<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/NCT02262299</url>
  </required_header>
  <id_info>
    <org_study_id>RH-HJE-2014-09</org_study_id>
    <nct_id>NCT02262299</nct_id>
  </id_info>
  <brief_title>European Trial of Pirfenidone in BOS, A European Multi-center Study</brief_title>
  <acronym>EPOS</acronym>
  <official_title>A European Multi-center, Randomised, Double-blind Trial of Pirfenidone in Bronchiolitis-obliterans-syndrome Grade 1-3 in Lung Transplant Recipients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A European multi-centre, randomised, double-blind placebo-controlled trial of Pirfenidone in&#xD;
      bronchiolitis-obliterans-syndrome grade 1-3 in lung transplant recipients.&#xD;
&#xD;
      Randomized double blinded, placebo controlled study. Eligible patients are to be randomized&#xD;
      in a 1:1 ratio to receive either Pirfenidone 2403 mg/d or the matching placebo treatment for&#xD;
      6 months.&#xD;
&#xD;
      Primary objective To evaluate the effect of Pirfenidone on the change in FEV1 in liters over&#xD;
      6 months in lung transplant recipients with bronchiolitis obliterans syndrome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Title of the study: A European multi-centre, randomised, double-blind placebo-controlled&#xD;
      trial of Pirfenidone in bronchiolitis-obliterans-syndrome grade 1-3 in lung transplant&#xD;
      recipients&#xD;
&#xD;
      Study design: Randomized double blinded, placebo controlled study. Eligible patients are to&#xD;
      be randomized in a 1:1 ratio to receive either Pirfenidone 2403 mg/d or the matching placebo&#xD;
      treatment for 6 months.&#xD;
&#xD;
      Study objectives Primary objective:&#xD;
&#xD;
      Change in FEV1 in liters over 6 months in lung transplant recipients with bronchiolitis&#xD;
      obliterans syndrome.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        -  Categorical percentage change in FEV1&#xD;
&#xD;
        -  Change in Forced Vital Capacity (FVC)&#xD;
&#xD;
        -  Change in Total Lung Capacity (TLC)&#xD;
&#xD;
        -  Change in FEV1/FVC ratio&#xD;
&#xD;
        -  Number of patients with treatment failure&#xD;
&#xD;
        -  Change in BOS grade&#xD;
&#xD;
        -  Change in percent predicted diffusion capacity (DLCO)&#xD;
&#xD;
        -  Change in functional level as assessed by the 6MWT&#xD;
&#xD;
        -  Hospital admission for any reason&#xD;
&#xD;
        -  Death or re-transplantation rates&#xD;
&#xD;
        -  Change in QoL as assessed by EQ5D&#xD;
&#xD;
      Methodology The study will be conducted in selected Lung Transplant expert centers across&#xD;
      Europe.&#xD;
&#xD;
      Trial duration Enrolment duration: planned 15 months Treatment duration: 6 months&#xD;
&#xD;
      Number of patients Number of sites Number of countries ~80 patients ( ~40 per Arm) A minimum&#xD;
      of 10 centers 7 (Denmark, Sweden, Norway, UK, Belgium, The Netherlands and Germany)&#xD;
&#xD;
      Study treatment: Patients will be randomized 1:1 to receive either placebo or Pirfenidone.&#xD;
&#xD;
      Pirfenidone dose will be adapted per the Investigator's Brochure in case of adverse events&#xD;
&#xD;
      Selection criteria: Inclusion criteria:&#xD;
&#xD;
      Patients can be included irrespective of pre-transplant disease, type of induction treatment&#xD;
      and immunosuppressive treatment. The following patients will be included in the study:&#xD;
&#xD;
        -  Patients &gt;18 years of age&#xD;
&#xD;
        -  Azithromycin therapy for at least 4 weeks prior to study start, with an Azithromycin&#xD;
           dose of minimum 250 mg/day at least 3 times per week as this is considered standard&#xD;
           therapy for bronchiolitis obliterans syndrome.&#xD;
&#xD;
        -  Double lung transplantation is required.&#xD;
&#xD;
        -  Patients must be at least 6 months after transplantation and must have documented&#xD;
           post-transplant baseline value of FEV1 (mean of the 2 highest values measured at least 3&#xD;
           weeks apart according to ISHLT criteria).&#xD;
&#xD;
        -  Patients must have BOS grade 1 to BOS grade 3.&#xD;
&#xD;
        -  Patients must have documented progressive disease as demonstrated by all of the&#xD;
           following criteria:&#xD;
&#xD;
        -  Patients must have at least 3 FEV1-measurements in the last 6 months, each at least 3&#xD;
           weeks apart&#xD;
&#xD;
        -  a total decline of at least 200ml in FEV1 in these last three measurements&#xD;
&#xD;
        -  a decline of at least 50 ml in the last two measurements&#xD;
&#xD;
      Exclusion Criteria:&#xD;
&#xD;
        -  Patients with lung redo transplantation, combined transplantation (including heart and&#xD;
           lung transplantation) or single lung recipients.&#xD;
&#xD;
        -  Patients with any severe comorbidity complicating BOS which might determine the&#xD;
           prognosis and functional level of the patient (e.g. invasive aspergillosis, active&#xD;
           malignant disease) within the last 12 months.&#xD;
&#xD;
        -  FEV1 decline related to other non BOS causes (eg pneumothorax, bronchial stenosis,&#xD;
           effusion, etc.)&#xD;
&#xD;
        -  Patients who on Thorax CT at entry demonstrate new significant findings which are not&#xD;
           compatible with BOS like interstitial fibrosis, consolidation, appearances suggesting&#xD;
           Restrictive Allograft Syndrome (RAS) and acute pulmonary infection as cause of decline&#xD;
           in lung function.&#xD;
&#xD;
        -  Documented acute perivascular rejection higher than grade A1 or findings compatible with&#xD;
           antibody mediated rejection&#xD;
&#xD;
        -  Pregnancy or lactation (women of childbearing capacity are required to have a negative&#xD;
           serum pregnancy test before treatment and must agree to maintain highly effective&#xD;
           contraception by practicing abstinence or by using at least two methods of birth control&#xD;
           from the date of consent through the end of the study).&#xD;
&#xD;
        -  Renal insufficiency (Creatinine clearance &lt;30 ml/min calculated by the CKD-Epi formula.&#xD;
&#xD;
        -  Any of the following liver test criteria above the specified limit:&#xD;
&#xD;
        -  Total bilirubin above the upper limit of the normal range (ULN), except in patients with&#xD;
           predominantly unconjugated hyperbilirubinemia (e.g., Gilbert's syndrome)&#xD;
&#xD;
        -  Aspartate or alanine aminotransferase (AST or ALT) &gt;3 × ULN&#xD;
&#xD;
        -  Known allergy or hypersensitivity to Pirfenidone&#xD;
&#xD;
        -  Ongoing use or expected use of any of the following therapies:&#xD;
&#xD;
        -  Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin)&#xD;
&#xD;
        -  Moderate inhibitors of CYP1A2 (e.g. mexiletine, thiabendazole, or phenylpropanolamine&#xD;
           [Note: ciprofloxacin will be allowed only at doses ≤500 mg BID])&#xD;
&#xD;
        -  Previous treatment with Pirfenidone after transplantation&#xD;
&#xD;
        -  Patients who have resumed smoking after transplantation&#xD;
&#xD;
      Data collection At screening:&#xD;
&#xD;
        -  Thorax HR-CT ( to exclude non-BOS pathology)&#xD;
&#xD;
        -  Chest X Ray&#xD;
&#xD;
        -  Spirometry and measurement of FEV1/FVC according to ERS criteria is required to&#xD;
           demonstrate typical obstruction&#xD;
&#xD;
        -  ECG to exclude QTc &gt; 500ms&#xD;
&#xD;
        -  Bronchoscopy with bronchoalveolar lavage (BAL) according to standard international&#xD;
           criteria. At least two aliquots of 50 ml are required. BAL to exclude concurrent&#xD;
           infections. BAL cultured for bacteria and fungi plus cytospin preparations or&#xD;
           immunological BAL for differential counts.&#xD;
&#xD;
        -  Transbronchial biopsy&#xD;
&#xD;
        -  Blood samples (haematology and chemistry) including liver function tests&#xD;
&#xD;
        -  Drug monitoring for immuno-suppressive treatment&#xD;
&#xD;
      Baseline:&#xD;
&#xD;
        -  Height&#xD;
&#xD;
        -  Weight&#xD;
&#xD;
        -  Basic demographic data including medication.&#xD;
&#xD;
        -  Physical examination and vital signs&#xD;
&#xD;
        -  Spirometry and measurement of FEV1/FVC&#xD;
&#xD;
        -  Blood samples (haematology and chemistry) including liver function tests&#xD;
&#xD;
        -  Drug monitoring for immuno-suppressive treatment&#xD;
&#xD;
        -  Record concomitant medications&#xD;
&#xD;
        -  Body-plethysmographic measurement to assess TLC and RV&#xD;
&#xD;
        -  DLco&#xD;
&#xD;
        -  6MWT&#xD;
&#xD;
        -  Quality of Life questionnaire&#xD;
&#xD;
      Monthly visits (Months 1, 2, 3, 4):&#xD;
&#xD;
        -  Weight&#xD;
&#xD;
        -  Spirometry and measurement of FEV1/FVC according to ATS/ERS criteria.&#xD;
&#xD;
        -  Safety monitoring (Record ADRs and blood lab tests, including liver tests)&#xD;
&#xD;
        -  Drug monitoring for immuno-suppressive treatment&#xD;
&#xD;
        -  Record concomitant medications&#xD;
&#xD;
        -  Clinical Status&#xD;
&#xD;
      Endpoints: 6 Month visit (or early termination visit):&#xD;
&#xD;
        -  Weight&#xD;
&#xD;
        -  Spirometry and measurement of FEV1/FVC according to ATS/ERS criteria.&#xD;
&#xD;
        -  Safety monitoring (Record ADRs and blood lab tests, including liver tests)&#xD;
&#xD;
        -  Drug monitoring for immuno-suppressive treatment&#xD;
&#xD;
        -  Record concomitant medications&#xD;
&#xD;
        -  Clinical Status&#xD;
&#xD;
        -  Body-plethysmographic measurement to assess TLC and RV&#xD;
&#xD;
        -  DLco&#xD;
&#xD;
        -  6MWT&#xD;
&#xD;
        -  Quality of Life questionnaire&#xD;
&#xD;
      Primary endpoints&#xD;
&#xD;
      - Change in FEV1 (ml) at 6 months&#xD;
&#xD;
      Secondary endpoints&#xD;
&#xD;
        -  Categorical percentage change in FEV1 (ml)&#xD;
&#xD;
           o Categorical percentage change in FEV1 ≥ 10 % (increase or decrease) relative to&#xD;
           FEV1(ml) at baseline&#xD;
&#xD;
        -  Change of FVC in liters&#xD;
&#xD;
        -  Change in TLC in liters&#xD;
&#xD;
        -  FEV1/FVC ratio change&#xD;
&#xD;
        -  Number of patients with treatment failure&#xD;
&#xD;
        -  Change in BOS grade&#xD;
&#xD;
        -  Change in percent predicted DLco.&#xD;
&#xD;
        -  Change in functional level as assessed by the 6MWT&#xD;
&#xD;
        -  Hospital admission for any reason&#xD;
&#xD;
        -  Death or re-transplantation rates&#xD;
&#xD;
        -  Change in EQ5D scale&#xD;
&#xD;
      Treatment failure during the study is defined as one or more of the following:&#xD;
&#xD;
        -  Redo transplantation&#xD;
&#xD;
        -  Death due to respiratory causes&#xD;
&#xD;
        -  Initiation of rescue therapy for worsening of BOS (worsening of BOS defined as a decline&#xD;
           of at least 600mL in 3 consecutive months) o Photophoresis, Montelukast or other&#xD;
           treatment considered as rescue therapy by the investigator&#xD;
&#xD;
      Statistical Methods Imputation:&#xD;
&#xD;
      In the ITT primary endpoint analysis, missing data due to treatment failure and death will be&#xD;
      imputed as 50% of baseline FEV1. For patients lost to follow-up or who withdrew from the&#xD;
      study for reasons not related to BOS, the last measured FEV1 (ml) will be imputed as the 6&#xD;
      month value.&#xD;
&#xD;
      Sample Size calculation:&#xD;
&#xD;
      Assumptions:&#xD;
&#xD;
        1. SD: To determine the SD of the FEV1 decline in the population, the 5 members of the&#xD;
           Steering committee collected the data from patients meeting the inclusion criteria. Mean&#xD;
           decline in FEV1 (in a 6 month period) in this sample was 561 ml and the SD of the&#xD;
           decline was 300 ml .&#xD;
&#xD;
        2. Treatment effect: A meaningful treatment effect of 50% should be expected based on the&#xD;
           mechanism of disease and preliminary data in BOS (In the publication) and personal&#xD;
           experience.&#xD;
&#xD;
      One standard deviation (SD) of FEV1 in groups will be assumed to be 300 mL based on data from&#xD;
      expert centers.&#xD;
&#xD;
      Monthly decline in FEV1 at onset of BOS is assumed to be approximately 75 ml, in 6 months 450&#xD;
      ml decline in FEV1 is expected for the placebo group.&#xD;
&#xD;
      A treatment effect of 50% reduction in decline is expected with Pirfenidone, which will lead&#xD;
      to an expected mean decline of 225 ml in 6 months.&#xD;
&#xD;
      With a beta error of 12% (power 88%) the study will be able to detect a difference of 225 ml&#xD;
      between the two treatment groups with a sample size of 36 patients in each group using a&#xD;
      two-sided t-test with significance level of 0.05. An estimated 80 patients will be recruited&#xD;
      to the trial allowing for a drop-out rate of 10%.&#xD;
&#xD;
      Concomitant treatment - Stopping Azithromycin will be allowed if not tolerated. Standard&#xD;
      treatment is continuation of Azithromycin.&#xD;
&#xD;
        -  Initiation on new bronchodilator therapy is not allowed&#xD;
&#xD;
        -  Photopheresis and Montelukast are not allowed while on Pirfenidone Study Committees&#xD;
           Steering Committee: M. Perch, P. Corris, G. Verleden, J. Gotlieb and E Verschuuren&#xD;
           Patient Review Committee Inclusion Criteria, exclusion criteria and BOS staging for all&#xD;
           patients enrolled will be reviewed by a committee.&#xD;
&#xD;
      Clinical Events Committee Group of physicians who will review the serious adverse events that&#xD;
      occur during the study to adjudicate their relationship to the study drug.&#xD;
&#xD;
      DSMB Independent group to review the safety and efficacy data during the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2015</start_date>
  <completion_date type="Actual">December 2019</completion_date>
  <primary_completion_date type="Actual">December 2019</primary_completion_date>
  <phase>Phase 2/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>To evaluate the effect of Pirfenidone on the change in FEV1 in liters over 6 months in lung transplant recipients with bronchiolitis obliterans syndrome.</measure>
    <time_frame>6 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>- Categorical percentage change in FEV1</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Change in Forced Vital Capacity (FVC)</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Change in Total Lung Capacity (TLC)</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Change in FEV1/FVC ratio</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Number of patients with treatment failure</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Change in BOS grade</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Change in percent predicted diffusion capacity (DLCO)</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Change in functional level as assessed by the 6MWT</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Hospital admission for any reason</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Death or re-transplantation rates</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>- Change in QoL as assessed by EQ5D</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Disorder Related to Lung Transplantation</condition>
  <condition>CLAD, Bronchiolitis Obliterans</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Receive placebo tablets</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pirfenidone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Upon enrollment, subjects will be randomized to either the treatment group (Pirfenidone) or to the placebo group (1:1 ratio). The trial medication will be administered as 267-mg oral capsules and titrated to a maintenance dose of 2403 mg/d (3 capsules TID, for a total of 9 capsules/day).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pirfenidone</intervention_name>
    <description>Receive tablets with pirfenidone</description>
    <arm_group_label>Pirfenidone</arm_group_label>
    <other_name>Esbriet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Recieve tablets with placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients &gt;18 years of age&#xD;
&#xD;
          -  Azithromycin therapy for at least 4 weeks prior to study start, with an Azithromycin&#xD;
             dose of minimum 250 mg/day at least 3 times per week as this is considered standard&#xD;
             therapy for bronchiolitis obliterans syndrome.&#xD;
&#xD;
          -  Double lung transplantation is required.&#xD;
&#xD;
          -  Patients must be at least 6 months after transplantation and must have documented&#xD;
             post-transplant baseline value of FEV1 (mean of the 2 highest values measured at least&#xD;
             3 weeks apart according to ISHLT criteria).&#xD;
&#xD;
          -  Patients must have BOS grade 1 to BOS grade 3.&#xD;
&#xD;
          -  Patients must have documented progressive disease as demonstrated by all of the&#xD;
             following criteria:&#xD;
&#xD;
          -  Patients must have at least 3 FEV1-measurements in the last 6 months, each at least 3&#xD;
             weeks apart&#xD;
&#xD;
          -  a total decline of at least 200ml in FEV1 i&#xD;
&#xD;
          -  a decline of at least 50 ml in the last two measurements&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Patients with lung redo transplantation, combined transplantation (including heart and&#xD;
             lung transplantation) or single lung recipients.&#xD;
&#xD;
          -  Patients with any severe comorbidity complicating BOS which might determine the&#xD;
             prognosis and functional level of the patient (e.g. invasive aspergillosis, active&#xD;
             malignant disease) within the last 12 months.&#xD;
&#xD;
          -  FEV1 decline related to other non BOS causes (eg pneumothorax, bronchial stenosis,&#xD;
             effusion, etc.)&#xD;
&#xD;
          -  Patients who have developed BOS grade 3.&#xD;
&#xD;
          -  Patients who on Thorax CT at entry demonstrate new significant findings which are not&#xD;
             compatible with BOS like interstitial fibrosis, consolidation, appearances suggesting&#xD;
             Restrictive Allograft Syndrome (RAS) and acute pulmonary infection as cause of decline&#xD;
             in lung function.&#xD;
&#xD;
          -  Documented acute perivascular rejection higher than grade A1 or findings compatible&#xD;
             with antibody mediated rejection&#xD;
&#xD;
          -  Pregnancy or lactation (women of childbearing capacity are required to have a negative&#xD;
             serum pregnancy test before treatment and must agree to maintain highly effective&#xD;
             contraception by practicing abstinence or by using at least two methods of birth&#xD;
             control from the date of consent through the end of the study).&#xD;
&#xD;
          -  Renal insufficiency (Creatinine clearance &lt;30 ml/min calculated by the CKD-Epi&#xD;
             formula.&#xD;
&#xD;
          -  Any of the following liver test criteria above the specified limit:&#xD;
&#xD;
          -  Total bilirubin above the upper limit of the normal range (ULN), except in patients&#xD;
             with predominantly unconjugated hyperbilirubinemia (e.g., Gilbert's syndrome)&#xD;
&#xD;
          -  Aspartate or alanine aminotransferase (AST or ALT) &gt;3 × ULN&#xD;
&#xD;
          -  Known allergy or hypersensitivity to Pirfenidone&#xD;
&#xD;
          -  Ongoing use or expected use of any of the following therapies:&#xD;
&#xD;
          -  Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin)&#xD;
&#xD;
          -  Moderate inhibitors of CYP1A2 (e.g. mexiletine, thiabendazole, or phenylpropanolamine&#xD;
             [Note: ciprofloxacin will be allowed only at doses ≤500 mg BID])&#xD;
&#xD;
          -  Previous treatment with Pirfenidone after transplantation&#xD;
&#xD;
          -  Patients who have resumed smoking after transplantation&#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>Michael Perch, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rigshospitalet, Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Gasthuisberg, Katholike Universiteit Leuven</name>
      <address>
        <city>Leuven</city>
        <zip>300</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rigshospitalet, Copenhagen University Hospital</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Essen, Department of Pneumonology</name>
      <address>
        <city>Essen</city>
        <zip>45239</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medizinische Hochschule Hannover, Klinik für Pneumonologie</name>
      <address>
        <city>Hannover</city>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Grosshadern, Division of Pulmonary Diseases</name>
      <address>
        <city>Munich</city>
        <zip>81377</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Groningen University Medical Center, Lung Transplant Team</name>
      <address>
        <city>Groningen</city>
        <zip>9700</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rikshospitalet, National University Hospital</name>
      <address>
        <city>Oslo</city>
        <zip>0424</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sahlgrenska University Hospital, Department of respiratory diseases</name>
      <address>
        <city>Gothenburg</city>
        <zip>41345</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Freeman Hospital</name>
      <address>
        <city>Newcastle</city>
        <zip>NE7 7DN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Denmark</country>
    <country>Germany</country>
    <country>Netherlands</country>
    <country>Norway</country>
    <country>Sweden</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>September 21, 2014</study_first_submitted>
  <study_first_submitted_qc>October 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <last_update_submitted>January 16, 2020</last_update_submitted>
  <last_update_submitted_qc>January 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Michael Perch</investigator_full_name>
    <investigator_title>Medical Director Danish National Lung Transplant Program</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bronchiolitis</mesh_term>
    <mesh_term>Bronchiolitis Obliterans</mesh_term>
    <mesh_term>Bronchiolitis Obliterans Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pirfenidone</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/NCT02262299
org study id: RH-HJE-2014-09
nct id: NCT02262299
lead sponsor: 
has dmc: Yes
A European multi-centre, randomised, double-blind placebo-controlled trial of Pirfenidone in
      bronchiolitis-obliterans-syndrome grade 1-3 in lung transplant recipients.

      Randomized double blinded, placebo controlled study. Eligible patients are to be randomized
      in a 1:1 ratio to receive either Pirfenidone 2403 mg/d or the matching placebo treatment for
      6 months.

      Primary objective To evaluate the effect of Pirfenidone on the change in FEV1 in liters over
      6 months in lung transplant recipients with bronchiolitis obliterans syndrome.
Title of the study: A European multi-centre, randomised, double-blind placebo-controlled
      trial of Pirfenidone in bronchiolitis-obliterans-syndrome grade 1-3 in lung transplant
      recipients

      Study design: Randomized double blinded, placebo controlled study. Eligible patients are to
      be randomized in a 1:1 ratio to receive either Pirfenidone 2403 mg/d or the matching placebo
      treatment for 6 months.

      Study objectives Primary objective:

      Change in FEV1 in liters over 6 months in lung transplant recipients with bronchiolitis
      obliterans syndrome.

      Secondary objectives:

        -  Categorical percentage change in FEV1

        -  Change in Forced Vital Capacity (FVC)

        -  Change in Total Lung Capacity (TLC)

        -  Change in FEV1/FVC ratio

        -  Number of patients with treatment failure

        -  Change in BOS grade

        -  Change in percent predicted diffusion capacity (DLCO)

        -  Change in functional level as assessed by the 6MWT

        -  Hospital admission for any reason

        -  Death or re-transplantation rates

        -  Change in QoL as assessed by EQ5D

      Methodology The study will be conducted in selected Lung Transplant expert centers across
      Europe.

      Trial duration Enrolment duration: planned 15 months Treatment duration: 6 months

      Number of patients Number of sites Number of countries ~80 patients ( ~40 per Arm) A minimum
      of 10 centers 7 (Denmark, Sweden, Norway, UK, Belgium, The Netherlands and Germany)

      Study treatment: Patients will be randomized 1:1 to receive either placebo or Pirfenidone.

      Pirfenidone dose will be adapted per the Investigator's Brochure in case of adverse events

      Selection criteria: Inclusion criteria:

      Patients can be included irrespective of pre-transplant disease, type of induction treatment
      and immunosuppressive treatment. The following patients will be included in the study:

        -  Patients >18 years of age

        -  Azithromycin therapy for at least 4 weeks prior to study start, with an Azithromycin
           dose of minimum 250 mg/day at least 3 times per week as this is considered standard
           therapy for bronchiolitis obliterans syndrome.

        -  Double lung transplantation is required.

        -  Patients must be at least 6 months after transplantation and must have documented
           post-transplant baseline value of FEV1 (mean of the 2 highest values measured at least 3
           weeks apart according to ISHLT criteria).

        -  Patients must have BOS grade 1 to BOS grade 3.

        -  Patients must have documented progressive disease as demonstrated by all of the
           following criteria:

        -  Patients must have at least 3 FEV1-measurements in the last 6 months, each at least 3
           weeks apart

        -  a total decline of at least 200ml in FEV1 in these last three measurements

        -  a decline of at least 50 ml in the last two measurements

      Exclusion Criteria:

        -  Patients with lung redo transplantation, combined transplantation (including heart and
           lung transplantation) or single lung recipients.

        -  Patients with any severe comorbidity complicating BOS which might determine the
           prognosis and functional level of the patient (e.g. invasive aspergillosis, active
           malignant disease) within the last 12 months.

        -  FEV1 decline related to other non BOS causes (eg pneumothorax, bronchial stenosis,
           effusion, etc.)

        -  Patients who on Thorax CT at entry demonstrate new significant findings which are not
           compatible with BOS like interstitial fibrosis, consolidation, appearances suggesting
           Restrictive Allograft Syndrome (RAS) and acute pulmonary infection as cause of decline
           in lung function.

        -  Documented acute perivascular rejection higher than grade A1 or findings compatible with
           antibody mediated rejection

        -  Pregnancy or lactation (women of childbearing capacity are required to have a negative
           serum pregnancy test before treatment and must agree to maintain highly effective
           contraception by practicing abstinence or by using at least two methods of birth control
           from the date of consent through the end of the study).

        -  Renal insufficiency (Creatinine clearance <30 ml/min calculated by the CKD-Epi formula.

        -  Any of the following liver test criteria above the specified limit:

        -  Total bilirubin above the upper limit of the normal range (ULN), except in patients with
           predominantly unconjugated hyperbilirubinemia (e.g., Gilbert's syndrome)

        -  Aspartate or alanine aminotransferase (AST or ALT) >3 × ULN

        -  Known allergy or hypersensitivity to Pirfenidone

        -  Ongoing use or expected use of any of the following therapies:

        -  Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin)

        -  Moderate inhibitors of CYP1A2 (e.g. mexiletine, thiabendazole, or phenylpropanolamine
           [Note: ciprofloxacin will be allowed only at doses ≤500 mg BID])

        -  Previous treatment with Pirfenidone after transplantation

        -  Patients who have resumed smoking after transplantation

      Data collection At screening:

        -  Thorax HR-CT ( to exclude non-BOS pathology)

        -  Chest X Ray

        -  Spirometry and measurement of FEV1/FVC according to ERS criteria is required to
           demonstrate typical obstruction

        -  ECG to exclude QTc > 500ms

        -  Bronchoscopy with bronchoalveolar lavage (BAL) according to standard international
           criteria. At least two aliquots of 50 ml are required. BAL to exclude concurrent
           infections. BAL cultured for bacteria and fungi plus cytospin preparations or
           immunological BAL for differential counts.

        -  Transbronchial biopsy

        -  Blood samples (haematology and chemistry) including liver function tests

        -  Drug monitoring for immuno-suppressive treatment

      Baseline:

        -  Height

        -  Weight

        -  Basic demographic data including medication.

        -  Physical examination and vital signs

        -  Spirometry and measurement of FEV1/FVC

        -  Blood samples (haematology and chemistry) including liver function tests

        -  Drug monitoring for immuno-suppressive treatment

        -  Record concomitant medications

        -  Body-plethysmographic measurement to assess TLC and RV

        -  DLco

        -  6MWT

        -  Quality of Life questionnaire

      Monthly visits (Months 1, 2, 3, 4):

        -  Weight

        -  Spirometry and measurement of FEV1/FVC according to ATS/ERS criteria.

        -  Safety monitoring (Record ADRs and blood lab tests, including liver tests)

        -  Drug monitoring for immuno-suppressive treatment

        -  Record concomitant medications

        -  Clinical Status

      Endpoints: 6 Month visit (or early termination visit):

        -  Weight

        -  Spirometry and measurement of FEV1/FVC according to ATS/ERS criteria.

        -  Safety monitoring (Record ADRs and blood lab tests, including liver tests)

        -  Drug monitoring for immuno-suppressive treatment

        -  Record concomitant medications

        -  Clinical Status

        -  Body-plethysmographic measurement to assess TLC and RV

        -  DLco

        -  6MWT

        -  Quality of Life questionnaire

      Primary endpoints

      - Change in FEV1 (ml) at 6 months

      Secondary endpoints

        -  Categorical percentage change in FEV1 (ml)

           o Categorical percentage change in FEV1 ≥ 10 % (increase or decrease) relative to
           FEV1(ml) at baseline

        -  Change of FVC in liters

        -  Change in TLC in liters

        -  FEV1/FVC ratio change

        -  Number of patients with treatment failure

        -  Change in BOS grade

        -  Change in percent predicted DLco.

        -  Change in functional level as assessed by the 6MWT

        -  Hospital admission for any reason

        -  Death or re-transplantation rates

        -  Change in EQ5D scale

      Treatment failure during the study is defined as one or more of the following:

        -  Redo transplantation

        -  Death due to respiratory causes

        -  Initiation of rescue therapy for worsening of BOS (worsening of BOS defined as a decline
           of at least 600mL in 3 consecutive months) o Photophoresis, Montelukast or other
           treatment considered as rescue therapy by the investigator

      Statistical Methods Imputation:

      In the ITT primary endpoint analysis, missing data due to treatment failure and death will be
      imputed as 50% of baseline FEV1. For patients lost to follow-up or who withdrew from the
      study for reasons not related to BOS, the last measured FEV1 (ml) will be imputed as the 6
      month value.

      Sample Size calculation:

      Assumptions:

        1. SD: To determine the SD of the FEV1 decline in the population, the 5 members of the
           Steering committee collected the data from patients meeting the inclusion criteria. Mean
           decline in FEV1 (in a 6 month period) in this sample was 561 ml and the SD of the
           decline was 300 ml .

        2. Treatment effect: A meaningful treatment effect of 50% should be expected based on the
           mechanism of disease and preliminary data in BOS (In the publication) and personal
           experience.

      One standard deviation (SD) of FEV1 in groups will be assumed to be 300 mL based on data from
      expert centers.

      Monthly decline in FEV1 at onset of BOS is assumed to be approximately 75 ml, in 6 months 450
      ml decline in FEV1 is expected for the placebo group.

      A treatment effect of 50% reduction in decline is expected with Pirfenidone, which will lead
      to an expected mean decline of 225 ml in 6 months.

      With a beta error of 12% (power 88%) the study will be able to detect a difference of 225 ml
      between the two treatment groups with a sample size of 36 patients in each group using a
      two-sided t-test with significance level of 0.05. An estimated 80 patients will be recruited
      to the trial allowing for a drop-out rate of 10%.

      Concomitant treatment - Stopping Azithromycin will be allowed if not tolerated. Standard
      treatment is continuation of Azithromycin.

        -  Initiation on new bronchodilator therapy is not allowed

        -  Photopheresis and Montelukast are not allowed while on Pirfenidone Study Committees
           Steering Committee: M. Perch, P. Corris, G. Verleden, J. Gotlieb and E Verschuuren
           Patient Review Committee Inclusion Criteria, exclusion criteria and BOS staging for all
           patients enrolled will be reviewed by a committee.

      Clinical Events Committee Group of physicians who will review the serious adverse events that
      occur during the study to adjudicate their relationship to the study drug.

      DSMB Independent group to review the safety and efficacy data during the study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: To evaluate the effect of Pirfenidone on the change in FEV1 in liters over 6 months in lung transplant recipients with bronchiolitis obliterans syndrome.
time frame: 6 months
measure: - Categorical percentage change in FEV1
time frame: 6 months
measure: - Change in Forced Vital Capacity (FVC)
time frame: 6 months
measure: - Change in Total Lung Capacity (TLC)
time frame: 6 months
measure: - Change in FEV1/FVC ratio
time frame: 6 months
measure: - Number of patients with treatment failure
time frame: 6 months
measure: - Change in BOS grade
time frame: 6 months
measure: - Change in percent predicted diffusion capacity (DLCO)
time frame: 6 months
measure: - Change in functional level as assessed by the 6MWT
time frame: 6 months
measure: - Hospital admission for any reason
time frame: 6 months
measure: - Death or re-transplantation rates
time frame: 6 months
measure: - Change in QoL as assessed by EQ5D
time frame: 6 months
arm group label: Placebo
arm group type: Placebo Comparator
description: Receive placebo tablets
arm group label: Pirfenidone
arm group type: Active Comparator
description: Upon enrollment, subjects will be randomized to either the treatment group (Pirfenidone) or to the placebo group (1:1 ratio). The trial medication will be administered as 267-mg oral capsules and titrated to a maintenance dose of 2403 mg/d (3 capsules TID, for a total of 9 capsules/day).
intervention type: Drug
intervention name: Pirfenidone
description: Receive tablets with pirfenidone
arm group label: Pirfenidone
other name: Esbriet
intervention type: Drug
intervention name: Placebo
description: Recieve tablets with placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Perch, MD
role: Principal Investigator
affiliation: Rigshospitalet, Denmark
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: Denmark
country: Germany
country: Netherlands
country: Norway
country: Sweden
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Michael Perch
investigator title: Medical Director Danish National Lung Transplant Program
mesh term: Bronchiolitis
mesh term: Bronchiolitis Obliterans
mesh term: Bronchiolitis Obliterans Syndrome
mesh term: Pirfenidone