condition that required treatment with oral or systemic&#xD;
             corticosteroids within 12 weeks prior to randomization&#xD;
&#xD;
         22. Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery.&#xD;
&#xD;
         23. Patients having received immunosuppressive treatment (such as cyclosporine,&#xD;
             mycophenolate mofetil, azathioprine), or any other treatment that might potentially be&#xD;
             active on MMP lesions (anti-TNF) within 4 weeks prior to baseline.&#xD;
&#xD;
         24. Treatment with intravenous immunoglobulins, plasmapheresis, or other similar procedure&#xD;
             within 8 weeks prior to randomization&#xD;
&#xD;
         25. Previous treatment of MMP with one of the test products: cyclophosphamide or rituximab&#xD;
&#xD;
         26. Previous treatment with a B cell-targeted therapy other than rituximab (e.g.,&#xD;
             anti-CD20, anti-CD22, or anti-BLyS)&#xD;
&#xD;
         27. Treatment with a live or attenuated vaccine within 28 days prior to randomization&#xD;
&#xD;
         28. Contraindication to MABTHERA 500 mg concentrate for solution for infusion&#xD;
&#xD;
         29. Contraindication to ENDOXAN 50 mg, tablets&#xD;
&#xD;
         30. Contraindication to methylprednisolone marketed as 120 mg powder for injectable&#xD;
             solution pharmaceutical form&#xD;
&#xD;
         31. Contraindication to paracetamol marketed as 10 mg/ml solution for infusion&#xD;
             pharmaceutical form&#xD;
&#xD;
         32. Contraindication to hydroxyzine marketed as 100 mg / 2 ml injectable solution&#xD;
             pharmaceutical form&#xD;
&#xD;
         33. Contraindication to sodium chloride marketed as 0,9% sodium chloride solution for&#xD;
             infusion pharmaceutical form&#xD;
&#xD;
         34. Contraindication to glucose marketed as 5% glucose solution for infusion&#xD;
             pharmaceutical form&#xD;
&#xD;
         35. Lactose intolerance&#xD;
&#xD;
         36. Lack of peripheral venous access&#xD;
&#xD;
         37. Women pregnant or lactating, or intending to become pregnant during and for 12 months&#xD;
             following the study. Women who are not postmenopausal (≥ 12 months of&#xD;
             non-therapy-induced amenorrhea) or surgically sterile must have a negative result from&#xD;
             a serum pregnancy test within 1 week prior to randomization.&#xD;
&#xD;
         38. Patients who plan on having children (due to the risk of amenorrhoea/azoospermia&#xD;
             related to cyclophosphamide) and due to the long retention time of rituximab in B&#xD;
             cells depleted patients, women of childbearing potential should use effective&#xD;
             contraceptive methods during and for 12 months following treatment with MABTHERA&#xD;
&#xD;
         39. Participation in another interventional clinical trial within 28 days prior to&#xD;
             randomization and during the study&#xD;
&#xD;
         40. Person deprived of liberty by administrative or judicial decision or placed under&#xD;
             judicial protection (guardianship or supervision)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pascal JOLY, Pr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rouen University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Pascal JOLY, Pr</last_name>
    <phone>+3323288</phone>
    <phone_ext>8059</phone_ext>
    <email>pascal.joly@chu-rouen.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Julien BLOT</last_name>
    <phone>+3323288</phone>
    <phone_ext>8265</phone_ext>
    <email>julien.blot@chu-rouen.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>CHU Amiens</name>
      <address>
        <city>Amiens</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Catherine Lok</last_name>
    </contact>
    <investigator>
      <last_name>Catherine Lok</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Angers</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Martine Avenel</last_name>
    </contact>
    <investigator>
      <last_name>Martine Avenel</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CH Argenteuil</name>
      <address>
        <city>Argenteuil</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Emmanuel Mahe</last_name>
    </contact>
    <investigator>
      <last_name>Emmanuel Mahe</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Bordeaux</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marie Beylot Barry</last_name>
    </contact>
    <investigator>
      <last_name>Marie Beylot Barry</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Brest University Hospital</name>
      <address>
        <city>Brest</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Misery, Pr</last_name>
    </contact>
    <investigator>
      <last_name>Laurent Misery</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Caen</name>
      <address>
        <city>Caen</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laurence Verneuil</last_name>
    </contact>
    <investigator>
      <last_name>Laurence Verneuil</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Clermont Ferrand</name>
      <address>
        <city>Clermont Ferrand</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michel D'Incan</last_name>
    </contact>
    <investigator>
      <last_name>Michel D'Incan</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Dijon</name>
      <address>
        <city>Dijon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pierre Vabres</last_name>
    </contact>
    <investigator>
      <last_name>Pierre Vabres</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CH Le Mans</name>
      <address>
        <city>Le Mans</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hervé Maillard</last_name>
    </contact>
    <investigator>
      <last_name>Hervé Maillard</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Lille</name>
      <address>
        <city>Lille</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Emmanuel Delaporte</last_name>
    </contact>
    <investigator>
      <last_name>Emmanuel Delaporte</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU de Limoges</name>
      <address>
        <city>Limoges</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christophe Bedane</last_name>
    </contact>
    <investigator>
      <last_name>Christophe Bedane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>HCL</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sébastien Debarbieux</last_name>
    </contact>
    <investigator>
      <last_name>Sébastien Debarbieux</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Denis Jullien</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>APHM La Timone</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marie-Aleth Richard</last_name>
    </contact>
    <investigator>
      <last_name>Marie-Aleth Richard</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Montpellier</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Olivier Dereure</last_name>
    </contact>
    <investigator>
      <last_name>Olivier Dereure</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Nantes</name>
      <address>
        <city>Nantes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gaelle Querreux</last_name>
    </contact>
    <investigator>
      <last_name>Gaelle Querreux</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Nice</name>
      <address>
        <city>Nice</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jean-Philippe Lacour</last_name>
    </contact>
    <investigator>
      <last_name>Jean-Philippe Lacour</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>APHP Avicennes</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Catherine Prost</last_name>
    </contact>
    <investigator>
      <last_name>Catherine Prost</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>APHP Bichat</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Catherine Picard-Dahan</last_name>
    </contact>
    <investigator>
      <last_name>Catherine Picard-Dahan</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>APHP Cochin</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nicolas Dupin</last_name>
    </contact>
    <investigator>
      <last_name>Nicolas Dupin</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>APHP Henri Mondor</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Oro Saskia</last_name>
    </contact>
    <investigator>
      <last_name>Oro Saskia</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>APHP Pitié Salpétrière</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stéphane Barete</last_name>
    </contact>
    <investigator>
      <last_name>Stéphane Barete</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>APHP Saint-Louis</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jean-David Bouaziz</last_name>
    </contact>
    <investigator>
      <last_name>Jean-David Bouaziz</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CH Quimper</name>
      <address>
        <city>Quimper</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Patrice Plantin</last_name>
    </contact>
    <investigator>
      <last_name>Patrice Plantin</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU de Reims</name>
      <address>
        <city>Reims</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bernard Philippe</last_name>
    </contact>
    <investigator>
      <last_name>Bernard Philippe</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Rennes</name>
      <address>
        <city>Rennes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alain Dupuy</last_name>
    </contact>
    <investigator>
      <last_name>Alain Dupuy</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU saint-Etienne</name>
      <address>
        <city>Saint-Étienne</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bruno Labeille</last_name>
    </contact>
    <investigator>
      <last_name>Bruno Labeille</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Tours</name>
      <address>
        <city>Tours</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laurent Machet</last_name>
    </contact>
    <investigator>
      <last_name>Laurent Machet</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>October 2019</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 23, 2019</last_update_submitted>
  <last_update_submitted_qc>October 23, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cyclophosphamide</keyword>
  <keyword>Rituximab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pemphigoid, Benign Mucous Membrane</mesh_term>
    <mesh_term>Pemphigoid, Bullous</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</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/NCT03295383
org study id: 2015/208/HP
nct id: NCT03295383
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Mucous membrane pemphigoid (MMP) describes a group of chronic auto-immune bullous diseases
      (AIBD) of the basement membrane zone (BMZ), characterized by predominant or exclusive mucosal
      involvement, including oral, naso-pharyngeal, laryngo-tracheal, genital, oesophageal, anal
      and ocular mucous membranes. Circulating autoantibodies are directed against various antigens
      of the BMZ: BP180, laminin 332 and type 7 collagen. MMP is a rare disease with an incidence
      of 1.8 new cases/million inhabitants/year in France.

      Scar formation which is secondary to initial inflammation, is a characteristic feature of
      MMP, leading to major disability (e.g blindness and oesophageal, anal, vaginal stenosis) and
      life-threatening situations (e.g. laryngeal stenosis leading to respiratory failure).

      Dapsone is the first line treatment of mild/moderate forms of MMP. Dapsone is used both as
      initial treatment, and as maintenance therapy. However, severe forms of MMP can rapidly
      worsen leading to blindness, aphagia due to esophageal stenosis, respiratory failure due to
      tracheal or laryngeal stenosis, and urinary and sexual dysfunctions due to genital
      involvement. These patients are usually treated using immunosuppressive drugs. Indeed,
      corticosteroids (CS) are not recommended in MMP.

      Cyclophosphamide was considered as the most effective immunosuppressant in severe forms of
      MMP, before the use of rituximab, an anti-CD20 monoclonal antibody (MAb).

      Two series from our group have assessed the advantages and disadvantages of IV pulse and oral
      administration of cyclophosphamide in MMP. Oral administration seems more rapidly effective
      with 54% of complete remission (CR) after a median time of 24 weeks (16-52 weeks).

      The results of 41 patients with severe types of MMP (including a French series of 20
      patients) treated with rituximab have been published. Rate of CR after one and two cycles
      were 66% and 90%, respectively. Clinical improvement was rapid, since a decrease in disease
      activity was observed after 4 weeks of treatment in 64% of patients.

      Our results and those of the literature suggest that rituximab might be more effective than
      cyclophosphamide, which has been considered as the gold standard of treatment in severe forms
      of disease, up to now.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Proportion of patients achieving CR or Partial Remission (PR)
time frame: Month 12
description: Complete remission: absence of any inflammatory lesion, blister or erosion, and, absence of new fibrosing lesions, and/or absence of worsening of established fibrosing lesions Partial remission: presence of transient new inflammatory lesions, blisters or erosions that heal within one week without treatment and, absence of new fibrosing lesions, and/or absence of worsening of established fibrosing lesions. (Murrell D et al. 2015)
measure: Mean evolution of MMP DAI activity score
time frame: Month 24
description: MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 "activity" and "damage" sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.
measure: Mean evolution of MMP DAI activity score
time frame: Month 6
description: MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 "activity" and "damage" sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.
measure: Evolution of MMP DAI activity score
time frame: Month 12
description: MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 "activity" and "damage" sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.
measure: Number of flares / relapses
time frame: Month 24
description: relapse / flare is defined as "the reappearance of at least 3 new lesions a month (blisters, erosions) that do not heal within one week, or the extension of established lesions in a patient who has achieved disease control." (Murrell D et al. 2015).
measure: Evolution of quality of life score (TAB QOL)
time frame: Month 12
description: ABQOL score is a quality of life questionnaires specifically developed for patients with autoimmune blistering disorders to assess quality of life (ABQOL)
measure: Evolution of quality of life score AB QOL
time frame: Month 12
description: TAB QOL score is a quality of life questionnaires specifically developed for patients with autoimmune blistering disorders to assess evolution under treatment (TAB QOL)
arm group label: Rituximab treatment
arm group type: Experimental
description: Rituximab at a dose of 1000 mg (or matching placebo) will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197
cyclophosphamide placebo will be administered orally once daily
arm group label: Cyclophosphamide treatment
arm group type: Active Comparator
description: cyclophosphamide will be administered orally once daily at the following initial doses:
patients younger than 75 years: 1.5 mg/kg/day, orally. patients older than 75 years: 1 mg/kg/day, orally.
Rituximab placebo (NaCl 0.9 %) will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197
intervention type: Drug
intervention name: Rituximab 1g IV
description: Rituximab at a dose of 1000 mg will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197
arm group label: Rituximab treatment
intervention type: Drug
intervention name: Cyclophosphamide 50Mg Oral Tablet
description: cyclophosphamide will be administered orally once daily at the following initial doses:
patients younger than 75 years: 1.5 mg/kg/day, orally.
patients older than 75 years: 1 mg/kg/day, orally.
arm group label: Cyclophosphamide treatment
intervention type: Drug
intervention name: Placebo of Rituximab
description: Rituximab placebo will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab administration on Day 182 and Day 197
arm group label: Cyclophosphamide treatment
intervention type: Drug
intervention name: Placebo Oral Tablet
description: cyclophosphamide placebo will be administered orally once daily
arm group label: Rituximab treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Pascal JOLY, Pr
role: Principal Investigator
affiliation: Rouen University Hospital
last name: Pascal JOLY, Pr
phone: +3323288
phone ext: 8059
email: pascal.joly@chu-rouen.fr
last name: Julien BLOT
phone: +3323288
phone ext: 8265
email: julien.blot@chu-rouen.fr
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Pemphigoid, Benign Mucous Membrane
mesh term: Pemphigoid, Bullous
mesh term: Cyclophosphamide
mesh term: Rituximab
sharing ipd: No