<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/NCT03042572</url>
  </required_header>
  <id_info>
    <org_study_id>NL59038.000.16</org_study_id>
    <nct_id>NCT03042572</nct_id>
  </id_info>
  <brief_title>Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs</brief_title>
  <acronym>SAIL</acronym>
  <official_title>Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Martin Teraa, MD, PhD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ZonMw: The Netherlands Organisation for Health Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</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 primary objective of this trial is to investigate whether intramuscular administration of&#xD;
      allogeneic mesenchymal stromal cells (MSC) is safe and potentially effective, assessed as a&#xD;
      composite outcome of mortality, limb status, clinical status (Rutherford classification) and&#xD;
      pain score (visual analogue scale), in patients with no-option severe limb ischemia (SLI).&#xD;
&#xD;
      The investigators will conduct a double-blind, placebo-controlled randomized clinical trial&#xD;
      to investigate the effect of allogeneic bone marrow(BM)-derived MSC in patients with SLI, who&#xD;
      are not eligible for conventional surgical or endovascular therapies. The investigators&#xD;
      intend to include 60 patients, who will be randomized to undergo 30 intramuscular injections&#xD;
      with either BM-MSC (30 injection sites with 5*10^6 MSCs each) or placebo in the lower leg of&#xD;
      the ischemic extremity. Primary outcome i.e. therapy success, a composite outcome considering&#xD;
      mortality, limb status, clinical status (Rutherford classification) and changes in pain&#xD;
      score, will be assessed at six months.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">December 2018</start_date>
  <completion_date type="Anticipated">July 2021</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Therapy Success</measure>
    <time_frame>6 months</time_frame>
    <description>Composite outcome measure considering mortality, limb status, clinical classification and changes in pain score. To be a &quot;success&quot; a subject must: A, be alive; B, be without a major amputation on the index limb; C, have not worsened in Rutherford classification or visual analog pain scale; and D, have improved in either Rutherford classification or visual analog pain scale. Subjects not meeting all of the criteria are classified as failures.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Major amputation</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Amputation sited proximal from the ankle joint</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minor amputation</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Amputation sited distal from the ankle joint</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Therapy Success</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Composite outcome measure considering mortality, limb status, clinical classification and changes in pain score. To be a &quot;success&quot; a subject must: A, be alive; B, be without a major amputation on the index limb; C, have not worsened in Rutherford classification or visual analog pain scale; and D, have improved in either Rutherford classification or visual analog pain scale. Subjects not meeting all of the criteria are classified as failures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ulcer healing</measure>
    <time_frame>2 and 6 months</time_frame>
    <description>Changes in the number and extent of leg ulcers,</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in pain</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Resolution of rest pain and alteration in visual analogue pain (VAS) score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain-free walking distance</measure>
    <time_frame>2 and 6 months</time_frame>
    <description>Changes in pain free walking distance (treadmill at 3 km/h without incline)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ankle-brachial index (ABI)</measure>
    <time_frame>2 and 6 months</time_frame>
    <description>Alterations in ankle-brachial index (ABI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toe-brachial index (TBI)</measure>
    <time_frame>2 and 6 months</time_frame>
    <description>Alterations in toe-brachial index (TBI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life based on EuroQol 5D (EQ5D) questionnaire scores</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life based on Short Form 36 (SF36) questionnaire scores</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Alterations in quality of life assessed using Short Form 36 quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical status according to Fontaine classification</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Alterations clinical status according to Fontaine classification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical status according to Rutherford classification</measure>
    <time_frame>2, 6, 12, 24, and 60 months</time_frame>
    <description>Alterations clinical status according to Rutherford classification</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation of in-vitro angiogenic assay (Boyden chamber migration assays to test migration towards a platelet derived growth factor gradient) of donor MSC with clinical effect</measure>
    <time_frame>6 months</time_frame>
    <description>The investigators will use Boyden chamber migration assays to test migration towards a platelet derived growth factor gradient in order to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (et al. Mol Ther. 2014).</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of in-vitro angiogenic assay (Endothelial repair assay using a scratch wound assay using MSC-derived conditioned medium) of donor MSC with clinical effect</measure>
    <time_frame>6 months</time_frame>
    <description>The investigators will use endothelial repair assays using a scratch wound assay with MSC-derived conditioned medium to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (see Gremmels et al. Mol Ther. 2014).</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect</measure>
    <time_frame>6 months</time_frame>
    <description>The investigators will use matrigel tubule forming assays using MSC-derived conditioned medium to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (see Gremmels et al. Mol Ther. 2014).</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Peripheral Arterial Disease</condition>
  <condition>Cardiovascular Diseases</condition>
  <condition>Vascular Diseases</condition>
  <arm_group>
    <arm_group_label>Allogeneic Mesenchymal Stromal Cell</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Intramuscular placebo injection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Allogeneic Mesenchymal Stromal Cell</intervention_name>
    <description>Intramuscular allogeneic BM-MSC injection: MSCs will be extracted from BM of healthy volunteers, expanded with human platelet lysate, and stored. Patients will receive intramuscular allogeneic BM-MSC injections at 30 sites in the lower leg of the ischemic limb. Blinded syringes are provided and cell suspensions will be injected intramuscularly by an experienced operator into multiple sites (30 sites, 1-1.5cm in depth, volume of 1.0mL containing 5*10^6 MSC per site; total 150*10^6 BM-MSCs) in the ischemic lower extremity. Injections will be performed under IV analgesia (fentanyl) and sedation (midazolam) if necessary.</description>
    <arm_group_label>Allogeneic Mesenchymal Stromal Cell</arm_group_label>
    <other_name>Allogeneic bone marrow-derived mesenchymal stromal cells</other_name>
    <other_name>Allogeneic bone marrow-derived mesenchymal stem cells</other_name>
    <other_name>Allogeneic BM-MSC</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Intramuscular placebo injections. Patients will receive intramuscular placebo injections at 30 prespecified sites in the lower leg of the ischemic limb. Blinded syringes are provided and will be injected intramuscularly by an experienced operator into multiple sites (30 sites, 1-1.5cm in depth, volume of 1.0mL placebo per site) in the ischemic lower extremity. Injections will be performed under IV analgesia (fentanyl) and sedation (midazolam) if necessary.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Severe Peripheral Artery Disease (PAD; Fontaine class III and / or IV):&#xD;
&#xD;
               -  Fontaine III (Rutherford 4): persistent, recurring rest pain requiring analgesia&#xD;
&#xD;
               -  Fontaine IV (Rutherford 5): non-healing ulcers present for &gt; 4 weeks without&#xD;
                  evidence of improvement in response to conventional therapies&#xD;
&#xD;
          -  Ankle brachial index &lt; 0.6 or unreliable (non-compressible or not in proportion to the&#xD;
             Fontaine classification)&#xD;
&#xD;
          -  Not eligible for surgical or endovascular revascularization&#xD;
&#xD;
          -  Written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of neoplasm or malignancy in the past 10 years&#xD;
&#xD;
          -  Serious known concomitant disease with life expectancy of less than one year&#xD;
&#xD;
          -  Rutherford 6 in which amputation on the short term (within 1-2 weeks) is inevitable&#xD;
&#xD;
          -  Pregnancy or unwillingness to use adequate contraception during study&#xD;
&#xD;
          -  Uncontrolled acute or chronic infection with systemic symptoms&#xD;
&#xD;
          -  Follow-up impossible.&#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>Marianne C Verhaar, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gert Jan de Borst, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Joep GJ Wijnand, MD</last_name>
    <phone>+31 88 755 9747</phone>
    <email>J.G.J.Wijnand-2@umcutrecht.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Martin Teraa, MD, PhD</last_name>
    <phone>+31 88 755 6965</phone>
    <email>m.teraa@umcutrecht.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3508 GA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <contact>
      <last_name>Joep GJ Wijnand, MD</last_name>
      <phone>+31 88 755 9747</phone>
      <email>J.G.J.Wijnand-2@umcutrecht.nl</email>
    </contact>
    <contact_backup>
      <last_name>Martin Teraa, MD, PhD</last_name>
      <phone>+31 88 755 6965</phone>
      <email>m.teraa@umcutrecht.nl</email>
    </contact_backup>
    <investigator>
      <last_name>Hendrik Gremmels, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <reference>
    <citation>Teraa M, Sprengers RW, Schutgens RE, Slaper-Cortenbach IC, van der Graaf Y, Algra A, van der Tweel I, Doevendans PA, Mali WP, Moll FL, Verhaar MC. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation. 2015 Mar 10;131(10):851-60. doi: 10.1161/CIRCULATIONAHA.114.012913. Epub 2015 Jan 7.</citation>
    <PMID>25567765</PMID>
  </reference>
  <reference>
    <citation>Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials. Eur J Vasc Endovasc Surg. 2015 Dec;50(6):775-83. doi: 10.1016/j.ejvs.2015.08.018. Epub 2015 Oct 12.</citation>
    <PMID>26460286</PMID>
  </reference>
  <reference>
    <citation>Teraa M, Sprengers RW, van der Graaf Y, Peters CE, Moll FL, Verhaar MC. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg. 2013 Dec;258(6):922-9. doi: 10.1097/SLA.0b013e3182854cf1.</citation>
    <PMID>23426345</PMID>
  </reference>
  <reference>
    <citation>Spreen MI, Gremmels H, Teraa M, Sprengers RW, Verhaar MC, Statius van Eps RG, de Vries JP, Mali WP, van Overhagen H; PADI and JUVENTAS Study Groups. Diabetes Is Associated With Decreased Limb Survival in Patients With Critical Limb Ischemia: Pooled Data From Two Randomized Controlled Trials. Diabetes Care. 2016 Nov;39(11):2058-2064. doi: 10.2337/dc16-0850. Epub 2016 Sep 9.</citation>
    <PMID>27612499</PMID>
  </reference>
  <reference>
    <citation>Teraa M, Conte MS, Moll FL, Verhaar MC. Critical Limb Ischemia: Current Trends and Future Directions. J Am Heart Assoc. 2016 Feb 23;5(2):e002938. doi: 10.1161/JAHA.115.002938. No abstract available.</citation>
    <PMID>26908409</PMID>
  </reference>
  <reference>
    <citation>Peeters Weem SM, Teraa M, den Ruijter HM, de Borst GJ, Verhaar MC, Moll FL. Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia. Eur J Vasc Endovasc Surg. 2016 Jan;51(1):83-9. doi: 10.1016/j.ejvs.2015.09.010. Epub 2015 Oct 26.</citation>
    <PMID>26511056</PMID>
  </reference>
  <reference>
    <citation>Teraa M, Schutgens RE, Sprengers RW, Slaper-Cortenbach I, Moll FL, Verhaar MC; Juventas Study Group. Core diameter of bone marrow aspiration devices influences cell density of bone marrow aspirate in patients with severe peripheral artery disease. Cytotherapy. 2015 Dec;17(12):1807-12. doi: 10.1016/j.jcyt.2015.08.004. Epub 2015 Sep 28.</citation>
    <PMID>26428987</PMID>
  </reference>
  <reference>
    <citation>Wisman PP, Teraa M, de Borst GJ, Verhaar MC, Roest M, Moll FL. Baseline Platelet Activation and Reactivity in Patients with Critical Limb Ischemia. PLoS One. 2015 Jul 6;10(7):e0131356. doi: 10.1371/journal.pone.0131356. eCollection 2015.</citation>
    <PMID>26148006</PMID>
  </reference>
  <reference>
    <citation>Gremmels H, Teraa M, Quax PH, den Ouden K, Fledderus JO, Verhaar MC. Neovascularization capacity of mesenchymal stromal cells from critical limb ischemia patients is equivalent to healthy controls. Mol Ther. 2014 Nov;22(11):1960-70. doi: 10.1038/mt.2014.161. Epub 2014 Sep 1.</citation>
    <PMID>25174586</PMID>
  </reference>
  <reference>
    <citation>Gremmels H, Fledderus JO, Teraa M, Verhaar MC. Mesenchymal stromal cells for the treatment of critical limb ischemia: context and perspective. Stem Cell Res Ther. 2013;4(6):140. doi: 10.1186/scrt351.</citation>
    <PMID>24246031</PMID>
  </reference>
  <reference>
    <citation>Teraa M, Fledderus JO, Rozbeh RI, Leguit RJ, Verhaar MC; Juventas Study Groupdagger. Bone marrow microvascular and neuropathic alterations in patients with critical limb ischemia. Circ Res. 2014 Jan 17;114(2):311-4. doi: 10.1161/CIRCRESAHA.114.302791. Epub 2013 Nov 11.</citation>
    <PMID>24218170</PMID>
  </reference>
  <reference>
    <citation>Niemansburg SL, Teraa M, Hesam H, van Delden JJ, Verhaar MC, Bredenoord AL. Stem cell trials for cardiovascular medicine: ethical rationale. Tissue Eng Part A. 2014 Oct;20(19-20):2567-74. doi: 10.1089/ten.TEA.2013.0332. Epub 2013 Dec 11.</citation>
    <PMID>24164351</PMID>
  </reference>
  <reference>
    <citation>Westerweel PE, Teraa M, Rafii S, Jaspers JE, White IA, Hooper AT, Doevendans PA, Verhaar MC. Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus. PLoS One. 2013;8(3):e60357. doi: 10.1371/journal.pone.0060357. Epub 2013 Mar 28.</citation>
    <PMID>23555959</PMID>
  </reference>
  <reference>
    <citation>Teraa M, Sprengers RW, Westerweel PE, Gremmels H, Goumans MJ, Teerlink T, Moll FL, Verhaar MC; JUVENTAS study group. Bone marrow alterations and lower endothelial progenitor cell numbers in critical limb ischemia patients. PLoS One. 2013;8(1):e55592. doi: 10.1371/journal.pone.0055592. Epub 2013 Jan 31.</citation>
    <PMID>23383236</PMID>
  </reference>
  <reference>
    <citation>Setacci C, de Donato G, Teraa M, Moll FL, Ricco JB, Becker F, Robert-Ebadi H, Cao P, Eckstein HH, De Rango P, Diehm N, Schmidli J, Dick F, Davies AH, Lepantalo M, Apelqvist J. Chapter IV: Treatment of critical limb ischaemia. Eur J Vasc Endovasc Surg. 2011 Dec;42 Suppl 2:S43-59. doi: 10.1016/S1078-5884(11)60014-2.</citation>
    <PMID>22172473</PMID>
  </reference>
  <reference>
    <citation>Sprengers RW, Teraa M, Moll FL, de Wit GA, van der Graaf Y, Verhaar MC; JUVENTAS Study Group; SMART Study Group. Quality of life in patients with no-option critical limb ischemia underlines the need for new effective treatment. J Vasc Surg. 2010 Oct;52(4):843-9, 849.e1. doi: 10.1016/j.jvs.2010.04.057.</citation>
    <PMID>20598482</PMID>
  </reference>
  <reference>
    <citation>Sprengers RW, Moll FL, Teraa M, Verhaar MC; JUVENTAS Study Group. Rationale and design of the JUVENTAS trial for repeated intra-arterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia. J Vasc Surg. 2010 Jun;51(6):1564-8. doi: 10.1016/j.jvs.2010.02.020.</citation>
    <PMID>20488328</PMID>
  </reference>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>January 27, 2017</study_first_submitted>
  <study_first_submitted_qc>February 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 3, 2017</study_first_posted>
  <last_update_submitted>May 2, 2018</last_update_submitted>
  <last_update_submitted_qc>May 2, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>Martin Teraa, MD, PhD</investigator_full_name>
    <investigator_title>Surgical Resident &amp; Postdoc Physician</investigator_title>
  </responsible_party>
  <keyword>Critical Limb Ischemia (CLI)</keyword>
  <keyword>Severe Limb Ischemia (SLI)</keyword>
  <keyword>Peripheral Artery Disease (PAD)</keyword>
  <keyword>Peripheral Artery Occlusive Disease (PAOD)</keyword>
  <keyword>Cardiovascular disease</keyword>
  <keyword>Mesenchymal stromal cell (MSC)</keyword>
  <keyword>Mesenchymal stem cell (MSC)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Peripheral Arterial Disease</mesh_term>
    <mesh_term>Peripheral Vascular Diseases</mesh_term>
    <mesh_term>Vascular Diseases</mesh_term>
    <mesh_term>Neovascularization, Pathologic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Study outcomes will be published in international peer-reviewed journals and individual participant data (IPD) will become available on request.</ipd_description>
  </patient_data>
  <!-- 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/NCT03042572
org study id: NL59038.000.16
nct id: NCT03042572
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The primary objective of this trial is to investigate whether intramuscular administration of
      allogeneic mesenchymal stromal cells (MSC) is safe and potentially effective, assessed as a
      composite outcome of mortality, limb status, clinical status (Rutherford classification) and
      pain score (visual analogue scale), in patients with no-option severe limb ischemia (SLI).

      The investigators will conduct a double-blind, placebo-controlled randomized clinical trial
      to investigate the effect of allogeneic bone marrow(BM)-derived MSC in patients with SLI, who
      are not eligible for conventional surgical or endovascular therapies. The investigators
      intend to include 60 patients, who will be randomized to undergo 30 intramuscular injections
      with either BM-MSC (30 injection sites with 5*10^6 MSCs each) or placebo in the lower leg of
      the ischemic extremity. Primary outcome i.e. therapy success, a composite outcome considering
      mortality, limb status, clinical status (Rutherford classification) and changes in pain
      score, will be assessed at six months.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Therapy Success
time frame: 6 months
description: Composite outcome measure considering mortality, limb status, clinical classification and changes in pain score. To be a "success" a subject must: A, be alive; B, be without a major amputation on the index limb; C, have not worsened in Rutherford classification or visual analog pain scale; and D, have improved in either Rutherford classification or visual analog pain scale. Subjects not meeting all of the criteria are classified as failures.
measure: Major amputation
time frame: 2, 6, 12, 24, and 60 months
description: Amputation sited proximal from the ankle joint
measure: Minor amputation
time frame: 2, 6, 12, 24, and 60 months
description: Amputation sited distal from the ankle joint
measure: Therapy Success
time frame: 2, 6, 12, 24, and 60 months
description: Composite outcome measure considering mortality, limb status, clinical classification and changes in pain score. To be a "success" a subject must: A, be alive; B, be without a major amputation on the index limb; C, have not worsened in Rutherford classification or visual analog pain scale; and D, have improved in either Rutherford classification or visual analog pain scale. Subjects not meeting all of the criteria are classified as failures.
measure: Mortality
time frame: 2, 6, 12, 24, and 60 months
description: Mortality
measure: Ulcer healing
time frame: 2 and 6 months
description: Changes in the number and extent of leg ulcers,
measure: Changes in pain
time frame: 2, 6, 12, 24, and 60 months
description: Resolution of rest pain and alteration in visual analogue pain (VAS) score
measure: Pain-free walking distance
time frame: 2 and 6 months
description: Changes in pain free walking distance (treadmill at 3 km/h without incline)
measure: Ankle-brachial index (ABI)
time frame: 2 and 6 months
description: Alterations in ankle-brachial index (ABI)
measure: Toe-brachial index (TBI)
time frame: 2 and 6 months
description: Alterations in toe-brachial index (TBI)
measure: Quality of life based on EuroQol 5D (EQ5D) questionnaire scores
time frame: 2, 6, 12, 24, and 60 months
description: Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire
measure: Quality of life based on Short Form 36 (SF36) questionnaire scores
time frame: 2, 6, 12, 24, and 60 months
description: Alterations in quality of life assessed using Short Form 36 quality of life questionnaire
measure: Clinical status according to Fontaine classification
time frame: 2, 6, 12, 24, and 60 months
description: Alterations clinical status according to Fontaine classification
measure: Clinical status according to Rutherford classification
time frame: 2, 6, 12, 24, and 60 months
description: Alterations clinical status according to Rutherford classification
measure: Correlation of in-vitro angiogenic assay (Boyden chamber migration assays to test migration towards a platelet derived growth factor gradient) of donor MSC with clinical effect
time frame: 6 months
description: The investigators will use Boyden chamber migration assays to test migration towards a platelet derived growth factor gradient in order to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (et al. Mol Ther. 2014).
measure: Correlation of in-vitro angiogenic assay (Endothelial repair assay using a scratch wound assay using MSC-derived conditioned medium) of donor MSC with clinical effect
time frame: 6 months
description: The investigators will use endothelial repair assays using a scratch wound assay with MSC-derived conditioned medium to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (see Gremmels et al. Mol Ther. 2014).
measure: Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect
time frame: 6 months
description: The investigators will use matrigel tubule forming assays using MSC-derived conditioned medium to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (see Gremmels et al. Mol Ther. 2014).
arm group label: Allogeneic Mesenchymal Stromal Cell
arm group type: Experimental
description: Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection
arm group label: Placebo
arm group type: Placebo Comparator
description: Intramuscular placebo injection
intervention type: Drug
intervention name: Allogeneic Mesenchymal Stromal Cell
description: Intramuscular allogeneic BM-MSC injection: MSCs will be extracted from BM of healthy volunteers, expanded with human platelet lysate, and stored. Patients will receive intramuscular allogeneic BM-MSC injections at 30 sites in the lower leg of the ischemic limb. Blinded syringes are provided and cell suspensions will be injected intramuscularly by an experienced operator into multiple sites (30 sites, 1-1.5cm in depth, volume of 1.0mL containing 5*10^6 MSC per site; total 150*10^6 BM-MSCs) in the ischemic lower extremity. Injections will be performed under IV analgesia (fentanyl) and sedation (midazolam) if necessary.
arm group label: Allogeneic Mesenchymal Stromal Cell
other name: Allogeneic bone marrow-derived mesenchymal stromal cells
other name: Allogeneic bone marrow-derived mesenchymal stem cells
other name: Allogeneic BM-MSC
intervention type: Other
intervention name: Placebo
description: Intramuscular placebo injections. Patients will receive intramuscular placebo injections at 30 prespecified sites in the lower leg of the ischemic limb. Blinded syringes are provided and will be injected intramuscularly by an experienced operator into multiple sites (30 sites, 1-1.5cm in depth, volume of 1.0mL placebo per site) in the ischemic lower extremity. Injections will be performed under IV analgesia (fentanyl) and sedation (midazolam) if necessary.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marianne C Verhaar, MD, PhD
role: Principal Investigator
affiliation: UMC Utrecht
last name: Gert Jan de Borst, MD, PhD
role: Study Chair
affiliation: UMC Utrecht
last name: Joep GJ Wijnand, MD
phone: +31 88 755 9747
email: J.G.J.Wijnand-2@umcutrecht.nl
last name: Martin Teraa, MD, PhD
phone: +31 88 755 6965
email: m.teraa@umcutrecht.nl
facility: 
contact: 
contact backup: 
investigator: 
country: Netherlands
citation: Teraa M, Sprengers RW, Schutgens RE, Slaper-Cortenbach IC, van der Graaf Y, Algra A, van der Tweel I, Doevendans PA, Mali WP, Moll FL, Verhaar MC. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation. 2015 Mar 10;131(10):851-60. doi: 10.1161/CIRCULATIONAHA.114.012913. Epub 2015 Jan 7.
PMID: 25567765
citation: Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials. Eur J Vasc Endovasc Surg. 2015 Dec;50(6):775-83. doi: 10.1016/j.ejvs.2015.08.018. Epub 2015 Oct 12.
PMID: 26460286
citation: Teraa M, Sprengers RW, van der Graaf Y, Peters CE, Moll FL, Verhaar MC. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg. 2013 Dec;258(6):922-9. doi: 10.1097/SLA.0b013e3182854cf1.
PMID: 23426345
citation: Spreen MI, Gremmels H, Teraa M, Sprengers RW, Verhaar MC, Statius van Eps RG, de Vries JP, Mali WP, van Overhagen H; PADI and JUVENTAS Study Groups. Diabetes Is Associated With Decreased Limb Survival in Patients With Critical Limb Ischemia: Pooled Data From Two Randomized Controlled Trials. Diabetes Care. 2016 Nov;39(11):2058-2064. doi: 10.2337/dc16-0850. Epub 2016 Sep 9.
PMID: 27612499
citation: Teraa M, Conte MS, Moll FL, Verhaar MC. Critical Limb Ischemia: Current Trends and Future Directions. J Am Heart Assoc. 2016 Feb 23;5(2):e002938. doi: 10.1161/JAHA.115.002938. No abstract available.
PMID: 26908409
citation: Peeters Weem SM, Teraa M, den Ruijter HM, de Borst GJ, Verhaar MC, Moll FL. Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia. Eur J Vasc Endovasc Surg. 2016 Jan;51(1):83-9. doi: 10.1016/j.ejvs.2015.09.010. Epub 2015 Oct 26.
PMID: 26511056
citation: Teraa M, Schutgens RE, Sprengers RW, Slaper-Cortenbach I, Moll FL, Verhaar MC; Juventas Study Group. Core diameter of bone marrow aspiration devices influences cell density of bone marrow aspirate in patients with severe peripheral artery disease. Cytotherapy. 2015 Dec;17(12):1807-12. doi: 10.1016/j.jcyt.2015.08.004. Epub 2015 Sep 28.
PMID: 26428987
citation: Wisman PP, Teraa M, de Borst GJ, Verhaar MC, Roest M, Moll FL. Baseline Platelet Activation and Reactivity in Patients with Critical Limb Ischemia. PLoS One. 2015 Jul 6;10(7):e0131356. doi: 10.1371/journal.pone.0131356. eCollection 2015.
PMID: 26148006
citation: Gremmels H, Teraa M, Quax PH, den Ouden K, Fledderus JO, Verhaar MC. Neovascularization capacity of mesenchymal stromal cells from critical limb ischemia patients is equivalent to healthy controls. Mol Ther. 2014 Nov;22(11):1960-70. doi: 10.1038/mt.2014.161. Epub 2014 Sep 1.
PMID: 25174586
citation: Gremmels H, Fledderus JO, Teraa M, Verhaar MC. Mesenchymal stromal cells for the treatment of critical limb ischemia: context and perspective. Stem Cell Res Ther. 2013;4(6):140. doi: 10.1186/scrt351.
PMID: 24246031
citation: Teraa M, Fledderus JO, Rozbeh RI, Leguit RJ, Verhaar MC; Juventas Study Groupdagger. Bone marrow microvascular and neuropathic alterations in patients with critical limb ischemia. Circ Res. 2014 Jan 17;114(2):311-4. doi: 10.1161/CIRCRESAHA.114.302791. Epub 2013 Nov 11.
PMID: 24218170
citation: Niemansburg SL, Teraa M, Hesam H, van Delden JJ, Verhaar MC, Bredenoord AL. Stem cell trials for cardiovascular medicine: ethical rationale. Tissue Eng Part A. 2014 Oct;20(19-20):2567-74. doi: 10.1089/ten.TEA.2013.0332. Epub 2013 Dec 11.
PMID: 24164351
citation: Westerweel PE, Teraa M, Rafii S, Jaspers JE, White IA, Hooper AT, Doevendans PA, Verhaar MC. Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus. PLoS One. 2013;8(3):e60357. doi: 10.1371/journal.pone.0060357. Epub 2013 Mar 28.
PMID: 23555959
citation: Teraa M, Sprengers RW, Westerweel PE, Gremmels H, Goumans MJ, Teerlink T, Moll FL, Verhaar MC; JUVENTAS study group. Bone marrow alterations and lower endothelial progenitor cell numbers in critical limb ischemia patients. PLoS One. 2013;8(1):e55592. doi: 10.1371/journal.pone.0055592. Epub 2013 Jan 31.
PMID: 23383236
citation: Setacci C, de Donato G, Teraa M, Moll FL, Ricco JB, Becker F, Robert-Ebadi H, Cao P, Eckstein HH, De Rango P, Diehm N, Schmidli J, Dick F, Davies AH, Lepantalo M, Apelqvist J. Chapter IV: Treatment of critical limb ischaemia. Eur J Vasc Endovasc Surg. 2011 Dec;42 Suppl 2:S43-59. doi: 10.1016/S1078-5884(11)60014-2.
PMID: 22172473
citation: Sprengers RW, Teraa M, Moll FL, de Wit GA, van der Graaf Y, Verhaar MC; JUVENTAS Study Group; SMART Study Group. Quality of life in patients with no-option critical limb ischemia underlines the need for new effective treatment. J Vasc Surg. 2010 Oct;52(4):843-9, 849.e1. doi: 10.1016/j.jvs.2010.04.057.
PMID: 20598482
citation: Sprengers RW, Moll FL, Teraa M, Verhaar MC; JUVENTAS Study Group. Rationale and design of the JUVENTAS trial for repeated intra-arterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia. J Vasc Surg. 2010 Jun;51(6):1564-8. doi: 10.1016/j.jvs.2010.02.020.
PMID: 20488328
responsible party type: Sponsor-Investigator
investigator affiliation: UMC Utrecht
investigator full name: Martin Teraa, MD, PhD
investigator title: Surgical Resident & Postdoc Physician
mesh term: Cardiovascular Diseases
mesh term: Peripheral Arterial Disease
mesh term: Peripheral Vascular Diseases
mesh term: Vascular Diseases
mesh term: Neovascularization, Pathologic
sharing ipd: Undecided
ipd description: Study outcomes will be published in international peer-reviewed journals and individual participant data (IPD) will become available on request.