<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/NCT01686139</url>
  </required_header>
  <id_info>
    <org_study_id>SHEBA-11-8802-IS-SMC</org_study_id>
    <nct_id>NCT01686139</nct_id>
  </id_info>
  <brief_title>Safety Study of Stem Cells Treatment in Diabetic Foot Ulcers</brief_title>
  <official_title>Phase 1 Study: Treatment of Patients With Diabetic Foot Complications With Allogeneic Bone Marrow Derived Mesenchymal Stromal Cells (ABMD-MSC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sheba Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Diabetes Mellitus (DM) can be regarded as one of the &quot;epidemics&quot; of the western world.&#xD;
&#xD;
      DM contributes to severe morbidity and mortality due to damage in the target organs&#xD;
      (neuropathy, vasculopathy, nephropathy, retinopathy).&#xD;
&#xD;
      It affects the quality of life of the patients because of increased rate of blindness, IHD,&#xD;
      stroke, end stage renal failure, hemodialysis and lower limb amputations (LLA).The Diabetic&#xD;
      Foot (DF) is defined as destruction or infection of tissue/s in the foot of diabetic patients&#xD;
      due to neurological damage and / or different levels of Peripheral Vascular Disease (PVD).&#xD;
      Diabetic foot complications are the most common cause of lower extremity amputations in the&#xD;
      industrialized world. The lifetime occurence of Diabetic Foot Ulcers (DFU) is 20% in diabetic&#xD;
      patients.&#xD;
&#xD;
      Between 15% - 25% of the foot ulcers will lead to lower limb amputations.&#xD;
&#xD;
      It has been shown that Mesenchymal Stem Cells (MSCs) could be an effective therapy for many&#xD;
      diseases including acute respiratory distress syndrome, spinal cord injury, liver injury and&#xD;
      critical limb ischemia.&#xD;
&#xD;
      Stem cells can be obtained from either the patient (autologous) or non-related healthy donors&#xD;
      (allogeneic).&#xD;
&#xD;
      The purpose of this study is to determine the safety and efficacy of cultured Bone Marrow&#xD;
      Mesenchymal Stromal Cells (BM-MSCs) from allogeneic donors for treatment of chronic leg&#xD;
      wounds of diabetic patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>March 2016</start_date>
  <completion_date type="Anticipated">December 2017</completion_date>
  <primary_completion_date type="Anticipated">March 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Frequency of Adverse Events</measure>
    <time_frame>6 months after treatment</time_frame>
    <description>Frequency and severity of Adverse Events.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Type I Diabetes Mellitus With Ulcer</condition>
  <condition>Type II Diabetes Mellitus With Ulcer</condition>
  <arm_group>
    <arm_group_label>ABDM-MSC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The patient will receive multiple injections in one session during the study. The injections will take place in the chronic wound bed and in the third distal part of the treated shin (in the form of a ring).&#xD;
Maximal amount of ABMD-MSC cells injected: 10-20*10^6 cells (up to volume of 20mL, depending on the wound size &amp; patient weight).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ABMD-MSC</intervention_name>
    <description>10-20 x 10^6 cells/20mL</description>
    <arm_group_label>ABDM-MSC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient signed informed consent.&#xD;
&#xD;
          -  Adult males or females between 18 and 81 years of age with diabetes mellitus type 1 or&#xD;
             type 2.&#xD;
&#xD;
          -  Patient has one Diabetic Foot Ulcer (DFU) on the treated leg. The size of the DFU is&#xD;
             no greater than 10 cm2 .&#xD;
&#xD;
          -  The Diabetic Foot Ulcer (DFU) is neuropathic: The patient is checked by a 5.27 mm&#xD;
             Monofilament, and doesn't have a sensation in at least 4 of 9 points in the foot.&#xD;
&#xD;
          -  No endovascular or surgical interventions are planned.&#xD;
&#xD;
          -  Patient isn't in an immediate life threat.&#xD;
&#xD;
          -  Normal organ and marrow function as defined:&#xD;
&#xD;
               1. Leukocytes ≥3,000/μL&#xD;
&#xD;
               2. Absolute neutrophil count ≥1,500/μL&#xD;
&#xD;
               3. Platelets ≥140,000/μL&#xD;
&#xD;
               4. AST (SGOT)/ALT (SGPT) ≤2.5 X institutional standards range&#xD;
&#xD;
               5. Creatinine ≤ 2.5 mg/dL&#xD;
&#xD;
          -  Patients with controlled blood pressure (defined as a systolic blood pressure ≤180&#xD;
             and/or a diastolic blood pressure of ≤110 mmHg) and established anti-hypertensive&#xD;
             therapy as necessary prior to entry into the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patient weight is greater than 120 Kg.&#xD;
&#xD;
          -  Patients with poorly controlled diabetes mellitus (HbA1c &gt; 10%).&#xD;
&#xD;
          -  Presence of osteomyelitis (stage B grade 3 and stage D grade 3 on the UT Scale).&#xD;
&#xD;
          -  More than one ulcer in the treated foot.&#xD;
&#xD;
          -  Patients with a known failed ipsilateral revascularization procedure within 4 weeks&#xD;
             prior to enrollment.&#xD;
&#xD;
          -  Patients with ABI &lt;= 0.3&#xD;
&#xD;
          -  Patients receiving treatment with hematopoietic growth factors.&#xD;
&#xD;
          -  (Actively) infected ulcer.&#xD;
&#xD;
          -  Infection of the involved extremity(ies) in the intended region of injection. Patient&#xD;
             will be included (injected) if there is a safe zone of 10 cm from any soft tissue&#xD;
             infection, manifested by fever, purulence and severe cellulitis.&#xD;
&#xD;
          -  Active wet gangrenous tissue.&#xD;
&#xD;
          -  Patients who require uninterrupted anticoagulation or anti-platelet therapy [i.e.&#xD;
             anticoagulation therapy (e.g. Coumadin) that cannot be stopped for 72 hours prior to&#xD;
             intramuscular injections.&#xD;
&#xD;
          -  Patients with a blood clotting disorder not caused by medication.&#xD;
&#xD;
          -  Patients with known cancer undergoing treatment including chemotherapy, radiotherapy&#xD;
             or immunotherapy.&#xD;
&#xD;
          -  Patients with end stage renal disease requiring dialysis.&#xD;
&#xD;
          -  Patients who are pregnant or lactating.&#xD;
&#xD;
          -  History of regular alcohol consumption exceeding 2 drinks/day (1 drink = 5 oz [150mL]&#xD;
             of wine or 12 oz [360mL] of beer or 1.5 oz [45mL] of hard liquor) within 6 months of&#xD;
             screening and/or history of illicit drug use.&#xD;
&#xD;
          -  Known allergies to protein products (horse or bovine serum, or porcine trypsin) used&#xD;
             in the cell production process.&#xD;
&#xD;
          -  Patients receiving experimental medications or participating in another clinical study&#xD;
             within 30 days of screening.&#xD;
&#xD;
          -  Immune deficient patients.&#xD;
&#xD;
          -  Patients with positive blood tests for Hepatitis B or Hepatitis C or HIV or Syphilis&#xD;
             at the time of screening.&#xD;
&#xD;
          -  Patients treated by Ilomedin (Iloprost).&#xD;
&#xD;
          -  Patients having received a new chronic pharmacologic treatment regimen within 4 weeks&#xD;
             prior to enrollment.&#xD;
&#xD;
          -  Patients undergoing hyperbaric oxygen treatment within 4 weeks of inclusion and/or&#xD;
             required throughout the trial.&#xD;
&#xD;
          -  Concomitant wound treatments that include growth factors or tissue engineered&#xD;
             products.&#xD;
&#xD;
          -  In the opinion of the investigator, the patient is unsuitable for cellular therapy.&#xD;
&#xD;
          -  Patients receiving systemic or direct target limb injection of antiangiogenic drugs.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>81 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Itzhak Siev-Ner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sheba Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Itzhak Siev-Ner, MD</last_name>
    <phone>03-530-3701</phone>
    <email>zivner@netvision.net.il</email>
  </overall_contact>
  <location>
    <facility>
      <name>Orthopedic Rehabilitation out-patient clinic, Sheba Medical Center</name>
      <address>
        <city>Ramat Gan</city>
        <country>Israel</country>
      </address>
    </facility>
    <contact>
      <last_name>Itzhak Siev-Ner, MD</last_name>
      <phone>03-530-3701</phone>
      <email>zivner@netvision.net.il</email>
    </contact>
    <investigator>
      <last_name>Itzhak Siev-Ner, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <reference>
    <citation>Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 1976 Sep;4(5):267-74.</citation>
    <PMID>976387</PMID>
  </reference>
  <reference>
    <citation>Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):419-27. doi: 10.1016/j.cytogfr.2009.10.002. Epub 2009 Nov 18.</citation>
    <PMID>19926330</PMID>
  </reference>
  <reference>
    <citation>Wu Y, Zhao RC, Tredget EE. Concise review: bone marrow-derived stem/progenitor cells in cutaneous repair and regeneration. Stem Cells. 2010 May;28(5):905-15. doi: 10.1002/stem.420.</citation>
    <PMID>20474078</PMID>
  </reference>
  <reference>
    <citation>Sensebe L, Krampera M, Schrezenmeier H, Bourin P, Giordano R. Mesenchymal stem cells for clinical application. Vox Sang. 2010 Feb;98(2):93-107. doi: 10.1111/j.1423-0410.2009.01227.x. Epub 2009 Aug 3.</citation>
    <PMID>19663934</PMID>
  </reference>
  <reference>
    <citation>Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008 Apr 2;3(4):e1886. doi: 10.1371/journal.pone.0001886.</citation>
    <PMID>18382669</PMID>
  </reference>
  <reference>
    <citation>Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen. 2006 May-Jun;14(3):325-35. doi: 10.1111/j.1743-6109.2006.00128.x.</citation>
    <PMID>16808812</PMID>
  </reference>
  <reference>
    <citation>McFarlin K, Gao X, Liu YB, Dulchavsky DS, Kwon D, Arbab AS, Bansal M, Li Y, Chopp M, Dulchavsky SA, Gautam SC. Bone marrow-derived mesenchymal stromal cells accelerate wound healing in the rat. Wound Repair Regen. 2006 Jul-Aug;14(4):471-8. doi: 10.1111/j.1743-6109.2006.00153.x.</citation>
    <PMID>16939576</PMID>
  </reference>
  <reference>
    <citation>Wu Y, Wang J, Scott PG, Tredget EE. Bone marrow-derived stem cells in wound healing: a review. Wound Repair Regen. 2007 Sep-Oct;15 Suppl 1:S18-26. doi: 10.1111/j.1524-475X.2007.00221.x. Erratum In: Wound Repair Regen. 2008 Jul-Aug;16(4):582.</citation>
    <PMID>17727462</PMID>
  </reference>
  <reference>
    <citation>Kwon DS, Gao X, Liu YB, Dulchavsky DS, Danyluk AL, Bansal M, Chopp M, McIntosh K, Arbab AS, Dulchavsky SA, Gautam SC. Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. Int Wound J. 2008 Jun;5(3):453-63. doi: 10.1111/j.1742-481X.2007.00408.x.</citation>
    <PMID>18593394</PMID>
  </reference>
  <reference>
    <citation>Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007 May;117(5):1219-22. doi: 10.1172/JCI32169.</citation>
    <PMID>17476353</PMID>
  </reference>
  <reference>
    <citation>Iwase T, Nagaya N, Fujii T, Itoh T, Murakami S, Matsumoto T, Kangawa K, Kitamura S. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res. 2005 Jun 1;66(3):543-51. doi: 10.1016/j.cardiores.2005.02.006. Epub 2005 Mar 2.</citation>
    <PMID>15914119</PMID>
  </reference>
  <reference>
    <citation>Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003 Jun;9(6):702-12. doi: 10.1038/nm0603-702.</citation>
    <PMID>12778169</PMID>
  </reference>
  <reference>
    <citation>Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, Shrayer D, Carson P. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007 Jun;13(6):1299-312. doi: 10.1089/ten.2006.0278.</citation>
    <PMID>17518741</PMID>
  </reference>
  <reference>
    <citation>Kirana S, Stratmann B, Lammers D, Negrean M, Stirban A, Minartz P, Koerperich H, Gastens MH, Gotting C, Prohaska W, Kleesiek K, Tschoepe D. Wound therapy with autologous bone marrow stem cells in diabetic patients with ischaemia-induced tissue ulcers affecting the lower limbs. Int J Clin Pract. 2007 Apr;61(4):690-2. doi: 10.1111/j.1742-1241.2007.01303.x.</citation>
    <PMID>17394441</PMID>
  </reference>
  <reference>
    <citation>Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009 Oct;12(5):359-66. doi: 10.1089/rej.2009.0872.</citation>
    <PMID>19929258</PMID>
  </reference>
  <reference>
    <citation>Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8932-7. doi: 10.1073/pnas.132252399.</citation>
    <PMID>12084934</PMID>
  </reference>
  <reference>
    <citation>Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002 Oct 8;106(15):1913-8. doi: 10.1161/01.cir.0000034046.87607.1c.</citation>
    <PMID>12370212</PMID>
  </reference>
  <reference>
    <citation>Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004 Jul 1;94(1):92-5. doi: 10.1016/j.amjcard.2004.03.034.</citation>
    <PMID>15219514</PMID>
  </reference>
  <reference>
    <citation>Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006 Sep 21;355(12):1199-209. doi: 10.1056/NEJMoa055706.</citation>
    <PMID>16990383</PMID>
  </reference>
  <reference>
    <citation>Fuchs S, Kornowski R, Weisz G, Satler LF, Smits PC, Okubagzi P, Baffour R, Aggarwal A, Weissman NJ, Cerqueira M, Waksman R, Serrruys P, Battler A, Moses JW, Leon MB, Epstein SE. Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease. Am J Cardiol. 2006 Mar 15;97(6):823-9. doi: 10.1016/j.amjcard.2005.09.132. Epub 2006 Jan 30.</citation>
    <PMID>16516583</PMID>
  </reference>
  <reference>
    <citation>Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A. Spontaneous human adult stem cell transformation. Cancer Res. 2005 Apr 15;65(8):3035-9. doi: 10.1158/0008-5472.CAN-04-4194. Erratum In: Cancer Res. 2005 Jun 1;65(11):4969.</citation>
    <PMID>15833829</PMID>
  </reference>
  <reference>
    <citation>Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007 Oct 1;67(19):9142-9. doi: 10.1158/0008-5472.CAN-06-4690.</citation>
    <PMID>17909019</PMID>
  </reference>
  <reference>
    <citation>Miura Y, Gao Z, Miura M, Seo BM, Sonoyama W, Chen W, Gronthos S, Zhang L, Shi S. Mesenchymal stem cell-organized bone marrow elements: an alternative hematopoietic progenitor resource. Stem Cells. 2006 Nov;24(11):2428-36. doi: 10.1634/stemcells.2006-0089.</citation>
    <PMID>17071859</PMID>
  </reference>
  <reference>
    <citation>Dahl JA, Duggal S, Coulston N, Millar D, Melki J, Shahdadfar A, Brinchmann JE, Collas P. Genetic and epigenetic instability of human bone marrow mesenchymal stem cells expanded in autologous serum or fetal bovine serum. Int J Dev Biol. 2008;52(8):1033-42. doi: 10.1387/ijdb.082663jd.</citation>
    <PMID>18956336</PMID>
  </reference>
  <reference>
    <citation>Tarte K, Gaillard J, Lataillade JJ, Fouillard L, Becker M, Mossafa H, Tchirkov A, Rouard H, Henry C, Splingard M, Dulong J, Monnier D, Gourmelon P, Gorin NC, Sensebe L; Societe Francaise de Greffe de Moelle et Therapie Cellulaire. Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood. 2010 Feb 25;115(8):1549-53. doi: 10.1182/blood-2009-05-219907. Epub 2009 Dec 23.</citation>
    <PMID>20032501</PMID>
  </reference>
  <reference>
    <citation>Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lonning PE, Bjerkvig R, Schichor C. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009 Jul 1;69(13):5331-9. doi: 10.1158/0008-5472.CAN-08-4630. Epub 2009 Jun 9.</citation>
    <PMID>19509230</PMID>
  </reference>
  <reference>
    <citation>Garcia S, Bernad A, Martin MC, Cigudosa JC, Garcia-Castro J, de la Fuente R. Pitfalls in spontaneous in vitro transformation of human mesenchymal stem cells. Exp Cell Res. 2010 May 15;316(9):1648-50. doi: 10.1016/j.yexcr.2010.02.016. Epub 2010 Feb 18. No abstract available.</citation>
    <PMID>20171963</PMID>
  </reference>
  <reference>
    <citation>Prockop DJ, Brenner M, Fibbe WE, Horwitz E, Le Blanc K, Phinney DG, Simmons PJ, Sensebe L, Keating A. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy. 2010 Sep;12(5):576-8. doi: 10.3109/14653249.2010.507330.</citation>
    <PMID>20735162</PMID>
  </reference>
  <reference>
    <citation>Ladwig GP, Robson MC, Liu R, Kuhn MA, Muir DF, Schultz GS. Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair Regen. 2002 Jan-Feb;10(1):26-37. doi: 10.1046/j.1524-475x.2002.10903.x.</citation>
    <PMID>11983004</PMID>
  </reference>
  <reference>
    <citation>Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen. 1996 Oct;4(4):411-20. doi: 10.1046/j.1524-475X.1996.40404.x.</citation>
    <PMID>17309691</PMID>
  </reference>
  <verification_date>January 2016</verification_date>
  <study_first_submitted>September 12, 2012</study_first_submitted>
  <study_first_submitted_qc>September 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 17, 2012</study_first_posted>
  <last_update_submitted>January 26, 2016</last_update_submitted>
  <last_update_submitted_qc>January 26, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 27, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sheba Medical Center</investigator_affiliation>
    <investigator_full_name>Dr. Itzhak Siev-Ner</investigator_full_name>
    <investigator_title>Head of the Orthopedic Rehabilitation Department</investigator_title>
  </responsible_party>
  <keyword>Diabetic mellitus</keyword>
  <keyword>Diabetic foot ulcers</keyword>
  <keyword>Ischemic Limb</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetic Foot</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
    <mesh_term>Ulcer</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/NCT01686139
org study id: SHEBA-11-8802-IS-SMC
nct id: NCT01686139
lead sponsor: 
has dmc: No
Diabetes Mellitus (DM) can be regarded as one of the "epidemics" of the western world.

      DM contributes to severe morbidity and mortality due to damage in the target organs
      (neuropathy, vasculopathy, nephropathy, retinopathy).

      It affects the quality of life of the patients because of increased rate of blindness, IHD,
      stroke, end stage renal failure, hemodialysis and lower limb amputations (LLA).The Diabetic
      Foot (DF) is defined as destruction or infection of tissue/s in the foot of diabetic patients
      due to neurological damage and / or different levels of Peripheral Vascular Disease (PVD).
      Diabetic foot complications are the most common cause of lower extremity amputations in the
      industrialized world. The lifetime occurence of Diabetic Foot Ulcers (DFU) is 20% in diabetic
      patients.

      Between 15% - 25% of the foot ulcers will lead to lower limb amputations.

      It has been shown that Mesenchymal Stem Cells (MSCs) could be an effective therapy for many
      diseases including acute respiratory distress syndrome, spinal cord injury, liver injury and
      critical limb ischemia.

      Stem cells can be obtained from either the patient (autologous) or non-related healthy donors
      (allogeneic).

      The purpose of this study is to determine the safety and efficacy of cultured Bone Marrow
      Mesenchymal Stromal Cells (BM-MSCs) from allogeneic donors for treatment of chronic leg
      wounds of diabetic patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Frequency of Adverse Events
time frame: 6 months after treatment
description: Frequency and severity of Adverse Events.
arm group label: ABDM-MSC
arm group type: Experimental
description: The patient will receive multiple injections in one session during the study. The injections will take place in the chronic wound bed and in the third distal part of the treated shin (in the form of a ring).
Maximal amount of ABMD-MSC cells injected: 10-20*10^6 cells (up to volume of 20mL, depending on the wound size & patient weight).
intervention type: Biological
intervention name: ABMD-MSC
description: 10-20 x 10^6 cells/20mL
arm group label: ABDM-MSC
criteria: 
gender: All
minimum age: 18 Years
maximum age: 81 Years
healthy volunteers: No
last name: Itzhak Siev-Ner, MD
role: Principal Investigator
affiliation: Sheba Medical Center
last name: Itzhak Siev-Ner, MD
phone: 03-530-3701
email: zivner@netvision.net.il
facility: 
contact: 
investigator: 
country: Israel
citation: Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 1976 Sep;4(5):267-74.
PMID: 976387
citation: Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):419-27. doi: 10.1016/j.cytogfr.2009.10.002. Epub 2009 Nov 18.
PMID: 19926330
citation: Wu Y, Zhao RC, Tredget EE. Concise review: bone marrow-derived stem/progenitor cells in cutaneous repair and regeneration. Stem Cells. 2010 May;28(5):905-15. doi: 10.1002/stem.420.
PMID: 20474078
citation: Sensebe L, Krampera M, Schrezenmeier H, Bourin P, Giordano R. Mesenchymal stem cells for clinical application. Vox Sang. 2010 Feb;98(2):93-107. doi: 10.1111/j.1423-0410.2009.01227.x. Epub 2009 Aug 3.
PMID: 19663934
citation: Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008 Apr 2;3(4):e1886. doi: 10.1371/journal.pone.0001886.
PMID: 18382669
citation: Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen. 2006 May-Jun;14(3):325-35. doi: 10.1111/j.1743-6109.2006.00128.x.
PMID: 16808812
citation: McFarlin K, Gao X, Liu YB, Dulchavsky DS, Kwon D, Arbab AS, Bansal M, Li Y, Chopp M, Dulchavsky SA, Gautam SC. Bone marrow-derived mesenchymal stromal cells accelerate wound healing in the rat. Wound Repair Regen. 2006 Jul-Aug;14(4):471-8. doi: 10.1111/j.1743-6109.2006.00153.x.
PMID: 16939576
citation: Wu Y, Wang J, Scott PG, Tredget EE. Bone marrow-derived stem cells in wound healing: a review. Wound Repair Regen. 2007 Sep-Oct;15 Suppl 1:S18-26. doi: 10.1111/j.1524-475X.2007.00221.x. Erratum In: Wound Repair Regen. 2008 Jul-Aug;16(4):582.
PMID: 17727462
citation: Kwon DS, Gao X, Liu YB, Dulchavsky DS, Danyluk AL, Bansal M, Chopp M, McIntosh K, Arbab AS, Dulchavsky SA, Gautam SC. Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. Int Wound J. 2008 Jun;5(3):453-63. doi: 10.1111/j.1742-481X.2007.00408.x.
PMID: 18593394
citation: Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007 May;117(5):1219-22. doi: 10.1172/JCI32169.
PMID: 17476353
citation: Iwase T, Nagaya N, Fujii T, Itoh T, Murakami S, Matsumoto T, Kangawa K, Kitamura S. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res. 2005 Jun 1;66(3):543-51. doi: 10.1016/j.cardiores.2005.02.006. Epub 2005 Mar 2.
PMID: 15914119
citation: Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003 Jun;9(6):702-12. doi: 10.1038/nm0603-702.
PMID: 12778169
citation: Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, Shrayer D, Carson P. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007 Jun;13(6):1299-312. doi: 10.1089/ten.2006.0278.
PMID: 17518741
citation: Kirana S, Stratmann B, Lammers D, Negrean M, Stirban A, Minartz P, Koerperich H, Gastens MH, Gotting C, Prohaska W, Kleesiek K, Tschoepe D. Wound therapy with autologous bone marrow stem cells in diabetic patients with ischaemia-induced tissue ulcers affecting the lower limbs. Int J Clin Pract. 2007 Apr;61(4):690-2. doi: 10.1111/j.1742-1241.2007.01303.x.
PMID: 17394441
citation: Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009 Oct;12(5):359-66. doi: 10.1089/rej.2009.0872.
PMID: 19929258
citation: Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8932-7. doi: 10.1073/pnas.132252399.
PMID: 12084934
citation: Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002 Oct 8;106(15):1913-8. doi: 10.1161/01.cir.0000034046.87607.1c.
PMID: 12370212
citation: Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004 Jul 1;94(1):92-5. doi: 10.1016/j.amjcard.2004.03.034.
PMID: 15219514
citation: Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006 Sep 21;355(12):1199-209. doi: 10.1056/NEJMoa055706.
PMID: 16990383
citation: Fuchs S, Kornowski R, Weisz G, Satler LF, Smits PC, Okubagzi P, Baffour R, Aggarwal A, Weissman NJ, Cerqueira M, Waksman R, Serrruys P, Battler A, Moses JW, Leon MB, Epstein SE. Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease. Am J Cardiol. 2006 Mar 15;97(6):823-9. doi: 10.1016/j.amjcard.2005.09.132. Epub 2006 Jan 30.
PMID: 16516583
citation: Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A. Spontaneous human adult stem cell transformation. Cancer Res. 2005 Apr 15;65(8):3035-9. doi: 10.1158/0008-5472.CAN-04-4194. Erratum In: Cancer Res. 2005 Jun 1;65(11):4969.
PMID: 15833829
citation: Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007 Oct 1;67(19):9142-9. doi: 10.1158/0008-5472.CAN-06-4690.
PMID: 17909019
citation: Miura Y, Gao Z, Miura M, Seo BM, Sonoyama W, Chen W, Gronthos S, Zhang L, Shi S. Mesenchymal stem cell-organized bone marrow elements: an alternative hematopoietic progenitor resource. Stem Cells. 2006 Nov;24(11):2428-36. doi: 10.1634/stemcells.2006-0089.
PMID: 17071859
citation: Dahl JA, Duggal S, Coulston N, Millar D, Melki J, Shahdadfar A, Brinchmann JE, Collas P. Genetic and epigenetic instability of human bone marrow mesenchymal stem cells expanded in autologous serum or fetal bovine serum. Int J Dev Biol. 2008;52(8):1033-42. doi: 10.1387/ijdb.082663jd.
PMID: 18956336
citation: Tarte K, Gaillard J, Lataillade JJ, Fouillard L, Becker M, Mossafa H, Tchirkov A, Rouard H, Henry C, Splingard M, Dulong J, Monnier D, Gourmelon P, Gorin NC, Sensebe L; Societe Francaise de Greffe de Moelle et Therapie Cellulaire. Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood. 2010 Feb 25;115(8):1549-53. doi: 10.1182/blood-2009-05-219907. Epub 2009 Dec 23.
PMID: 20032501
citation: Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lonning PE, Bjerkvig R, Schichor C. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009 Jul 1;69(13):5331-9. doi: 10.1158/0008-5472.CAN-08-4630. Epub 2009 Jun 9.
PMID: 19509230
citation: Garcia S, Bernad A, Martin MC, Cigudosa JC, Garcia-Castro J, de la Fuente R. Pitfalls in spontaneous in vitro transformation of human mesenchymal stem cells. Exp Cell Res. 2010 May 15;316(9):1648-50. doi: 10.1016/j.yexcr.2010.02.016. Epub 2010 Feb 18. No abstract available.
PMID: 20171963
citation: Prockop DJ, Brenner M, Fibbe WE, Horwitz E, Le Blanc K, Phinney DG, Simmons PJ, Sensebe L, Keating A. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy. 2010 Sep;12(5):576-8. doi: 10.3109/14653249.2010.507330.
PMID: 20735162
citation: Ladwig GP, Robson MC, Liu R, Kuhn MA, Muir DF, Schultz GS. Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair Regen. 2002 Jan-Feb;10(1):26-37. doi: 10.1046/j.1524-475x.2002.10903.x.
PMID: 11983004
citation: Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen. 1996 Oct;4(4):411-20. doi: 10.1046/j.1524-475X.1996.40404.x.
PMID: 17309691
responsible party type: Principal Investigator
investigator affiliation: Sheba Medical Center
investigator full name: Dr. Itzhak Siev-Ner
investigator title: Head of the Orthopedic Rehabilitation Department
mesh term: Diabetic Foot
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Diabetes Mellitus, Type 1
mesh term: Ulcer