<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/NCT03000296</url>
  </required_header>
  <id_info>
    <org_study_id>autocrohnproject1</org_study_id>
    <nct_id>NCT03000296</nct_id>
  </id_info>
  <brief_title>Autologous Unselected Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease</brief_title>
  <acronym>AutoChron</acronym>
  <official_title>Autologous Unselected Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beneficência Portuguesa de São Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Beneficência Portuguesa de São Paulo</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the safety and clinical benefits of a therapeutic approach using the&#xD;
      cyclophosphamide (Cy) + thymoglobulin® (ATG) + granulocyte colony-stimulating factor (G-CSF)&#xD;
      conditioning regimen followed by autologous hematopoietic stem cell transplantation (HSCT)&#xD;
      rescue in the treatment of refractory Crohn's disease. Adverse events, and clinical and&#xD;
      endoscopic conditions will be assessed at different short and long-term time points.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Crohn's disease (CD) is a chronic, refractory inflammatory bowel disease that affects the&#xD;
      entire digestive tract associated with intestinal and extra intestinal manifestations or&#xD;
      other autoimmune diseases. Conventional therapy for Crohn's disease includes&#xD;
      anti-inflammatory, immunosuppressant and/or biologic drugs/corticosteroids. This treatment&#xD;
      benefits the majority of patients. However, a proportion of patients fail to achieve complete&#xD;
      and long-term disease control and often require multiple intestinal surgeries with a risk of&#xD;
      developing short bowel syndrome.&#xD;
&#xD;
      Hematopoietic stem cell transplantation (HSCT) has been proposed to cause lymphoablation and&#xD;
      reset of the immune system as an alternative strategy to induce long-term disease control in&#xD;
      this high-risk population.&#xD;
&#xD;
      This study enrolled Crohn's disease patients not responsive to conventional therapy.&#xD;
&#xD;
      Initially safety and the clinical outcome will be evaluated. The selected patients will be&#xD;
      admitted to the bone marrow transplant (BMT) unit for the mobilization regimen using&#xD;
      cyclophosphamide (Cy - 60 mg/kg) and G-CSF (10 mcg/kg/day) from the 5th day after Cy&#xD;
      administration until harvesting progenitor cells from peripheral blood by leukapheresis.&#xD;
&#xD;
      After seven days of rest, the conditioning regimen consists of Cy (200 mg/kg total dose for&#xD;
      four days), rabbit antithymocyte globulin (6.5 mg/kg total dose for four days) and&#xD;
      methylprednisolone (500 mg/day).&#xD;
&#xD;
      The clinical course of patients with refractory Crohn´s disease will be evaluated to&#xD;
      determine the efficacy of HSCT as a therapeutic tool including the adverse aspects of the&#xD;
      procedure, clinical outcome and quality of life.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>October 2013</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of unselected autologous HSCT in refractory Crohn´s disease patients</measure>
    <time_frame>12 months</time_frame>
    <description>HHSCT safety will be analyzed by laboratory tests and treatment-related adverse events. Safety will be evaluated by treatment-related adverse events. All adverse events will be recorded in a standardized way and their relationship to the study protocol will be assessed at different short- and long-term time points.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Crohn´s Disease Activity Index (CDAI)</measure>
    <time_frame>12 months</time_frame>
    <description>Duration of disease remission, defined as a CDAI ≤ 150, will be assessed at 1, 3, 6, 12 and 24 months after transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CRAIG Crohn´s Severity Score (CSS)</measure>
    <time_frame>12 months</time_frame>
    <description>The CRAIG CSS will be assessed at 1, 3, 6, 12 and 24 months after transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory Bowel Disease Questionnaire (IBDQ)</measure>
    <time_frame>24 months</time_frame>
    <description>The IBDQ will be administered at 1, 3, 6, 12 and 24 months after transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Short Form-36 Health Survey (SF-36)</measure>
    <time_frame>24 months</time_frame>
    <description>The SF-36 will be administered at 1, 3, 6, 12 and 24 months after transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Simple Endoscopic Activity Score (SES)</measure>
    <time_frame>24 months</time_frame>
    <description>The SES will be assessed at 6, 12 and 24 months after HSCT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Crohn's Disease Endoscopic Index of Severity (CDEIS)</measure>
    <time_frame>24 months</time_frame>
    <description>The CDEIS will be assessed at 6, 12 and 24 months after HSCT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rutgeerts endoscopic score</measure>
    <time_frame>24 months</time_frame>
    <description>Rutgeerts endoscopic score will be assessed at 6, 12 and 24 months after HSCT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Harvey &amp; Bradshaw Index (HBI)</measure>
    <time_frame>24 months</time_frame>
    <description>The HBI will be assessed at 1, 3, 6, 12 and 24 months after HSCT.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Crohn's Disease</condition>
  <condition>Inflammatory Bowel Diseases</condition>
  <condition>Gastroenteritis</condition>
  <arm_group>
    <arm_group_label>Hematopoietic Stem Cell Transplantation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>High doses immunosuppression Cyclophosphamide (200 mg/kg total dose for four days) and rabbit antithymocyte globulin (6.5 mg/kg total dose for four days) followed by unselected autologous hematopoietic stem cell transplantation rescue.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Autologous Hematopoietic Stem Cell Transplantation</intervention_name>
    <description>Hematopoietic stem cell transplantation Lymphoablation followed by hematopoietic stem cell transplantation to rescue the immune system.</description>
    <arm_group_label>Hematopoietic Stem Cell Transplantation</arm_group_label>
    <other_name>Bone Marrow Transplantation</other_name>
    <other_name>Hematopoietic Stem Cell Transplatation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age between 14 and 50 years (patients aged 50 - 70 can participate at the principal&#xD;
             investigators discretion).&#xD;
&#xD;
          2. Confirmed diagnosis of active Crohn's disease:&#xD;
&#xD;
               -  Diagnosis of Crohn's disease based on typical radiological findingsand or typical&#xD;
                  histology at least 6 months prior to screening.&#xD;
&#xD;
               -  Active disease at the time of registration to the trial, defined as&#xD;
&#xD;
                  *Crohn's Disease Activity Index (CDAI) &gt; 150, and ii) Two of the following:&#xD;
&#xD;
               -  Harvey Bradshaw Index &gt; 4&#xD;
&#xD;
               -  Endoscopic evidence of active disease confirmed by histology&#xD;
&#xD;
               -  Clear evidence of active small bowel Crohn's disease on computed tomography (CT)&#xD;
                  or magnetic resonance (MR) enterography.&#xD;
&#xD;
          3. Unsatisfactory course despite immunosuppressive agents (usually azathioprine,&#xD;
             methotrexate and two biologic agents (normally infliximab, adalimumab and/or&#xD;
             certolizumab) in addition to corticosteroids. Patients should have relapsing and&#xD;
             refractory disease despite thiopurines, methotrexate and/or&#xD;
             infliximab/adalimumab/certolizumab maintenance therapy or clear demonstration of&#xD;
             intolerance / toxicity to these drugs.&#xD;
&#xD;
          4. Current problems unsuitable for surgery or patient at risk for developing short bowel&#xD;
             syndrome.&#xD;
&#xD;
          5. Informed consent:&#xD;
&#xD;
               -  Prepared to undergo additional study procedures as per trial schedule&#xD;
&#xD;
               -  Patient has undergone intensive counseling about risks&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or unwillingness to use adequate contraception during the study, in women of&#xD;
             childbearing age. Unwillingness of using appropriate contraceptive measures in males.&#xD;
&#xD;
          2. Concomitant severe disease&#xD;
&#xD;
               -  renal: creatinine clearance &lt; 30 mL/min (measured or estimated)&#xD;
&#xD;
               -  cardiac: clinical evidence of refractory congestive heart failure; left&#xD;
                  ventricular ejection fraction &lt; 40% by multigated radionuclide angiography (MUGA)&#xD;
                  or cardiac echo; chronic atrial fibrillation necessitating oral anticoagulation;&#xD;
                  uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic&#xD;
                  consequences as evaluated by an experienced echo cardiographer.&#xD;
&#xD;
               -  pulmonary: diffusion capacity &lt;40%&#xD;
&#xD;
               -  psychiatric disorders including active drug or alcohol abuse&#xD;
&#xD;
               -  concurrent or recent history of malignant disease (excluding non-melanoma skin&#xD;
                  cancer)&#xD;
&#xD;
               -  uncontrolled hypertension, defined as resting systolic blood pressure ≥ 140&#xD;
                  and/or resting diastolic pressure ≥ 90 despite at least 2 anti-hypertensive&#xD;
                  agents.&#xD;
&#xD;
               -  uncontrolled acute or chronic infection with HIV, Human T-lymphotropic virus&#xD;
                  (HTLV-1 or 2), hepatitis viruses or any other infection the investigators&#xD;
                  consider a contraindication to participation.&#xD;
&#xD;
               -  other chronic disease causing significant organ failure.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>14 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Milton A Ruiz, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beneficencia Portuguesa</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beneficencia Portuguesa</name>
      <address>
        <city>Sao Jose do Rio Preto</city>
        <state>SP</state>
        <zip>15015-750</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>December 9, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 22, 2016</study_first_posted>
  <last_update_submitted>January 13, 2021</last_update_submitted>
  <last_update_submitted_qc>January 13, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 15, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beneficência Portuguesa de São Paulo</investigator_affiliation>
    <investigator_full_name>Milton Artur Ruiz</investigator_full_name>
    <investigator_title>MD,PhD.</investigator_title>
  </responsible_party>
  <keyword>autologous</keyword>
  <keyword>lymphoablation</keyword>
  <keyword>hematopoetic stem cell transplant</keyword>
  <keyword>immune system</keyword>
  <keyword>Bone marrow transplant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Crohn Disease</mesh_term>
    <mesh_term>Inflammatory Bowel Diseases</mesh_term>
    <mesh_term>Gastroenteritis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The main objective is to observe the safety and clinical benefit of autologous HSCT therapy in refractory patients with Crohn's disease. Evaluation during transplant period and 1, 3, 6, 12 and 24 months post-transplant. Safety be evaluated by the amount of treatment-related adverse events. Record adverse events in a standardized way. Secondary outcome measures will be disease remission: 1, 3, 6, 12 and 24 months post-transplant both clinical and endoscopic remission. The percentage of patients in sustained disease remission at 1, 3, 6, 12 and 24 months post HSCT will be determined. Sustained disease remission is defined as a CDAI &lt; 150; HBI &lt;4, CCSI&lt; 16, without the use of corticosteroids, immunosuppressant or biologic agents. Mucosal healing will be assessed during ileocolonoscopy at 6, 12, and 24 months following HSCT using SES, CDEIS and Rutgeerts endoscopy index. Heath Quality life, Short Form 36 and IBDQ at 1 3 6 12 and 24 months post-Transplant.</ipd_description>
  </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/NCT03000296
org study id: autocrohnproject1
nct id: NCT03000296
lead sponsor: 
has dmc: Yes
This study evaluates the safety and clinical benefits of a therapeutic approach using the
      cyclophosphamide (Cy) + thymoglobulin® (ATG) + granulocyte colony-stimulating factor (G-CSF)
      conditioning regimen followed by autologous hematopoietic stem cell transplantation (HSCT)
      rescue in the treatment of refractory Crohn's disease. Adverse events, and clinical and
      endoscopic conditions will be assessed at different short and long-term time points.
Crohn's disease (CD) is a chronic, refractory inflammatory bowel disease that affects the
      entire digestive tract associated with intestinal and extra intestinal manifestations or
      other autoimmune diseases. Conventional therapy for Crohn's disease includes
      anti-inflammatory, immunosuppressant and/or biologic drugs/corticosteroids. This treatment
      benefits the majority of patients. However, a proportion of patients fail to achieve complete
      and long-term disease control and often require multiple intestinal surgeries with a risk of
      developing short bowel syndrome.

      Hematopoietic stem cell transplantation (HSCT) has been proposed to cause lymphoablation and
      reset of the immune system as an alternative strategy to induce long-term disease control in
      this high-risk population.

      This study enrolled Crohn's disease patients not responsive to conventional therapy.

      Initially safety and the clinical outcome will be evaluated. The selected patients will be
      admitted to the bone marrow transplant (BMT) unit for the mobilization regimen using
      cyclophosphamide (Cy - 60 mg/kg) and G-CSF (10 mcg/kg/day) from the 5th day after Cy
      administration until harvesting progenitor cells from peripheral blood by leukapheresis.

      After seven days of rest, the conditioning regimen consists of Cy (200 mg/kg total dose for
      four days), rabbit antithymocyte globulin (6.5 mg/kg total dose for four days) and
      methylprednisolone (500 mg/day).

      The clinical course of patients with refractory Crohn´s disease will be evaluated to
      determine the efficacy of HSCT as a therapeutic tool including the adverse aspects of the
      procedure, clinical outcome and quality of life.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety of unselected autologous HSCT in refractory Crohn´s disease patients
time frame: 12 months
description: HHSCT safety will be analyzed by laboratory tests and treatment-related adverse events. Safety will be evaluated by treatment-related adverse events. All adverse events will be recorded in a standardized way and their relationship to the study protocol will be assessed at different short- and long-term time points.
measure: Crohn´s Disease Activity Index (CDAI)
time frame: 12 months
description: Duration of disease remission, defined as a CDAI ≤ 150, will be assessed at 1, 3, 6, 12 and 24 months after transplant.
measure: CRAIG Crohn´s Severity Score (CSS)
time frame: 12 months
description: The CRAIG CSS will be assessed at 1, 3, 6, 12 and 24 months after transplant.
measure: Inflammatory Bowel Disease Questionnaire (IBDQ)
time frame: 24 months
description: The IBDQ will be administered at 1, 3, 6, 12 and 24 months after transplant.
measure: Short Form-36 Health Survey (SF-36)
time frame: 24 months
description: The SF-36 will be administered at 1, 3, 6, 12 and 24 months after transplant.
measure: Simple Endoscopic Activity Score (SES)
time frame: 24 months
description: The SES will be assessed at 6, 12 and 24 months after HSCT.
measure: Crohn's Disease Endoscopic Index of Severity (CDEIS)
time frame: 24 months
description: The CDEIS will be assessed at 6, 12 and 24 months after HSCT.
measure: Rutgeerts endoscopic score
time frame: 24 months
description: Rutgeerts endoscopic score will be assessed at 6, 12 and 24 months after HSCT.
measure: Harvey & Bradshaw Index (HBI)
time frame: 24 months
description: The HBI will be assessed at 1, 3, 6, 12 and 24 months after HSCT.
arm group label: Hematopoietic Stem Cell Transplantation
arm group type: Experimental
description: High doses immunosuppression Cyclophosphamide (200 mg/kg total dose for four days) and rabbit antithymocyte globulin (6.5 mg/kg total dose for four days) followed by unselected autologous hematopoietic stem cell transplantation rescue.
intervention type: Procedure
intervention name: Autologous Hematopoietic Stem Cell Transplantation
description: Hematopoietic stem cell transplantation Lymphoablation followed by hematopoietic stem cell transplantation to rescue the immune system.
arm group label: Hematopoietic Stem Cell Transplantation
other name: Bone Marrow Transplantation
other name: Hematopoietic Stem Cell Transplatation
criteria: 
gender: All
minimum age: 14 Years
maximum age: 70 Years
healthy volunteers: No
last name: Milton A Ruiz, MD, PhD
role: Principal Investigator
affiliation: Beneficencia Portuguesa
facility: 
country: Brazil
responsible party type: Principal Investigator
investigator affiliation: Beneficência Portuguesa de São Paulo
investigator full name: Milton Artur Ruiz
investigator title: MD,PhD.
mesh term: Crohn Disease
mesh term: Inflammatory Bowel Diseases
mesh term: Gastroenteritis
sharing ipd: Yes
ipd description: The main objective is to observe the safety and clinical benefit of autologous HSCT therapy in refractory patients with Crohn's disease. Evaluation during transplant period and 1, 3, 6, 12 and 24 months post-transplant. Safety be evaluated by the amount of treatment-related adverse events. Record adverse events in a standardized way. Secondary outcome measures will be disease remission: 1, 3, 6, 12 and 24 months post-transplant both clinical and endoscopic remission. The percentage of patients in sustained disease remission at 1, 3, 6, 12 and 24 months post HSCT will be determined. Sustained disease remission is defined as a CDAI < 150; HBI <4, CCSI< 16, without the use of corticosteroids, immunosuppressant or biologic agents. Mucosal healing will be assessed during ileocolonoscopy at 6, 12, and 24 months following HSCT using SES, CDEIS and Rutgeerts endoscopy index. Heath Quality life, Short Form 36 and IBDQ at 1 3 6 12 and 24 months post-Transplant.