xml: <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/NCT05985863</url>
    </required_header>
    <id_info>
      <org_study_id>2022YFC2304402</org_study_id>
      <nct_id>NCT05985863</nct_id>
    </id_info>
    <brief_title>Human Umbilical Cord Mesenchymal Stem Cell Transplantation for The Treatment of Acute-on-Chronic Liver Failure</brief_title>
    <official_title>Clinical Research of Human Umbilical Cord Mesenchymal Stem Cell Transplantation for The Treatment of Acute-on-Chronic Liver Failure</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Beijing 302 Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Shulan (Hang Zhou) Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>BeijingYouan Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Shenzhen Third People's Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Shen Zhen Wingor Biotechnology CO. LTD</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Beijing 302 Hospital</source>
    <oversight_info>
      <has_dmc>No</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>
        This study is a randomized double-blind placebo-controlled multicenter clinical trial to&#xD;
        evaluate the safety and efficacy of human umbilical cord mesenchymal stem cell (UC-MSC)&#xD;
        transplantation for the treatment of acute-on-chronic liver failure (ACLF). UC-MSC therapy&#xD;
        may improve the clinical outcomes of patients with ACLF. The trial would provide scientific&#xD;
        evidence for UC-MSC transplantation as a potential treatment for ACLF.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Acute-on-chronic liver failure (ACLF) has been proposed to define a distinct syndrome which&#xD;
        is characterized by an intense systemic inflammatory response, single- or multiple organ&#xD;
        system failures, and high 28-day mortality. Current treatments for liver failure are still&#xD;
        limited, and liver transplantation remains the only available approach to improve survival&#xD;
        but is restricted by a shortage of organ resources, rejection after transplantation, and&#xD;
        heavy financial costs. In the past decade, a series of new applications based on mesenchymal&#xD;
        stem cell (MSC) therapy have been studied as an alternative interventional method for chronic&#xD;
        liver diseases. This randomized double-blind placebo-controlled multicenter clinical trial is&#xD;
        aimed at determining the safety and clinical efficacy of UC-MSC transfusions in ACLF&#xD;
        patients.&#xD;
  &#xD;
        A total of 150 ACLF patients would be enrolled,100patients would be assigned to the MSC&#xD;
        intervention group and the other 50 patients would be assigned to the placebo control group.&#xD;
        This trial is two-stage randomized designed. At the first stage, the patients would be&#xD;
        randomized into two groups, the placebo short control group would receive standard medical&#xD;
        treatment plus 3 times placebo (at week0, week1 and week2), while the MSC short treatment&#xD;
        group would receive standard medical treatment plus 3 times hUC-MSC (1.5×10^8, Peripheral IV,&#xD;
        at week0, week1 and week2). The two groups would be followed up for 2 weeks, and unblinding&#xD;
        would be conducted at week4. At the second stage, the survived patients of the MSC short&#xD;
        treatment group would be further randomized and blinded into another two groups. The MSC&#xD;
        Prolonged treatment group would receive another 2 times hUC-MSC (1.5×10^8, Peripheral IV, at&#xD;
        week4 and week5), while the MSC Prolonged control group would receive 2 times placebo (at&#xD;
        week4 and week5).&#xD;
  &#xD;
        Transplantation free survival rate and incidence of treatment-emergent adverse events would&#xD;
        be the primary outcomes, and other outcomes such as international normalized ratio (INR),&#xD;
        total bilirubin (TBIL, mg/dL), serum albumin (ALB, g/L), blood urea nitrogen (BUN, mmol/l),&#xD;
        the model for end-stage liver disease(MELD) score and child-turcotte-pugh(CTP) score would&#xD;
        also be measured.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 30, 2023</start_date>
    <completion_date type="Anticipated">December 30, 2028</completion_date>
    <primary_completion_date type="Anticipated">December 30, 2026</primary_completion_date>
    <phase>Phase 1/Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Double (Participant, Investigator)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Transplantation free survival rate</measure>
      <time_frame>week1, week2, week3, week4, week5, week8, week12, week24, week53</time_frame>
      <description>Transplantation free survival rate of ACLF patients.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Incidence of Treatment-Emergent Adverse Events</measure>
      <time_frame>day0, day3, week1, week2, week3, week4, week5, week8, week12, week24, week53</time_frame>
      <description>Safety and Tolerability of UC-MSCs transplantation.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>International Normalized Ratio (INR)</measure>
      <time_frame>week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53</time_frame>
      <description>INR was introduced as a standardized reporting mechanism allowing comparisons across laboratories and patients. Consensus guidelines recommend that INR ≥ 1.5 can be used as a threshold, and current recommendations for targeting an INR of &lt; 1.5 were based on studies across all surgical disciplines.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Concentration of Total Bilirubin (TBIL, mg/dL)</measure>
      <time_frame>week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53</time_frame>
      <description>Total bilirubin refers to the concentration of bilirubin in a patient's blood sample, which is automatically measured by the laboratories in accordance with standard operating procedures. APASL defines ACLF as &quot;an acute hepatic insult manifesting as jaundice (Serum Bilirubin ≥ 5 mg/dL) and coagulopathy (international normalized ratio [INR] ≥ 1.5) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, that is associated with a high 28-day mortality.&quot;</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Concentration of Serum Albumin (ALB, g/L)</measure>
      <time_frame>week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53</time_frame>
      <description>Serum albumin refers to the concentration of albumin in a patient's serum, which is automatically measured by the laboratory in accordance with standard operating procedures. Serum albumin is an independent protective factor for 30-day prognosis in ACLF patients.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Concentration of Blood Urea Nitrogen (BUN, mmol/L)</measure>
      <time_frame>week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53</time_frame>
      <description>Blood urea nitrogen refers to the concentration of urea nitrogen in a patient's blood sample. Blood urea nitrogen is a commonly used indicator of renal function in clinic.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The Model for End-Stage Liver Disease(MELD) score</measure>
      <time_frame>week-1, week1, week2, week4, week5, week12, week24, week53</time_frame>
      <description>R = 3.8×ln [TBiL (mg/dl)] +11.2×ln (INR) +9.6×ln [Cr (mg/dl)] +6.4× (Cause: biliary or alcoholic is 0, other is 1), the result is taken as an integer. Studies have shown that the optimal critical value of MELD score to judge the short-term prognosis of ACLF patients is 30, and when MELD score is greater than 30, the case fatality rate of patients within 3 months is significantly increased.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Child-Turcotte-Pugh(CTP) score</measure>
      <time_frame>week-1, week1, week2, week4, week5, week12, week24, week53</time_frame>
      <description>CTP score is currently the most commonly used model to evaluate liver reserve function and prognosis in patients with cirrhosis. This model evaluates liver function based on HE grade, degree of abdominal fluid accumulation, bilirubin (TBiL), albumin (Alb) and prothrombin time (PT). The score ranges from 0 to 15, with the higher the score, the worse the prognosis.</description>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">150</enrollment>
    <condition>Acute-On-Chronic Liver Failure</condition>
    <arm_group>
      <arm_group_label>Group Control</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>standard medical treatment+Placebo(5% human serum albumin in 0.9% saline, at week0, week1 and week2)</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Group MSC-1</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients received standard medical treatment and infusions of hUC-MSC(1.5×10^8) via peripheral veins once a week for 3 timess(at week0, week1, and week2).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Group MSC-2</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients in Group MSC-1 received standard medical treatment and infusions of hUC-MSC(1.5×10^8) via peripheral veins once a week for another 2 timess(at week4 and week5).</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>standard medical treatment</intervention_name>
      <description>standard medical treatment for ACLF</description>
      <arm_group_label>Group Control</arm_group_label>
      <arm_group_label>Group MSC-1</arm_group_label>
      <arm_group_label>Group MSC-2</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>5% human serum albumin in 0.9% saline (at week0, week1 and week2)</description>
      <arm_group_label>Group Control</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>hUC-MSC</intervention_name>
      <description>hUC-MSC (1.5×10^8 cells/time, Peripheral IV, at week0, week1 and week2)</description>
      <arm_group_label>Group MSC-1</arm_group_label>
      <arm_group_label>Group MSC-2</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>hUC-MSC_Prolonged</intervention_name>
      <description>hUC-MSC (1.5×10^8 cells/time, Peripheral IV, at week4 and week5)</description>
      <arm_group_label>Group MSC-2</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. 18 years old ≤ age ≤ 70 years old, gender is not limited.&#xD;
  &#xD;
            2. Meet the APASL definition of ACLF: acute liver injury in patients with previously&#xD;
               diagnosed or undiagnosed chronic liver disease or cirrhosis, manifested as jaundice&#xD;
               (total bilirubin levels of 5 mg/dl or more) and coagulopathy (INR of 1.5 or more, or&#xD;
               prothrombin activity of less than 40%） complicated within 4 weeks by clinical ascites,&#xD;
               encephalopathy, or both.&#xD;
  &#xD;
            3. Willing to sign the informed consent form.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Patients with acute kidney injury, upper gastrointestinal hemorrhage, hepatic&#xD;
               encephalopathy above grade II (inclusive) or uncontrolled infection at baseline;&#xD;
  &#xD;
            2. Before the onset of liver failure, the previous indicators of the patient included&#xD;
               PLT&lt;50×10^9/L or Child-Pugh score&gt;9;&#xD;
  &#xD;
            3. Combined with liver cancer or other malignant tumors;&#xD;
  &#xD;
            4. Patients with previous liver transplantation or planned liver transplantation within 3&#xD;
               months;&#xD;
  &#xD;
            5. Severe organic disease of primary extrahepatic organs;&#xD;
  &#xD;
            6. Those who have a history of venous thrombosis or pulmonary embolism are judged by the&#xD;
               investigator to be ineligible to participate in this trial;&#xD;
  &#xD;
            7. Pregnant, breastfeeding women or those who plan to have a baby in the near future;&#xD;
  &#xD;
            8. Those who are highly allergic or have a history of severe allergies;&#xD;
  &#xD;
            9. Those who have received immunosuppressant and immune enhancer treatment within 1&#xD;
               month;&#xD;
  &#xD;
           10. Drug abuse in the past 5 years;&#xD;
  &#xD;
           11. Alcohol withdrawal symptoms;&#xD;
  &#xD;
           12. A history of severe mental disorders within 24 months before screening, including&#xD;
               uncontrolled major depression or controlled or uncontrolled psychosis;&#xD;
  &#xD;
           13. Those who have participated or are participating in other clinical trials within three&#xD;
               months before screening, or have previously received stem cell therapy;&#xD;
  &#xD;
           14. Other conditions that the investigator thinks that the patient is not suitable to&#xD;
               participate in this study.&#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>Ming Shi, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>the Fifth Medical Center, Chinese PLA General Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Tao Yang, MD</last_name>
      <phone>86-010-66933333</phone>
      <email>y_t_0321@163.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Yanhu Wang, MM</last_name>
      <phone>86-010-66933328</phone>
      <email>2440477984@qq.com</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>the Fifth Medical Center, Chinese PLA General Hospital</name>
        <address>
          <city>Beijing</city>
          <state>Beijing</state>
          <zip>100039</zip>
          <country>China</country>
        </address>
      </facility>
      <contact>
        <last_name>Tao Yang, MD</last_name>
        <phone>010-66933333</phone>
        <email>y_t_0321@163.com</email>
      </contact>
      <contact_backup>
        <last_name>Mengyao Li, MB</last_name>
        <phone>010-66933333</phone>
        <email>qianlimengyao@163.com</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <reference>
      <citation>Lin BL, Chen JF, Qiu WH, Wang KW, Xie DY, Chen XY, Liu QL, Peng L, Li JG, Mei YY, Weng WZ, Peng YW, Cao HJ, Xie JQ, Xie SB, Xiang AP, Gao ZL. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial. Hepatology. 2017 Jul;66(1):209-219. doi: 10.1002/hep.29189. Epub 2017 May 27.</citation>
      <PMID>28370357</PMID>
    </reference>
    <reference>
      <citation>Schacher FC, Martins Pezzi da Silva A, Silla LMDR, Alvares-da-Silva MR. Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial. Can J Gastroenterol Hepatol. 2021 Aug 4;2021:3662776. doi: 10.1155/2021/3662776. eCollection 2021.</citation>
      <PMID>34395335</PMID>
    </reference>
    <reference>
      <citation>Xu WX, He HL, Pan SW, Chen YL, Zhang ML, Zhu S, Gao ZL, Peng L, Li JG. Combination Treatments of Plasma Exchange and Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure: A Clinical Trial in China. Stem Cells Int. 2019 Feb 4;2019:4130757. doi: 10.1155/2019/4130757. eCollection 2019.</citation>
      <PMID>30863450</PMID>
    </reference>
    <reference>
      <citation>Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv S, He W, Geng H, Jin L, Liu Z, Wang FS. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012 Oct;1(10):725-31. doi: 10.5966/sctm.2012-0034. Epub 2012 Oct 11.</citation>
      <PMID>23197664</PMID>
    </reference>
    <reference>
      <citation>Li YH, Xu Y, Wu HM, Yang J, Yang LH, Yue-Meng W. Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation in Hepatitis B Virus Related Acute-on-Chronic Liver Failure Treated with Plasma Exchange and Entecavir: a 24-Month Prospective Study. Stem Cell Rev Rep. 2016 Dec;12(6):645-653. doi: 10.1007/s12015-016-9683-3.</citation>
      <PMID>27687792</PMID>
    </reference>
    <reference>
      <citation>Yu H, Feng Y, Du W, Zhao M, Jia H, Wei Z, Yan S, Han Z, Zhang L, Li Z, Han Z. Off-the-shelf GMP-grade UC-MSCs as therapeutic drugs for the amelioration of CCl4-induced acute-on-chronic liver failure in NOD-SCID mice. Int Immunopharmacol. 2022 Dec;113(Pt A):109408. doi: 10.1016/j.intimp.2022.109408. Epub 2022 Nov 9.</citation>
      <PMID>36461584</PMID>
    </reference>
    <reference>
      <citation>Gilsanz C, Aller MA, Fuentes-Julian S, Prieto I, Blazquez-Martinez A, Argudo S, Fernandez-Delgado J, Belena J, Arias J, De Miguel MP. Adipose-derived mesenchymal stem cells slow disease progression of acute-on-chronic liver failure. Biomed Pharmacother. 2017 Jul;91:776-787. doi: 10.1016/j.biopha.2017.04.117. Epub 2017 May 10.</citation>
      <PMID>28501004</PMID>
    </reference>
    <reference>
      <citation>Maheshwari D, Kumar D, Jagdish RK, Nautiyal N, Hidam A, Kumari R, Sehgal R, Trehanpati N, Baweja S, Kumar G, Sinha S, Bajpai M, Pamecha V, Bihari C, Maiwall R, Sarin SK, Kumar A. Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure. Front Immunol. 2022 Jun 3;13:856587. doi: 10.3389/fimmu.2022.856587. eCollection 2022.</citation>
      <PMID>35747140</PMID>
    </reference>
    <reference>
      <citation>He Y, Guo X, Lan T, Xia J, Wang J, Li B, Peng C, Chen Y, Hu X, Meng Z. Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling. Stem Cell Res Ther. 2021 Jul 13;12(1):396. doi: 10.1186/s13287-021-02468-6. Erratum In: Stem Cell Res Ther. 2022 Feb 7;13(1):65.</citation>
      <PMID>34256837</PMID>
    </reference>
    <reference>
      <citation>Lin D, Chen H, Xiong J, Zhang J, Hu Z, Gao J, Gao B, Zhang S, Chen J, Cao H, Li Z, Lin B, Gao Z. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB. Cell Death Dis. 2022 Oct 12;13(10):865. doi: 10.1038/s41419-022-05303-9.</citation>
      <PMID>36224178</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 24, 2023</study_first_submitted>
    <study_first_submitted_qc>August 3, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 31, 2023</last_update_submitted>
    <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 6, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Beijing 302 Hospital</investigator_affiliation>
      <investigator_full_name>Shi Ming</investigator_full_name>
      <investigator_title>Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases</investigator_title>
    </responsible_party>
    <keyword>Mesenchymal Stem Cells</keyword>
    <keyword>Acute-On-Chronic Liver Failure</keyword>
    <keyword>Therapeutics</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Liver Failure</mesh_term>
      <mesh_term>Hepatic Insufficiency</mesh_term>
      <mesh_term>End Stage Liver Disease</mesh_term>
      <mesh_term>Acute-On-Chronic Liver Failure</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05985863
  org study id: 2022YFC2304402
  nct id: NCT05985863
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  This study is a randomized double-blind placebo-controlled multicenter clinical trial to
        evaluate the safety and efficacy of human umbilical cord mesenchymal stem cell (UC-MSC)
        transplantation for the treatment of acute-on-chronic liver failure (ACLF). UC-MSC therapy
        may improve the clinical outcomes of patients with ACLF. The trial would provide scientific
        evidence for UC-MSC transplantation as a potential treatment for ACLF.
  Acute-on-chronic liver failure (ACLF) has been proposed to define a distinct syndrome which
        is characterized by an intense systemic inflammatory response, single- or multiple organ
        system failures, and high 28-day mortality. Current treatments for liver failure are still
        limited, and liver transplantation remains the only available approach to improve survival
        but is restricted by a shortage of organ resources, rejection after transplantation, and
        heavy financial costs. In the past decade, a series of new applications based on mesenchymal
        stem cell (MSC) therapy have been studied as an alternative interventional method for chronic
        liver diseases. This randomized double-blind placebo-controlled multicenter clinical trial is
        aimed at determining the safety and clinical efficacy of UC-MSC transfusions in ACLF
        patients.
  
        A total of 150 ACLF patients would be enrolled,100patients would be assigned to the MSC
        intervention group and the other 50 patients would be assigned to the placebo control group.
        This trial is two-stage randomized designed. At the first stage, the patients would be
        randomized into two groups, the placebo short control group would receive standard medical
        treatment plus 3 times placebo (at week0, week1 and week2), while the MSC short treatment
        group would receive standard medical treatment plus 3 times hUC-MSC (1.5×10^8, Peripheral IV,
        at week0, week1 and week2). The two groups would be followed up for 2 weeks, and unblinding
        would be conducted at week4. At the second stage, the survived patients of the MSC short
        treatment group would be further randomized and blinded into another two groups. The MSC
        Prolonged treatment group would receive another 2 times hUC-MSC (1.5×10^8, Peripheral IV, at
        week4 and week5), while the MSC Prolonged control group would receive 2 times placebo (at
        week4 and week5).
  
        Transplantation free survival rate and incidence of treatment-emergent adverse events would
        be the primary outcomes, and other outcomes such as international normalized ratio (INR),
        total bilirubin (TBIL, mg/dL), serum albumin (ALB, g/L), blood urea nitrogen (BUN, mmol/l),
        the model for end-stage liver disease(MELD) score and child-turcotte-pugh(CTP) score would
        also be measured.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Double (Participant, Investigator)
  measure: Transplantation free survival rate
  time frame: week1, week2, week3, week4, week5, week8, week12, week24, week53
  description: Transplantation free survival rate of ACLF patients.
  measure: Incidence of Treatment-Emergent Adverse Events
  time frame: day0, day3, week1, week2, week3, week4, week5, week8, week12, week24, week53
  description: Safety and Tolerability of UC-MSCs transplantation.
  measure: International Normalized Ratio (INR)
  time frame: week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
  description: INR was introduced as a standardized reporting mechanism allowing comparisons across laboratories and patients. Consensus guidelines recommend that INR ≥ 1.5 can be used as a threshold, and current recommendations for targeting an INR of < 1.5 were based on studies across all surgical disciplines.
  measure: Concentration of Total Bilirubin (TBIL, mg/dL)
  time frame: week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
  description: Total bilirubin refers to the concentration of bilirubin in a patient's blood sample, which is automatically measured by the laboratories in accordance with standard operating procedures. APASL defines ACLF as "an acute hepatic insult manifesting as jaundice (Serum Bilirubin ≥ 5 mg/dL) and coagulopathy (international normalized ratio [INR] ≥ 1.5) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, that is associated with a high 28-day mortality."
  measure: Concentration of Serum Albumin (ALB, g/L)
  time frame: week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
  description: Serum albumin refers to the concentration of albumin in a patient's serum, which is automatically measured by the laboratory in accordance with standard operating procedures. Serum albumin is an independent protective factor for 30-day prognosis in ACLF patients.
  measure: Concentration of Blood Urea Nitrogen (BUN, mmol/L)
  time frame: week-1, week0, day3, week1, week2, week3, week4, week5, week12, week24, week53
  description: Blood urea nitrogen refers to the concentration of urea nitrogen in a patient's blood sample. Blood urea nitrogen is a commonly used indicator of renal function in clinic.
  measure: The Model for End-Stage Liver Disease(MELD) score
  time frame: week-1, week1, week2, week4, week5, week12, week24, week53
  description: R = 3.8×ln [TBiL (mg/dl)] +11.2×ln (INR) +9.6×ln [Cr (mg/dl)] +6.4× (Cause: biliary or alcoholic is 0, other is 1), the result is taken as an integer. Studies have shown that the optimal critical value of MELD score to judge the short-term prognosis of ACLF patients is 30, and when MELD score is greater than 30, the case fatality rate of patients within 3 months is significantly increased.
  measure: Child-Turcotte-Pugh(CTP) score
  time frame: week-1, week1, week2, week4, week5, week12, week24, week53
  description: CTP score is currently the most commonly used model to evaluate liver reserve function and prognosis in patients with cirrhosis. This model evaluates liver function based on HE grade, degree of abdominal fluid accumulation, bilirubin (TBiL), albumin (Alb) and prothrombin time (PT). The score ranges from 0 to 15, with the higher the score, the worse the prognosis.
  arm group label: Group Control
  arm group type: Placebo Comparator
  description: standard medical treatment+Placebo(5% human serum albumin in 0.9% saline, at week0, week1 and week2)
  arm group label: Group MSC-1
  arm group type: Experimental
  description: Patients received standard medical treatment and infusions of hUC-MSC(1.5×10^8) via peripheral veins once a week for 3 timess(at week0, week1, and week2).
  arm group label: Group MSC-2
  arm group type: Experimental
  description: Patients in Group MSC-1 received standard medical treatment and infusions of hUC-MSC(1.5×10^8) via peripheral veins once a week for another 2 timess(at week4 and week5).
  intervention type: Drug
  intervention name: standard medical treatment
  description: standard medical treatment for ACLF
  arm group label: Group Control
  arm group label: Group MSC-1
  arm group label: Group MSC-2
  intervention type: Drug
  intervention name: Placebo
  description: 5% human serum albumin in 0.9% saline (at week0, week1 and week2)
  arm group label: Group Control
  intervention type: Drug
  intervention name: hUC-MSC
  description: hUC-MSC (1.5×10^8 cells/time, Peripheral IV, at week0, week1 and week2)
  arm group label: Group MSC-1
  arm group label: Group MSC-2
  intervention type: Drug
  intervention name: hUC-MSC_Prolonged
  description: hUC-MSC (1.5×10^8 cells/time, Peripheral IV, at week4 and week5)
  arm group label: Group MSC-2
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 70 Years
  healthy volunteers: No
  last name: Ming Shi, PhD
  role: Principal Investigator
  affiliation: the Fifth Medical Center, Chinese PLA General Hospital
  last name: Tao Yang, MD
  phone: 86-010-66933333
  email: y_t_0321@163.com
  last name: Yanhu Wang, MM
  phone: 86-010-66933328
  email: 2440477984@qq.com
  facility: 
  contact: 
  contact backup: 
  country: China
  citation: Lin BL, Chen JF, Qiu WH, Wang KW, Xie DY, Chen XY, Liu QL, Peng L, Li JG, Mei YY, Weng WZ, Peng YW, Cao HJ, Xie JQ, Xie SB, Xiang AP, Gao ZL. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial. Hepatology. 2017 Jul;66(1):209-219. doi: 10.1002/hep.29189. Epub 2017 May 27.
  PMID: 28370357
  citation: Schacher FC, Martins Pezzi da Silva A, Silla LMDR, Alvares-da-Silva MR. Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial. Can J Gastroenterol Hepatol. 2021 Aug 4;2021:3662776. doi: 10.1155/2021/3662776. eCollection 2021.
  PMID: 34395335
  citation: Xu WX, He HL, Pan SW, Chen YL, Zhang ML, Zhu S, Gao ZL, Peng L, Li JG. Combination Treatments of Plasma Exchange and Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure: A Clinical Trial in China. Stem Cells Int. 2019 Feb 4;2019:4130757. doi: 10.1155/2019/4130757. eCollection 2019.
  PMID: 30863450
  citation: Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv S, He W, Geng H, Jin L, Liu Z, Wang FS. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012 Oct;1(10):725-31. doi: 10.5966/sctm.2012-0034. Epub 2012 Oct 11.
  PMID: 23197664
  citation: Li YH, Xu Y, Wu HM, Yang J, Yang LH, Yue-Meng W. Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation in Hepatitis B Virus Related Acute-on-Chronic Liver Failure Treated with Plasma Exchange and Entecavir: a 24-Month Prospective Study. Stem Cell Rev Rep. 2016 Dec;12(6):645-653. doi: 10.1007/s12015-016-9683-3.
  PMID: 27687792
  citation: Yu H, Feng Y, Du W, Zhao M, Jia H, Wei Z, Yan S, Han Z, Zhang L, Li Z, Han Z. Off-the-shelf GMP-grade UC-MSCs as therapeutic drugs for the amelioration of CCl4-induced acute-on-chronic liver failure in NOD-SCID mice. Int Immunopharmacol. 2022 Dec;113(Pt A):109408. doi: 10.1016/j.intimp.2022.109408. Epub 2022 Nov 9.
  PMID: 36461584
  citation: Gilsanz C, Aller MA, Fuentes-Julian S, Prieto I, Blazquez-Martinez A, Argudo S, Fernandez-Delgado J, Belena J, Arias J, De Miguel MP. Adipose-derived mesenchymal stem cells slow disease progression of acute-on-chronic liver failure. Biomed Pharmacother. 2017 Jul;91:776-787. doi: 10.1016/j.biopha.2017.04.117. Epub 2017 May 10.
  PMID: 28501004
  citation: Maheshwari D, Kumar D, Jagdish RK, Nautiyal N, Hidam A, Kumari R, Sehgal R, Trehanpati N, Baweja S, Kumar G, Sinha S, Bajpai M, Pamecha V, Bihari C, Maiwall R, Sarin SK, Kumar A. Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure. Front Immunol. 2022 Jun 3;13:856587. doi: 10.3389/fimmu.2022.856587. eCollection 2022.
  PMID: 35747140
  citation: He Y, Guo X, Lan T, Xia J, Wang J, Li B, Peng C, Chen Y, Hu X, Meng Z. Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling. Stem Cell Res Ther. 2021 Jul 13;12(1):396. doi: 10.1186/s13287-021-02468-6. Erratum In: Stem Cell Res Ther. 2022 Feb 7;13(1):65.
  PMID: 34256837
  citation: Lin D, Chen H, Xiong J, Zhang J, Hu Z, Gao J, Gao B, Zhang S, Chen J, Cao H, Li Z, Lin B, Gao Z. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB. Cell Death Dis. 2022 Oct 12;13(10):865. doi: 10.1038/s41419-022-05303-9.
  PMID: 36224178
  responsible party type: Principal Investigator
  investigator affiliation: Beijing 302 Hospital
  investigator full name: Shi Ming
  investigator title: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases
  mesh term: Liver Failure
  mesh term: Hepatic Insufficiency
  mesh term: End Stage Liver Disease
  mesh term: Acute-On-Chronic Liver Failure
  sharing ipd: No