<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/NCT04501341</url>
  </required_header>
  <id_info>
    <org_study_id>132/PT02.FK25/U.Eu113/METEND/V</org_study_id>
    <nct_id>NCT04501341</nct_id>
  </id_info>
  <brief_title>BM-MNC and UCMSC for Type 2 Diabetes Mellitus Patients</brief_title>
  <official_title>Effectivity and Safety of Autologous BM-MNC Stem Cell Therapy and Allogenic Umbilical Cord Mesenchymal Stem Cell for Type 2 Diabetes Mellitus Patients&quot;</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Indonesia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dr Cipto Mangunkusumo General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Indonesia University</source>
  <oversight_info>
    <has_dmc>Yes</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>
      The aim of this preliminary study is to evaluate the safety and efficacy of bone-marrow&#xD;
      mononuclear cells (BM-MNCs) and umbilical-cord tissue-derived mesenchymal stem cells&#xD;
      (UC-MSCs) administration in type 2 diabetes patients&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Type 2 diabetes (T2D) patients had peripheral insulin resistance accompanied by progressive&#xD;
      pancreatic beta cell degeneration and dysfunction due to glucotoxicity and lipotoxicity.&#xD;
      Several studies have shown that the immune system plays a significant role in the&#xD;
      pathogenesis of T2D. Bone-marrow mononuclear cells (BM-MNCs) and umbilical-cord&#xD;
      tissue-derived mesenchymal stem cells (UC-MSCs) via its immunomodulatory properties have the&#xD;
      potential to improve insulin resistance condition and pancreatic beta-cells dysfunction thus&#xD;
      improve the glycemic control and insulin requirement in T2D patients. In this pilot study, we&#xD;
      plan to recruit 15 T2D patients with total daily dose of insulin &gt;= 0.5 unit/kgBW/day to&#xD;
      receive BM-MNCs (5 subjects) or UC-MSCs injections (10 subjects). These subjects will be&#xD;
      closely followed up for 12 months for evaluation of primary and secondary outcome.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">March 14, 2016</start_date>
  <completion_date type="Anticipated">December 1, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2021</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>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>5 subjects receive BM-MNC and 10 subjects receive UC-MSC</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Decreasing total daily dose of insulin (&gt;= 30%)</measure>
    <time_frame>Before intervention, 1st, 3rd, 6th, and 12th month after intervention</time_frame>
    <description>After intervention, blood glucose level will be reported by the subjects on weekly basis. The insulin dose and/or oral medication will be adjusted accordingly.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Increasing of C-peptide level</measure>
    <time_frame>Before intervention, 1st, 3rd, 6th, and 12th month after intervention</time_frame>
    <description>Measurements were obtained with mixed meal tolerance test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decreasing of insulin resistance level</measure>
    <time_frame>Before intervention, 1st, 3rd, 6th, and 12th month after intervention</time_frame>
    <description>Measurement of HOMA-IR, calculated using fasting C-peptide and fasting plasma glucose formula</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunology/inflammatory markers</measure>
    <time_frame>Before intervention, 1st, 3rd, 6th, and 12th month after intervention</time_frame>
    <description>Measurements of Interleukin-10 and TNF-alfa from serum and supernatant from PBMC stimulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>Up to 12 months after intervention</time_frame>
    <description>Thrombosis, hemorrhage, and infection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HbA1c</measure>
    <time_frame>Before intervention, 1st, 3rd, 6th, and 12th month after intervention</time_frame>
    <description>Stable HbA1c or decreasing HbA1c (from baseline)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>T2D</condition>
  <arm_group>
    <arm_group_label>BM-MNC experimental</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Autologue bone marrow mononuclear cell</description>
  </arm_group>
  <arm_group>
    <arm_group_label>UC-MSC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Umbilical cord mesenchymal stem cell</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bone-marrow aspiration, Intra-pancreatic Catheterisation of BM-MNC</intervention_name>
    <description>Autologous bone-marrow mononuclear cells infused to the main blood vessels that supply the pancreas according to the results of previous pancreatic CT-scan, performed by interventional radiologist. The target is to distribute the BM-MNCs equally in all part of the pancreas. Dosage: 1 x 10^5 - 1 x 10^6 CD34 cells/kgBW</description>
    <arm_group_label>BM-MNC experimental</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Intravenous Infusion of UC-MSC</intervention_name>
    <description>Allogeneic umbilical cord tissue-derived mesenchymal stem cells will be given via intravenous infusion. Dosage: 2 x 10^6 cells/kgBW, twice, with three months interval</description>
    <arm_group_label>UC-MSC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 2 diabetes patients on insulin therapy with or without oral hypoglycemic agents,&#xD;
             with total daily dose of insulin &gt;= 0,5 unit/kg body weight&#xD;
&#xD;
          -  Stable HbA1C in the last six months (HbA1c &lt;= 8.5%)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Type 1 diabetes mellitus&#xD;
&#xD;
          -  eGFR &lt; 45 mL/min/m2 (for BM-MNC)&#xD;
&#xD;
          -  Liver disease (moderate- severe)&#xD;
&#xD;
          -  Active infection&#xD;
&#xD;
          -  Contrast hypersensitivity (for BM-MNC)&#xD;
&#xD;
          -  History of Malignancy&#xD;
&#xD;
          -  Acute coronary syndrome in last three months&#xD;
&#xD;
          -  Coronary arterial diseases with significant stenosis and has not carried out&#xD;
             revascularization&#xD;
&#xD;
          -  Pregnancy (for women subjects)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Faculty of Medicine, Universitas Indonesia</name>
      <address>
        <city>Jakarta Pusat</city>
        <state>DKI Jakarta</state>
        <zip>10430</zip>
        <country>Indonesia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pradana Soewondo, Prof</last_name>
      <phone>+628188160756</phone>
      <email>pradana.soewondo@ui.ac.id</email>
    </contact>
  </location>
  <location_countries>
    <country>Indonesia</country>
  </location_countries>
  <reference>
    <citation>Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus - a mini-review. Gerontology. 2014;60(3):189-96. doi: 10.1159/000356747. Epub 2014 Jan 22.</citation>
    <PMID>24457898</PMID>
  </reference>
  <reference>
    <citation>Tsai S, Clemente-Casares X, Revelo XS, Winer S, Winer DA. Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes. 2015 Jun;64(6):1886-97. doi: 10.2337/db14-1488.</citation>
    <PMID>25999531</PMID>
  </reference>
  <reference>
    <citation>Campbell RK, Martin TM. The chronic burden of diabetes. Am J Manag Care. 2009 Sep;15(9 Suppl):S248-54.</citation>
    <PMID>19817513</PMID>
  </reference>
  <reference>
    <citation>Fery F, Paquot N. [Etiopathogenesis and pathophysiology of type 2 diabetes]. Rev Med Liege. 2005 May-Jun;60(5-6):361-8. French.</citation>
    <PMID>16035295</PMID>
  </reference>
  <reference>
    <citation>Wehbe T, Chahine NA, Sissi S, Abou-Joaude I, Chalhoub L. Bone marrow derived stem cell therapy for type 2 diabetes mellitus. Stem Cell Investig. 2016 Dec 6;3:87. doi: 10.21037/sci.2016.11.14. eCollection 2016.</citation>
    <PMID>28066789</PMID>
  </reference>
  <reference>
    <citation>Guan LX, Guan H, Li HB, Ren CA, Liu L, Chu JJ, Dai LJ. Therapeutic efficacy of umbilical cord-derived mesenchymal stem cells in patients with type 2 diabetes. Exp Ther Med. 2015 May;9(5):1623-1630. doi: 10.3892/etm.2015.2339. Epub 2015 Mar 9.</citation>
    <PMID>26136869</PMID>
  </reference>
  <reference>
    <citation>Estrada EJ, Valacchi F, Nicora E, Brieva S, Esteve C, Echevarria L, Froud T, Bernetti K, Cayetano SM, Velazquez O, Alejandro R, Ricordi C. Combined treatment of intrapancreatic autologous bone marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus. Cell Transplant. 2008;17(12):1295-304. doi: 10.3727/096368908787648119.</citation>
    <PMID>19364067</PMID>
  </reference>
  <reference>
    <citation>Bhansali A, Asokumar P, Walia R, Bhansali S, Gupta V, Jain A, Sachdeva N, Sharma RR, Marwaha N, Khandelwal N. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study. Cell Transplant. 2014;23(9):1075-85. doi: 10.3727/096368913X665576.</citation>
    <PMID>23561959</PMID>
  </reference>
  <reference>
    <citation>Hu J, Li C, Wang L, Zhang X, Zhang M, Gao H, Yu X, Wang F, Zhao W, Yan S, Wang Y. Long term effects of the implantation of autologous bone marrow mononuclear cells for type 2 diabetes mellitus. Endocr J. 2012;59(11):1031-9. doi: 10.1507/endocrj.ej12-0092. Epub 2012 Jul 13.</citation>
    <PMID>22814142</PMID>
  </reference>
  <reference>
    <citation>Chao YH, Wu HP, Chan CK, Tsai C, Peng CT, Wu KH. Umbilical cord-derived mesenchymal stem cells for hematopoietic stem cell transplantation. J Biomed Biotechnol. 2012;2012:759503. doi: 10.1155/2012/759503. Epub 2012 Oct 3.</citation>
    <PMID>23093863</PMID>
  </reference>
  <results_reference>
    <citation>Weiss ARR, Dahlke MH. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs. Front Immunol. 2019 Jun 4;10:1191. doi: 10.3389/fimmu.2019.01191. eCollection 2019.</citation>
    <PMID>31214172</PMID>
  </results_reference>
  <results_reference>
    <citation>Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, Tse HF, Fu QL, Lian Q. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016 Jan 21;7(1):e2062. doi: 10.1038/cddis.2015.327.</citation>
    <PMID>26794657</PMID>
  </results_reference>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>July 26, 2020</study_first_submitted>
  <study_first_submitted_qc>August 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>August 2, 2020</last_update_submitted>
  <last_update_submitted_qc>August 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fakultas Kedokteran Universitas Indonesia</investigator_affiliation>
    <investigator_full_name>Prof. Dr. dr. Pradana Soewondo, SpPD-KEMD</investigator_full_name>
    <investigator_title>Prof</investigator_title>
  </responsible_party>
  <keyword>type 2 diabetes</keyword>
  <keyword>Bone-marrow mononuclear cells</keyword>
  <keyword>Umbilical cord mesenchymal stem cells</keyword>
  <keyword>Glycemic control</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 2</mesh_term>
  </condition_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/NCT04501341
org study id: 132/PT02.FK25/U.Eu113/METEND/V
nct id: NCT04501341
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The aim of this preliminary study is to evaluate the safety and efficacy of bone-marrow
      mononuclear cells (BM-MNCs) and umbilical-cord tissue-derived mesenchymal stem cells
      (UC-MSCs) administration in type 2 diabetes patients
Type 2 diabetes (T2D) patients had peripheral insulin resistance accompanied by progressive
      pancreatic beta cell degeneration and dysfunction due to glucotoxicity and lipotoxicity.
      Several studies have shown that the immune system plays a significant role in the
      pathogenesis of T2D. Bone-marrow mononuclear cells (BM-MNCs) and umbilical-cord
      tissue-derived mesenchymal stem cells (UC-MSCs) via its immunomodulatory properties have the
      potential to improve insulin resistance condition and pancreatic beta-cells dysfunction thus
      improve the glycemic control and insulin requirement in T2D patients. In this pilot study, we
      plan to recruit 15 T2D patients with total daily dose of insulin >= 0.5 unit/kgBW/day to
      receive BM-MNCs (5 subjects) or UC-MSCs injections (10 subjects). These subjects will be
      closely followed up for 12 months for evaluation of primary and secondary outcome.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: 5 subjects receive BM-MNC and 10 subjects receive UC-MSC
primary purpose: Treatment
masking: None (Open Label)
measure: Decreasing total daily dose of insulin (>= 30%)
time frame: Before intervention, 1st, 3rd, 6th, and 12th month after intervention
description: After intervention, blood glucose level will be reported by the subjects on weekly basis. The insulin dose and/or oral medication will be adjusted accordingly.
measure: Increasing of C-peptide level
time frame: Before intervention, 1st, 3rd, 6th, and 12th month after intervention
description: Measurements were obtained with mixed meal tolerance test
measure: Decreasing of insulin resistance level
time frame: Before intervention, 1st, 3rd, 6th, and 12th month after intervention
description: Measurement of HOMA-IR, calculated using fasting C-peptide and fasting plasma glucose formula
measure: Immunology/inflammatory markers
time frame: Before intervention, 1st, 3rd, 6th, and 12th month after intervention
description: Measurements of Interleukin-10 and TNF-alfa from serum and supernatant from PBMC stimulation
measure: Adverse events
time frame: Up to 12 months after intervention
description: Thrombosis, hemorrhage, and infection
measure: HbA1c
time frame: Before intervention, 1st, 3rd, 6th, and 12th month after intervention
description: Stable HbA1c or decreasing HbA1c (from baseline)
arm group label: BM-MNC experimental
arm group type: Experimental
description: Autologue bone marrow mononuclear cell
arm group label: UC-MSC
arm group type: Experimental
description: Umbilical cord mesenchymal stem cell
intervention type: Biological
intervention name: Bone-marrow aspiration, Intra-pancreatic Catheterisation of BM-MNC
description: Autologous bone-marrow mononuclear cells infused to the main blood vessels that supply the pancreas according to the results of previous pancreatic CT-scan, performed by interventional radiologist. The target is to distribute the BM-MNCs equally in all part of the pancreas. Dosage: 1 x 10^5 - 1 x 10^6 CD34 cells/kgBW
arm group label: BM-MNC experimental
intervention type: Biological
intervention name: Intravenous Infusion of UC-MSC
description: Allogeneic umbilical cord tissue-derived mesenchymal stem cells will be given via intravenous infusion. Dosage: 2 x 10^6 cells/kgBW, twice, with three months interval
arm group label: UC-MSC
criteria: 
gender: All
minimum age: 30 Years
maximum age: 65 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
country: Indonesia
citation: Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus - a mini-review. Gerontology. 2014;60(3):189-96. doi: 10.1159/000356747. Epub 2014 Jan 22.
PMID: 24457898
citation: Tsai S, Clemente-Casares X, Revelo XS, Winer S, Winer DA. Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes. 2015 Jun;64(6):1886-97. doi: 10.2337/db14-1488.
PMID: 25999531
citation: Campbell RK, Martin TM. The chronic burden of diabetes. Am J Manag Care. 2009 Sep;15(9 Suppl):S248-54.
PMID: 19817513
citation: Fery F, Paquot N. [Etiopathogenesis and pathophysiology of type 2 diabetes]. Rev Med Liege. 2005 May-Jun;60(5-6):361-8. French.
PMID: 16035295
citation: Wehbe T, Chahine NA, Sissi S, Abou-Joaude I, Chalhoub L. Bone marrow derived stem cell therapy for type 2 diabetes mellitus. Stem Cell Investig. 2016 Dec 6;3:87. doi: 10.21037/sci.2016.11.14. eCollection 2016.
PMID: 28066789
citation: Guan LX, Guan H, Li HB, Ren CA, Liu L, Chu JJ, Dai LJ. Therapeutic efficacy of umbilical cord-derived mesenchymal stem cells in patients with type 2 diabetes. Exp Ther Med. 2015 May;9(5):1623-1630. doi: 10.3892/etm.2015.2339. Epub 2015 Mar 9.
PMID: 26136869
citation: Estrada EJ, Valacchi F, Nicora E, Brieva S, Esteve C, Echevarria L, Froud T, Bernetti K, Cayetano SM, Velazquez O, Alejandro R, Ricordi C. Combined treatment of intrapancreatic autologous bone marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus. Cell Transplant. 2008;17(12):1295-304. doi: 10.3727/096368908787648119.
PMID: 19364067
citation: Bhansali A, Asokumar P, Walia R, Bhansali S, Gupta V, Jain A, Sachdeva N, Sharma RR, Marwaha N, Khandelwal N. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study. Cell Transplant. 2014;23(9):1075-85. doi: 10.3727/096368913X665576.
PMID: 23561959
citation: Hu J, Li C, Wang L, Zhang X, Zhang M, Gao H, Yu X, Wang F, Zhao W, Yan S, Wang Y. Long term effects of the implantation of autologous bone marrow mononuclear cells for type 2 diabetes mellitus. Endocr J. 2012;59(11):1031-9. doi: 10.1507/endocrj.ej12-0092. Epub 2012 Jul 13.
PMID: 22814142
citation: Chao YH, Wu HP, Chan CK, Tsai C, Peng CT, Wu KH. Umbilical cord-derived mesenchymal stem cells for hematopoietic stem cell transplantation. J Biomed Biotechnol. 2012;2012:759503. doi: 10.1155/2012/759503. Epub 2012 Oct 3.
PMID: 23093863
citation: Weiss ARR, Dahlke MH. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs. Front Immunol. 2019 Jun 4;10:1191. doi: 10.3389/fimmu.2019.01191. eCollection 2019.
PMID: 31214172
citation: Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, Tse HF, Fu QL, Lian Q. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016 Jan 21;7(1):e2062. doi: 10.1038/cddis.2015.327.
PMID: 26794657
responsible party type: Principal Investigator
investigator affiliation: Fakultas Kedokteran Universitas Indonesia
investigator full name: Prof. Dr. dr. Pradana Soewondo, SpPD-KEMD
investigator title: Prof
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2