<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/NCT03011021</url>
  </required_header>
  <id_info>
    <org_study_id>0001</org_study_id>
    <nct_id>NCT03011021</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes</brief_title>
  <official_title>Phase 1/ Phase 2 Study of the Therapeutic Effect of Ex-vivo Expanded Umbilical Cord Blood Regulatory T Cells With Liraglutide on Autoimmune Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Second Xiangya Hospital of Central South University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Second Xiangya Hospital of Central South University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to investigate the safety and therapeutic effect of ex-vivo&#xD;
      expanded umbilical cord blood regulatory T cells adjunct with Liraglutide on autoimmune&#xD;
      diabetes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Autoimmune Diabetes Mellitus (AIDM) is a subtype of diabetes mellitus caused by autoimmune&#xD;
      destruction of beta cells in the islet, including Type 1 diabetes and Latent Autoimmune&#xD;
      Diabetes in Adults (LADA). Insulin has been used as a routine therapy for AIDM to alleviate&#xD;
      the hyperglycemic status, yet cannot effectively prevent the progressing destruction of beta&#xD;
      cells or preserve its function. Regulatory T cells expanded from umbilical cord blood&#xD;
      (UCB-Treg) ex-vivo have shown strong capacity to control immune responses in autoimmune&#xD;
      diseases, offering a hopeful therapeutic way for AIDM. Glucagon-like peptide (GLP-1) analog&#xD;
      Liraglutide has been tested in large-scale clinical trial to prove its various benefits for&#xD;
      beta cells and glucolipid metabolism in Type 2 diabetes and obesity patients. However, its&#xD;
      clinical application in AIDM is not well-defined so far. The aim of this study is to&#xD;
      investigate the potential use of Liraglutide with UCB-Treg infusion in AIDM and examine the&#xD;
      safety and efficacy of this new therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>January 2017</start_date>
  <completion_date type="Anticipated">June 2025</completion_date>
  <primary_completion_date type="Anticipated">June 2025</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Adverse effects</measure>
    <time_frame>2 years</time_frame>
    <description>Primary outcome measures will be the number of participants with adverse events, laboratory abnormalities and other signs of toxicity. Particular focus will be on the number and severity of infusion reactions, complications related to infection, and any potential negative impact on the course of diabetes.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in HbA1C</measure>
    <time_frame>2 years</time_frame>
    <description>Measure the HbA1C level after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in C-peptide</measure>
    <time_frame>2 years</time_frame>
    <description>Measure the C-peptide level after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in insulin dose</measure>
    <time_frame>2 years</time_frame>
    <description>Measure insulin dose patient used after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hypoglycaemic events</measure>
    <time_frame>2 years</time_frame>
    <description>Measure the number of participants with Hypoglycaemic events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in titer of autoantibodies</measure>
    <time_frame>2 years</time_frame>
    <description>Measure the titer of antoantibodies of participant after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in immune cells diversities and quantities.</measure>
    <time_frame>2 years</time_frame>
    <description>Measure the immune cells diversities and quantities after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in autoimmune-related cytokines</measure>
    <time_frame>2 years</time_frame>
    <description>Measure the change of autoimmune- related cytokines after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Life quality evaluation</measure>
    <time_frame>2 years</time_frame>
    <description>Number of participants with disturbance of emotion, sleep, resting or energy.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Type1 Diabetes Mellitus</condition>
  <condition>Autoimmune Diabetes</condition>
  <arm_group>
    <arm_group_label>UCB-Treg plus Liraglutide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive a single infusion of ex vivo expanded umbilical cord blood derived Treg product (2 x 10^6). Dose escalation of liraglutide up to 1.2 mg will be started 3 days after Treg infusion only if no severe side effects showed. Subjects continue to receive the reached liraglutide dose once daily for 6 months thereafter. Insulin will be continued as a routine therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>UCB-Treg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will receive a single infusion of ex vivo expanded Treg product (2 x 10^6). Insulin will be continued as a routine therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Liraglutide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will be subjected to a dose escalation of liraglutide up to 1.2 mg, then continue to receive the reached liraglutide dose once daily for 6 months thereafter. Insulin will be continued as routine therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Insulin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive insulin injection as a routine therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liraglutide</intervention_name>
    <description>Dose escalation of Liraglutide starts from 0.6 mg up to 1.2 mg per day.</description>
    <arm_group_label>Liraglutide</arm_group_label>
    <arm_group_label>UCB-Treg plus Liraglutide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>UCB-Treg</intervention_name>
    <description>Receive Treg infusion: 1~5*10^6/kg b.w. in 100ml normal saline</description>
    <arm_group_label>UCB-Treg</arm_group_label>
    <arm_group_label>UCB-Treg plus Liraglutide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Insulin</intervention_name>
    <description>Receive insulin following clinician's instruction.</description>
    <arm_group_label>Insulin</arm_group_label>
    <arm_group_label>Liraglutide</arm_group_label>
    <arm_group_label>UCB-Treg</arm_group_label>
    <arm_group_label>UCB-Treg plus Liraglutide</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 1 diabetes according to ADA criteria &lt;3 years.&#xD;
&#xD;
          -  Age≥ 18 years.&#xD;
&#xD;
          -  Positive for at least one of the anti-islet autoantibodies: GADA, IA2A, ZnT8A&#xD;
&#xD;
          -  Fasting or postprandial plasma C-peptide more than 100 pmol/L&#xD;
&#xD;
          -  Written informed consent from the patient or family representative.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History or family history of medullary thyroid carcinoma or MEN 2 syndrome;&#xD;
&#xD;
          -  History of chronic or acute pancreatitis;&#xD;
&#xD;
          -  Allergic to liraglutide or any components in Victoza®;&#xD;
&#xD;
          -  Hepatic abnormalities (transaminase &gt; 2 times normal);&#xD;
&#xD;
          -  Renal impairments (serum creatinine &gt;133 umol/L);&#xD;
&#xD;
          -  Cardiovascular diseases (hypertension, coronary heart disease, etc.);&#xD;
&#xD;
          -  Presence of anemia (Hb ≤100g/L), leukopenia (&lt;3.5×109/L);&#xD;
&#xD;
          -  Presence of disorder in coagulation or anticoagulation, or thrombocytopenia (platelets&#xD;
             &lt;100×109/L);&#xD;
&#xD;
          -  Presence of acute metabolic disorders; In the case of acute ketone acidosis, with&#xD;
             blood ketone over 0.3mmol/L and pH lower than 7.30;&#xD;
&#xD;
          -  Presence of any kind of chronic infection or immune deficiency, including hepatitis B,&#xD;
             hepatitis C, HIV, syphilis or tuberculosis, etc.;&#xD;
&#xD;
          -  Chronic use of systemic glucocorticoids or other immunosuppressive agents for over 3&#xD;
             months;&#xD;
&#xD;
          -  Any history of malignancy;&#xD;
&#xD;
          -  Female patients who are pregnant or breastfeeding; any female who is unwilling to use&#xD;
             a reliable and effective form of contraception for 2 years after recruitment;&#xD;
&#xD;
          -  Presence of any infectious diseases, including active skin infections, flu, fever,&#xD;
             upper or lower respiratory tract infections; those who wish to participate in the&#xD;
             study should keep the infection under control for at least 1 week before receiving&#xD;
             Treg product infusion;&#xD;
&#xD;
          -  Any medical condition that, in the opinion of the investigator, will interfere with&#xD;
             safe participation in the trial.&#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>Zhiguang Zhou, MD/PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Second Xiangya Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Haibo Yu, MD/PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Second Xiangya Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Zhiguang Zhou, MD/PhD</last_name>
    <phone>86-731-85292154</phone>
    <email>zhouzg@hotmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <zip>410011</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Zhiguang Zhou, MD/PhD</last_name>
      <phone>86-731-85292154</phone>
      <email>zhouzg@hotmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Milward K, Issa F, Hester J, Figueroa-Tentori D, Madrigal A, Wood KJ. Multiple unit pooled umbilical cord blood is a viable source of therapeutic regulatory T cells. Transplantation. 2013 Jan 15;95(1):85-93. doi: 10.1097/TP.0b013e31827722ed.</citation>
    <PMID>23263503</PMID>
  </reference>
  <reference>
    <citation>Fan H, Yang J, Hao J, Ren Y, Chen L, Li G, Xie R, Yang Y, Gao F, Liu M. Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood. Immunology. 2012 Jun;136(2):218-30. doi: 10.1111/j.1365-2567.2012.03573.x.</citation>
    <PMID>22348606</PMID>
  </reference>
  <reference>
    <citation>Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15.</citation>
    <PMID>20952687</PMID>
  </reference>
  <reference>
    <citation>Rondas D, D'Hertog W, Overbergh L, Mathieu C. Glucagon-like peptide-1: modulator of beta-cell dysfunction and death. Diabetes Obes Metab. 2013 Sep;15 Suppl 3:185-92. doi: 10.1111/dom.12165.</citation>
    <PMID>24003936</PMID>
  </reference>
  <reference>
    <citation>Chang TJ, Tseng HC, Liu MW, Chang YC, Hsieh ML, Chuang LM. Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation. Sci Rep. 2016 Mar 21;6:23403. doi: 10.1038/srep23403. Erratum In: Sci Rep. 2016 May 31;6:26917.</citation>
    <PMID>26997114</PMID>
  </reference>
  <reference>
    <citation>Zoso A, Serafini P, Lanzoni G, Peixoto E, Messinger S, Mantero A, Padilla-Tellez ND, Baidal DA, Alejandro R, Ricordi C, Inverardi L. G-CSF and Exenatide Might Be Associated with Increased Long-Term Survival of Allogeneic Pancreatic Islet Grafts. PLoS One. 2016 Jun 10;11(6):e0157245. doi: 10.1371/journal.pone.0157245. eCollection 2016.</citation>
    <PMID>27285580</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 2, 2017</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>March 13, 2023</last_update_submitted>
  <last_update_submitted_qc>March 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Second Xiangya Hospital of Central South University</investigator_affiliation>
    <investigator_full_name>Zhiguang Zhou</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Autoimmune Diabetes</keyword>
  <keyword>Umbilical Cord Blood Regulatory T Lymphocyte</keyword>
  <keyword>Liraglutide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liraglutide</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/NCT03011021
org study id: 0001
nct id: NCT03011021
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to investigate the safety and therapeutic effect of ex-vivo
      expanded umbilical cord blood regulatory T cells adjunct with Liraglutide on autoimmune
      diabetes.
Autoimmune Diabetes Mellitus (AIDM) is a subtype of diabetes mellitus caused by autoimmune
      destruction of beta cells in the islet, including Type 1 diabetes and Latent Autoimmune
      Diabetes in Adults (LADA). Insulin has been used as a routine therapy for AIDM to alleviate
      the hyperglycemic status, yet cannot effectively prevent the progressing destruction of beta
      cells or preserve its function. Regulatory T cells expanded from umbilical cord blood
      (UCB-Treg) ex-vivo have shown strong capacity to control immune responses in autoimmune
      diseases, offering a hopeful therapeutic way for AIDM. Glucagon-like peptide (GLP-1) analog
      Liraglutide has been tested in large-scale clinical trial to prove its various benefits for
      beta cells and glucolipid metabolism in Type 2 diabetes and obesity patients. However, its
      clinical application in AIDM is not well-defined so far. The aim of this study is to
      investigate the potential use of Liraglutide with UCB-Treg infusion in AIDM and examine the
      safety and efficacy of this new therapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Adverse effects
time frame: 2 years
description: Primary outcome measures will be the number of participants with adverse events, laboratory abnormalities and other signs of toxicity. Particular focus will be on the number and severity of infusion reactions, complications related to infection, and any potential negative impact on the course of diabetes.
measure: Change in HbA1C
time frame: 2 years
description: Measure the HbA1C level after treatment
measure: Change in C-peptide
time frame: 2 years
description: Measure the C-peptide level after treatment
measure: Change in insulin dose
time frame: 2 years
description: Measure insulin dose patient used after treatment
measure: Hypoglycaemic events
time frame: 2 years
description: Measure the number of participants with Hypoglycaemic events
measure: Change in titer of autoantibodies
time frame: 2 years
description: Measure the titer of antoantibodies of participant after treatment
measure: Change in immune cells diversities and quantities.
time frame: 2 years
description: Measure the immune cells diversities and quantities after treatment
measure: Change in autoimmune-related cytokines
time frame: 2 years
description: Measure the change of autoimmune- related cytokines after treatment
measure: Life quality evaluation
time frame: 2 years
description: Number of participants with disturbance of emotion, sleep, resting or energy.
arm group label: UCB-Treg plus Liraglutide
arm group type: Experimental
description: Subjects will receive a single infusion of ex vivo expanded umbilical cord blood derived Treg product (2 x 10^6). Dose escalation of liraglutide up to 1.2 mg will be started 3 days after Treg infusion only if no severe side effects showed. Subjects continue to receive the reached liraglutide dose once daily for 6 months thereafter. Insulin will be continued as a routine therapy.
arm group label: UCB-Treg
arm group type: Active Comparator
description: Subjects will receive a single infusion of ex vivo expanded Treg product (2 x 10^6). Insulin will be continued as a routine therapy.
arm group label: Liraglutide
arm group type: Active Comparator
description: Patients will be subjected to a dose escalation of liraglutide up to 1.2 mg, then continue to receive the reached liraglutide dose once daily for 6 months thereafter. Insulin will be continued as routine therapy.
arm group label: Insulin
arm group type: Active Comparator
description: Patients will receive insulin injection as a routine therapy.
intervention type: Drug
intervention name: Liraglutide
description: Dose escalation of Liraglutide starts from 0.6 mg up to 1.2 mg per day.
arm group label: Liraglutide
arm group label: UCB-Treg plus Liraglutide
intervention type: Biological
intervention name: UCB-Treg
description: Receive Treg infusion: 1~5*10^6/kg b.w. in 100ml normal saline
arm group label: UCB-Treg
arm group label: UCB-Treg plus Liraglutide
intervention type: Drug
intervention name: Insulin
description: Receive insulin following clinician's instruction.
arm group label: Insulin
arm group label: Liraglutide
arm group label: UCB-Treg
arm group label: UCB-Treg plus Liraglutide
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Zhiguang Zhou, MD/PhD
role: Principal Investigator
affiliation: Second Xiangya Hospital
last name: Haibo Yu, MD/PhD
role: Principal Investigator
affiliation: Second Xiangya Hospital
last name: Zhiguang Zhou, MD/PhD
phone: 86-731-85292154
email: zhouzg@hotmail.com
facility: 
status: Recruiting
contact: 
country: China
citation: Milward K, Issa F, Hester J, Figueroa-Tentori D, Madrigal A, Wood KJ. Multiple unit pooled umbilical cord blood is a viable source of therapeutic regulatory T cells. Transplantation. 2013 Jan 15;95(1):85-93. doi: 10.1097/TP.0b013e31827722ed.
PMID: 23263503
citation: Fan H, Yang J, Hao J, Ren Y, Chen L, Li G, Xie R, Yang Y, Gao F, Liu M. Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood. Immunology. 2012 Jun;136(2):218-30. doi: 10.1111/j.1365-2567.2012.03573.x.
PMID: 22348606
citation: Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15.
PMID: 20952687
citation: Rondas D, D'Hertog W, Overbergh L, Mathieu C. Glucagon-like peptide-1: modulator of beta-cell dysfunction and death. Diabetes Obes Metab. 2013 Sep;15 Suppl 3:185-92. doi: 10.1111/dom.12165.
PMID: 24003936
citation: Chang TJ, Tseng HC, Liu MW, Chang YC, Hsieh ML, Chuang LM. Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation. Sci Rep. 2016 Mar 21;6:23403. doi: 10.1038/srep23403. Erratum In: Sci Rep. 2016 May 31;6:26917.
PMID: 26997114
citation: Zoso A, Serafini P, Lanzoni G, Peixoto E, Messinger S, Mantero A, Padilla-Tellez ND, Baidal DA, Alejandro R, Ricordi C, Inverardi L. G-CSF and Exenatide Might Be Associated with Increased Long-Term Survival of Allogeneic Pancreatic Islet Grafts. PLoS One. 2016 Jun 10;11(6):e0157245. doi: 10.1371/journal.pone.0157245. eCollection 2016.
PMID: 27285580
responsible party type: Principal Investigator
investigator affiliation: Second Xiangya Hospital of Central South University
investigator full name: Zhiguang Zhou
investigator title: Principal Investigator
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Liraglutide