<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/NCT01690247</url>
  </required_header>
  <id_info>
    <org_study_id>Beijing302-008</org_study_id>
    <nct_id>NCT01690247</nct_id>
  </id_info>
  <brief_title>Human Mesenchymal Stem Cells Induce Liver Transplant Tolerance</brief_title>
  <official_title>Human Umbilical Cord Mesenchymal Stem Cell Induce Liver Allografts Tolerance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beijing 302 Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Beijing 302 Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Liver transplantation is the only lifesaving intervention for patients with end-stage liver&#xD;
      diseases. Despite the ability of current immunosuppressive agents to reduce the incidence of&#xD;
      acute rejection, the rate of acute rejection reaches to 20-50% after liver transplantation.&#xD;
      Furthermore, the long-term toxicity associated with current regimens for liver transplant&#xD;
      recipients now is increasingly being perceived as an unmet clinical need. Mesenchymal stem&#xD;
      cells (MSC) appeared to be effective in regulating the invoked immune response in setting&#xD;
      such as tissue injury, transplantation, and autoimmunity, and have been used successfully to&#xD;
      treat graft versus host disease and show immune modulation function both in vitro and in vivo&#xD;
      and may help in repairing damaged tissue(s). Here, we evaluate umbilical cord derived MSC&#xD;
      (UC-MSC) as an alternative immunosuppressive agents for liver transplanted patients, and&#xD;
      examine if UC-MSC could improve the recovery of liver function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Liver transplantation is the only lifesaving intervention for patients with end-stage liver&#xD;
      diseases. The current immunosuppressive agents reduce the incidence of acute cellular&#xD;
      rejection; however, the rate of acute rejection reaches to 20-50% after liver&#xD;
      transplantation. Furthermore, the long-term side effects of these regimens now has become a&#xD;
      major challenge for liver transplant recipients and is increasingly being perceived as an&#xD;
      unmet clinical need, for example, increases in the incidence of bacterial, viral infections,&#xD;
      nephrotoxicity with chronic renal impairment, de novo diabetes mellitus, hyperlipidemia,&#xD;
      arterial hypertension, cardiovascular disease, osteoporosis, neurotoxicity, hematological&#xD;
      toxicity.&#xD;
&#xD;
      Mesenchymal stem cells (MSC) appeared to be effective in regulating the invoked immune&#xD;
      response in setting such as tissue injury, transplantation, and autoimmunity, and have been&#xD;
      used successfully to treat graft versus host disease and show immune modulation function both&#xD;
      in vitro and in vivo and may help in repairing damaged tissue(s). Current clinical trails&#xD;
      demonstrated that the use of autologous bone marrow MSC (BM-MSC) for renal transplanted&#xD;
      patients resulted in lower incidence of acute rejection, decreased risk of opportunistic&#xD;
      infection, and better estimated renal function. Compared with BM-MSC, umbilical cord derived&#xD;
      MSC (UC-MSC) may be the better choice for clinical application. One main reason is that the&#xD;
      collection of BM-MSC from liver transplanted patients would be harmful for the patients.&#xD;
      Moreover, the proliferative abilities of BM-MSC from patients with liver disease are&#xD;
      deficient, whereas, UC-MSC can be obtained from discarded umbilical cords and can be produced&#xD;
      on a larger scale. Our and other studies reported that the infusion of human UC-MSC are&#xD;
      feasible and can improve liver function of liver fibrosis and liver failure.&#xD;
&#xD;
      The purpose of this study is to learn whether and how UC-MSC can improve the conditions in&#xD;
      liver transplanted patients. This study will also look at how well UC-MSC is tolerated and&#xD;
      its safety in liver transplanted patients.&#xD;
&#xD;
      Participants in the study will be randomly assigned to one of two treatment arms:&#xD;
&#xD;
      Arm A: Participants will receive 12 weeks of standard regular immunosuppressive agents plus&#xD;
      UC-MSC treatment. Arm B: Participants will receive 12 weeks of standard regular&#xD;
      immunosuppressive agents plus placebo. UC-MSC will be prepared according to standard&#xD;
      procedures and is collected in plastic bags containing anti coagulant. MSCs are given via&#xD;
      i.v. under sonography monitoring. After UC-MSC transfusion, patients are followed up at week&#xD;
      4, 8, 12, 24, 36 and 48, and the evaluation of liver function recovery was performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>February 2012</start_date>
  <completion_date type="Anticipated">February 2015</completion_date>
  <primary_completion_date type="Anticipated">February 2014</primary_completion_date>
  <phase>Phase 1</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence rate of acute rejection and early liver function recovery</measure>
    <time_frame>48 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patient and graft survival, and prevalence of adverse events</measure>
    <time_frame>48 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Evidence of Liver Transplantation</condition>
  <arm_group>
    <arm_group_label>Conventional plus UC-MSC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive conventional treatment plus a dose of UC-MSC from day 0 through the week 12 study visit. Participants will then be followed until the week 48 study visit</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Conventional plus placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive conventional plus placebo treatment from day 0 through the week 12 study visit. Participants will then be followed until the week 48 study visit.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Conventional plus UC-MSC</intervention_name>
    <description>Received conventional treatment and taken i.v., once per 4 week, at a dose of 1×106 UC-MSC/kg body weight for 12 weeks.</description>
    <arm_group_label>Conventional plus UC-MSC</arm_group_label>
    <other_name>Immunosuppressive agents plus umbilical cord stem cells</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Conventional plus placebo</intervention_name>
    <description>Received conventional treatment and taken i.v., once per 4 week, at 50 ml saline for 12 weeks.</description>
    <arm_group_label>Conventional plus placebo</arm_group_label>
    <other_name>Immunosuppressive agents plus saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent.&#xD;
&#xD;
          2. Patients must be between the ages of 18 and 70 years and meet the criteria for liver&#xD;
             transplantation.&#xD;
&#xD;
          3. Patient is receiving the first liver transplant.&#xD;
&#xD;
          4. Patient is receiving a liver transplant only.&#xD;
&#xD;
          5. Negative pregnancy test (female patients in fertile age).&#xD;
&#xD;
          6. Willing to comply with the study visits.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previously received or is receiving an organ transplant other than a liver.&#xD;
&#xD;
          2. Vital organs failure (Cardiac, Renal or Respiratory, et al).&#xD;
&#xD;
          3. Currently receiving an investigational drug or received an investigational drug within&#xD;
             30 days prior to transplant.&#xD;
&#xD;
          4. Currently receiving any immunosuppressive agent.&#xD;
&#xD;
          5. Clinically active bacterial, fungal, viral or parasitic infection.&#xD;
&#xD;
          6. Pregnant or lactating women.&#xD;
&#xD;
          7. Other candidates who are judged to be not applicable to this study by investigators.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Fu-Sheng Wang, PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beijing 302 Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Fu-Sheng Wang, PHD</last_name>
    <phone>86-10-63879735</phone>
    <phone_ext>2015.12</phone_ext>
    <email>fswang302@163.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ming Shi, PHD</last_name>
    <phone>86-10-63879735</phone>
    <phone_ext>2015.12</phone_ext>
    <email>shiming302@sina.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Beijing 302 Hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100039</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Fu-Sheng Wang, PHD</last_name>
      <phone>86-10-63879735</phone>
      <phone_ext>2015.12</phone_ext>
      <email>fswang302@163.com</email>
    </contact>
    <contact_backup>
      <last_name>Ming Shi, PHD</last_name>
      <phone>86-10-63879735</phone>
      <phone_ext>2015.12</phone_ext>
      <email>shiming302@sina.com</email>
    </contact_backup>
    <investigator>
      <last_name>Fu-Sheng Wang, PHD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Zhenwen Liu, Doctor</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ming Shi, PHD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <results_reference>
    <citation>Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, Sun X, Chen J, Yang S, Cai J, Gao X, Pileggi A, Ricordi C. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 2012 Mar 21;307(11):1169-77. doi: 10.1001/jama.2012.316.</citation>
    <PMID>22436957</PMID>
  </results_reference>
  <results_reference>
    <citation>Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P, Cortinovis M, Marasa M, Golay J, Noris M, Remuzzi G. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011 Feb;6(2):412-22. doi: 10.2215/CJN.04950610. Epub 2010 Oct 7.</citation>
    <PMID>20930086</PMID>
  </results_reference>
  <results_reference>
    <citation>Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008 May 10;371(9624):1579-86. doi: 10.1016/S0140-6736(08)60690-X.</citation>
    <PMID>18468541</PMID>
  </results_reference>
  <results_reference>
    <citation>Shi M, Liu ZW, Wang FS. Immunomodulatory properties and therapeutic application of mesenchymal stem cells. Clin Exp Immunol. 2011 Apr;164(1):1-8. doi: 10.1111/j.1365-2249.2011.04327.x. Epub 2011 Feb 24.</citation>
    <PMID>21352202</PMID>
  </results_reference>
  <results_reference>
    <citation>Zhang Z, Lin H, Shi M, Xu R, Fu J, Lv J, Chen L, Lv S, Li Y, Yu S, Geng H, Jin L, Lau GK, Wang FS. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:112-20. doi: 10.1111/j.1440-1746.2011.07024.x.</citation>
    <PMID>22320928</PMID>
  </results_reference>
  <verification_date>May 2013</verification_date>
  <study_first_submitted>September 19, 2012</study_first_submitted>
  <study_first_submitted_qc>September 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 21, 2012</study_first_posted>
  <last_update_submitted>May 30, 2013</last_update_submitted>
  <last_update_submitted_qc>May 30, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 31, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beijing 302 Hospital</investigator_affiliation>
    <investigator_full_name>Fu-Sheng Wang</investigator_full_name>
    <investigator_title>Research Center for Biotherapy</investigator_title>
  </responsible_party>
  <keyword>mesenchymal stem cells</keyword>
  <keyword>liver transplantation</keyword>
  <keyword>clinical trial</keyword>
  <keyword>rejection</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunosuppressive Agents</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/NCT01690247
org study id: Beijing302-008
nct id: NCT01690247
lead sponsor: 
has dmc: Yes
Liver transplantation is the only lifesaving intervention for patients with end-stage liver
      diseases. Despite the ability of current immunosuppressive agents to reduce the incidence of
      acute rejection, the rate of acute rejection reaches to 20-50% after liver transplantation.
      Furthermore, the long-term toxicity associated with current regimens for liver transplant
      recipients now is increasingly being perceived as an unmet clinical need. Mesenchymal stem
      cells (MSC) appeared to be effective in regulating the invoked immune response in setting
      such as tissue injury, transplantation, and autoimmunity, and have been used successfully to
      treat graft versus host disease and show immune modulation function both in vitro and in vivo
      and may help in repairing damaged tissue(s). Here, we evaluate umbilical cord derived MSC
      (UC-MSC) as an alternative immunosuppressive agents for liver transplanted patients, and
      examine if UC-MSC could improve the recovery of liver function.
Liver transplantation is the only lifesaving intervention for patients with end-stage liver
      diseases. The current immunosuppressive agents reduce the incidence of acute cellular
      rejection; however, the rate of acute rejection reaches to 20-50% after liver
      transplantation. Furthermore, the long-term side effects of these regimens now has become a
      major challenge for liver transplant recipients and is increasingly being perceived as an
      unmet clinical need, for example, increases in the incidence of bacterial, viral infections,
      nephrotoxicity with chronic renal impairment, de novo diabetes mellitus, hyperlipidemia,
      arterial hypertension, cardiovascular disease, osteoporosis, neurotoxicity, hematological
      toxicity.

      Mesenchymal stem cells (MSC) appeared to be effective in regulating the invoked immune
      response in setting such as tissue injury, transplantation, and autoimmunity, and have been
      used successfully to treat graft versus host disease and show immune modulation function both
      in vitro and in vivo and may help in repairing damaged tissue(s). Current clinical trails
      demonstrated that the use of autologous bone marrow MSC (BM-MSC) for renal transplanted
      patients resulted in lower incidence of acute rejection, decreased risk of opportunistic
      infection, and better estimated renal function. Compared with BM-MSC, umbilical cord derived
      MSC (UC-MSC) may be the better choice for clinical application. One main reason is that the
      collection of BM-MSC from liver transplanted patients would be harmful for the patients.
      Moreover, the proliferative abilities of BM-MSC from patients with liver disease are
      deficient, whereas, UC-MSC can be obtained from discarded umbilical cords and can be produced
      on a larger scale. Our and other studies reported that the infusion of human UC-MSC are
      feasible and can improve liver function of liver fibrosis and liver failure.

      The purpose of this study is to learn whether and how UC-MSC can improve the conditions in
      liver transplanted patients. This study will also look at how well UC-MSC is tolerated and
      its safety in liver transplanted patients.

      Participants in the study will be randomly assigned to one of two treatment arms:

      Arm A: Participants will receive 12 weeks of standard regular immunosuppressive agents plus
      UC-MSC treatment. Arm B: Participants will receive 12 weeks of standard regular
      immunosuppressive agents plus placebo. UC-MSC will be prepared according to standard
      procedures and is collected in plastic bags containing anti coagulant. MSCs are given via
      i.v. under sonography monitoring. After UC-MSC transfusion, patients are followed up at week
      4, 8, 12, 24, 36 and 48, and the evaluation of liver function recovery was performed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence rate of acute rejection and early liver function recovery
time frame: 48 weeks
measure: Patient and graft survival, and prevalence of adverse events
time frame: 48 weeks
arm group label: Conventional plus UC-MSC
arm group type: Experimental
description: Participants will receive conventional treatment plus a dose of UC-MSC from day 0 through the week 12 study visit. Participants will then be followed until the week 48 study visit
arm group label: Conventional plus placebo
arm group type: Placebo Comparator
description: Participants will receive conventional plus placebo treatment from day 0 through the week 12 study visit. Participants will then be followed until the week 48 study visit.
intervention type: Drug
intervention name: Conventional plus UC-MSC
description: Received conventional treatment and taken i.v., once per 4 week, at a dose of 1×106 UC-MSC/kg body weight for 12 weeks.
arm group label: Conventional plus UC-MSC
other name: Immunosuppressive agents plus umbilical cord stem cells
intervention type: Drug
intervention name: Conventional plus placebo
description: Received conventional treatment and taken i.v., once per 4 week, at 50 ml saline for 12 weeks.
arm group label: Conventional plus placebo
other name: Immunosuppressive agents plus saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Fu-Sheng Wang, PHD
role: Principal Investigator
affiliation: Beijing 302 Hospital
last name: Fu-Sheng Wang, PHD
phone: 86-10-63879735
phone ext: 2015.12
email: fswang302@163.com
last name: Ming Shi, PHD
phone: 86-10-63879735
phone ext: 2015.12
email: shiming302@sina.com
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
country: China
citation: Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, Sun X, Chen J, Yang S, Cai J, Gao X, Pileggi A, Ricordi C. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 2012 Mar 21;307(11):1169-77. doi: 10.1001/jama.2012.316.
PMID: 22436957
citation: Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P, Cortinovis M, Marasa M, Golay J, Noris M, Remuzzi G. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011 Feb;6(2):412-22. doi: 10.2215/CJN.04950610. Epub 2010 Oct 7.
PMID: 20930086
citation: Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008 May 10;371(9624):1579-86. doi: 10.1016/S0140-6736(08)60690-X.
PMID: 18468541
citation: Shi M, Liu ZW, Wang FS. Immunomodulatory properties and therapeutic application of mesenchymal stem cells. Clin Exp Immunol. 2011 Apr;164(1):1-8. doi: 10.1111/j.1365-2249.2011.04327.x. Epub 2011 Feb 24.
PMID: 21352202
citation: Zhang Z, Lin H, Shi M, Xu R, Fu J, Lv J, Chen L, Lv S, Li Y, Yu S, Geng H, Jin L, Lau GK, Wang FS. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:112-20. doi: 10.1111/j.1440-1746.2011.07024.x.
PMID: 22320928
responsible party type: Principal Investigator
investigator affiliation: Beijing 302 Hospital
investigator full name: Fu-Sheng Wang
investigator title: Research Center for Biotherapy
mesh term: Immunosuppressive Agents