<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/NCT04432545</url>
  </required_header>
  <id_info>
    <org_study_id>2019-10</org_study_id>
    <nct_id>NCT04432545</nct_id>
  </id_info>
  <brief_title>Infusion of Allogeneic Mesenchymal Stem Cells in Patients With Diffuse Cutaneous Systemic Sclerosis With Refractory Pulmonary Involvement</brief_title>
  <official_title>Infusion of Allogeneic Stromal Mesenchymal Stem Cells From Wharton´s Jelly in Patients With Diffuse Cutaneous Systemic Sclerosis With Refractory Pulmonary Involvement to Treatment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universidad de la Sabana</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fundación Neumologica Colombiana</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stem Medicina Regenerativa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>CryoHoldco LATAM</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universidad de la Sabana</source>
  <brief_summary>
    <textblock>
      Progressive SSc is an entity with limited therapeutic alternatives and with asurvival rate of&#xD;
      less than 45% in the first 3 to 5 years. The disease causessevere limitation in quality of&#xD;
      life ranging from functional limitation to depression. Up to 20% of patients will be&#xD;
      refractory to conventional treatment with diseasemodifying anti-rheumatic drugs (DMARDs) and&#xD;
      cyclophosphamide therapy.This favors the progression to visceral involvement including&#xD;
      gastrointestinal,lung and pulmonary hypertension. The latter being a poor prognostic&#xD;
      factor,increases mortality in this group of patients and drastically affects their qualityof&#xD;
      life. For this reason, different therapeutic options have been considered including cell&#xD;
      transplantation and Stem Cell use. Among the options that have been studied so far are&#xD;
      stromal mesenchymal cells from Wharton ́s jelly. These have been used in intravenous infusion&#xD;
      or direct application in different disease scenarios ranging from vascular involvement to&#xD;
      interstitial lung involvement and cases of pulmonary hypertension, with promising results in&#xD;
      terms of clinical progression,improvement in quality of life and prognostic indices. This&#xD;
      therapy has proven to have a significant margin of safety at the time of administration and a&#xD;
      low rate of adverse events, a self-limiting fever as the most frequent event. Based on the&#xD;
      above and considering the possibility of offering patients without therapeutic alternatives&#xD;
      to their disease in addition to palliative options, an intravenous infusion of stromal&#xD;
      mesenchymal stem cells from Wharton ́s jellyis proposed for three patients with progressive&#xD;
      SSc refractory to conventional therapy with pulmonary involvement due to pulmonary&#xD;
      hypertension.&#xD;
&#xD;
      Under this premise the question posed in our work is; What are the effects of the infusion of&#xD;
      allogeneic mesenchymal stromal cells from Wharton ́s jellyin patients with systemic sclerosis&#xD;
      refractory to conventional treatment with Methotrexate or Cyclophosphamide in a population of&#xD;
      three patients with severe pulmonary involvement due to pulmonary hypertension.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study aims to evaluate the therapeutic effects of allogeneic mesenchymal stromal cell&#xD;
      infusion as a treatment in patients with systemic sclerosis refractoryto conventional&#xD;
      therapy. The group of patients will be collected from the database of families of Stem&#xD;
      Regenerative Medicine according to the inclusion and exclusion criteria and verified in the&#xD;
      academic committee.&#xD;
&#xD;
      The administration will be intravenously, with a concentration of 2 X 10^6 mesenchymal cells&#xD;
      per kilogram of patient weight. The infusions will be carried out nested at cyclophosphamide&#xD;
      application cycles ten days after each application of the cyclophosphamide schedule for each&#xD;
      patient. To assess safety and therapeutic effects, the occurrence of any adverse event will&#xD;
      be described from start of infusion until the conclusion of the trial in six months.&#xD;
&#xD;
      To assess the response, a pre-infusion and sixth-month post-infusion instrument will be&#xD;
      applied that includes clinical variables, paraclinical and hemodynamic tests to evaluate skin&#xD;
      involvement using the modified RODNAN score, changes in nail capillaroscopy, lung function&#xD;
      and structural involvement by high-resolution chest tomography (hrCT), diffusion capacity for&#xD;
      carbon monoxide (DLCO) and a 6-minute walk. As part of the cardiovascular assessment,&#xD;
      cerebral natriuretic peptide (BNP), transthoracic echocardiogramwill be performed; The&#xD;
      Cambridge Pulmonary Hypertension Outcome Review(CAMPHOR) and Sysq will be used as tools for&#xD;
      the assessment of pulmonary hypertension. A comparison of these tests before initiation of&#xD;
      therapy and after completion of 24 weeks of infusion scheme should be performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Available</overall_status>
  <study_type>Expanded Access</study_type>
  <has_expanded_access>No</has_expanded_access>
  <expanded_access_info>
    <expanded_access_type_intermediate>Yes</expanded_access_type_intermediate>
  </expanded_access_info>
  <condition>Systemic Sclerosis Pulmonary</condition>
  <condition>Pulmonary Hypertension</condition>
  <condition>Pulmonary Fibrosis</condition>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mesenchymal Stem Cells from Wharton ́s jellyintravenous infusion of Mesenchymal Stem Cells from Wharton ́s jelly</intervention_name>
    <description>Mesenchymal Stem Cells from Wharton ́s jellyintravenous infusion of Mesenchymal Stem Cells from Wharton ́s jelly</description>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age&gt; 18 years and &lt;65 years.• Established diagnosis of systemic sclerosis according to&#xD;
             the criteria of theAmerican College of Rheumatology• SSc of poor prognosis, involving&#xD;
             life-threatening severe visceralinvolvement (cardiac or pulmonary hypertension ), lack&#xD;
             of response toconventional immunosuppressive therapy used in severe forms of&#xD;
             thedisease according to the European recommendations of EUSTAR and EBMT, relying on&#xD;
             high doses of IV cyclophosphamide (either in monthlybolus for at least six months); or&#xD;
             SSc with life-threatening pulmonaryhypertension. Patients may or may not have&#xD;
             pulmonary fibrosis.• Signed informed consent.• Presence of a consenting MSC donor•&#xD;
             Affiliation to social security&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or absence of appropriate contraception throughout the study.• Pulmonary&#xD;
             artery systolic pressure (PASP) &gt;75mmHg (onechocardiography or after right heart&#xD;
             catheterization);- Theorical DLCO &lt;30%• Calculated creatinine clearance &lt;30 ml/mn/m2•&#xD;
             Clinical sign of a congestive heart failure refractory ;• Left ventricular ejection&#xD;
             fraction &lt;35% at myocardial scintigraphy orechocardiography;• Chronic atrial&#xD;
             fibrillation requiring oral anticoagulant therapy;• Uncontrolled ventricular&#xD;
             arrhythmia;• Pericardial effusion with hemodynamic compromise assessed&#xD;
             byechocardiography.• Hepatic impairment defined as a persistent increase in&#xD;
             transaminases orbilirubin to 3 times normal.• Psychiatric disorders, including drug&#xD;
             taking and alcohol abuse.• Active neoplasia or concomitant myelodysplasia, antecedent&#xD;
             of neoplasia.• Bone marrow failure defined by neutropenia &lt;0.5 x 109 /&#xD;
             L,thrombocytopenia &lt;50 x 109 / L, anemia &lt;8 g / dL, CD4 lymphopenia &lt;200x 106 / L.•&#xD;
             Uncontrolled systemic hypertension.• Uncontrolled acute or chronic infection, HIV1, 2&#xD;
             or HTLV-1, 2seropositivity.• Chronic hepatitis B or C active.• Significant exposure to&#xD;
             bleomycin, toxic oils, vinyl chloride,trichloroethylene or silica;&#xD;
             eosinophilia-myalgia syndrome, eosinophiliafasciitis.• Risk of poor patient compliance&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Londono, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universidad de la Sabana</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>John Londono, MD,PhD</last_name>
    <phone>+573187114885</phone>
    <email>john.londono@unisabana.edu.co</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mabel Avila, MD,PhD</last_name>
    <phone>+573114747335</phone>
    <email>dircientifica@bancodecelulas.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Universidad de la Sabana</name>
      <address>
        <city>Chía</city>
        <state>Chia</state>
        <country>Colombia</country>
      </address>
    </facility>
    <status>Available</status>
    <contact>
      <last_name>John Londono, MD,PhD</last_name>
      <phone>573187114885</phone>
      <email>john.londono@unisabana.edu.co</email>
    </contact>
    <contact_backup>
      <last_name>Mabel Avila, MD,PhD</last_name>
      <phone>573114747335</phone>
      <email>dircientifica@bancodecelulas.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Colombia</country>
  </location_countries>
  <reference>
    <citation>Jaeger VK, Wirz EG, Allanore Y, Rossbach P, Riemekasten G, Hachulla E, Distler O, Airo P, Carreira PE, Balbir Gurman A, Tikly M, Vettori S, Damjanov N, Muller-Ladner U, Distler JH, Li M, Walker UA; EUSTAR co-authors. Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study. PLoS One. 2016 Oct 5;11(10):e0163894. doi: 10.1371/journal.pone.0163894. eCollection 2016.</citation>
    <PMID>27706206</PMID>
  </reference>
  <reference>
    <citation>McNearney TA, Reveille JD, Fischbach M, Friedman AW, Lisse JR, Goel N, Tan FK, Zhou X, Ahn C, Feghali-Bostwick CA, Fritzler M, Arnett FC, Mayes MD. Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheum. 2007 Mar 15;57(2):318-26. doi: 10.1002/art.22532.</citation>
    <PMID>17330281</PMID>
  </reference>
  <reference>
    <citation>Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE; SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. 2018 Jan 4;378(1):35-47. doi: 10.1056/nejmoa1703327.</citation>
    <PMID>29298160</PMID>
  </reference>
  <reference>
    <citation>van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV, Matucci-Cerinic M, Voskuyl AE, van de Loosdrecht AA, Daikeler T, Kotter I, Schmalzing M, Martin T, Lioure B, Weiner SM, Kreuter A, Deligny C, Durand JM, Emery P, Machold KP, Sarrot-Reynauld F, Warnatz K, Adoue DF, Constans J, Tony HP, Del Papa N, Fassas A, Himsel A, Launay D, Lo Monaco A, Philippe P, Quere I, Rich E, Westhovens R, Griffiths B, Saccardi R, van den Hoogen FH, Fibbe WE, Socie G, Gratwohl A, Tyndall A; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368.</citation>
    <PMID>25058083</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 10, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>June 11, 2020</last_update_submitted>
  <last_update_submitted_qc>June 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Refractory systemic sclerosis</keyword>
  <keyword>systemic sclerosis</keyword>
  <keyword>pulmonary hypertension</keyword>
  <keyword>mesenchymal stem cells</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Pulmonary Fibrosis</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Scleroderma, Systemic</mesh_term>
    <mesh_term>Scleroderma, Diffuse</mesh_term>
    <mesh_term>Sclerosis</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/NCT04432545
org study id: 2019-10
nct id: NCT04432545
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
Progressive SSc is an entity with limited therapeutic alternatives and with asurvival rate of
      less than 45% in the first 3 to 5 years. The disease causessevere limitation in quality of
      life ranging from functional limitation to depression. Up to 20% of patients will be
      refractory to conventional treatment with diseasemodifying anti-rheumatic drugs (DMARDs) and
      cyclophosphamide therapy.This favors the progression to visceral involvement including
      gastrointestinal,lung and pulmonary hypertension. The latter being a poor prognostic
      factor,increases mortality in this group of patients and drastically affects their qualityof
      life. For this reason, different therapeutic options have been considered including cell
      transplantation and Stem Cell use. Among the options that have been studied so far are
      stromal mesenchymal cells from Wharton ́s jelly. These have been used in intravenous infusion
      or direct application in different disease scenarios ranging from vascular involvement to
      interstitial lung involvement and cases of pulmonary hypertension, with promising results in
      terms of clinical progression,improvement in quality of life and prognostic indices. This
      therapy has proven to have a significant margin of safety at the time of administration and a
      low rate of adverse events, a self-limiting fever as the most frequent event. Based on the
      above and considering the possibility of offering patients without therapeutic alternatives
      to their disease in addition to palliative options, an intravenous infusion of stromal
      mesenchymal stem cells from Wharton ́s jellyis proposed for three patients with progressive
      SSc refractory to conventional therapy with pulmonary involvement due to pulmonary
      hypertension.

      Under this premise the question posed in our work is; What are the effects of the infusion of
      allogeneic mesenchymal stromal cells from Wharton ́s jellyin patients with systemic sclerosis
      refractory to conventional treatment with Methotrexate or Cyclophosphamide in a population of
      three patients with severe pulmonary involvement due to pulmonary hypertension.
This study aims to evaluate the therapeutic effects of allogeneic mesenchymal stromal cell
      infusion as a treatment in patients with systemic sclerosis refractoryto conventional
      therapy. The group of patients will be collected from the database of families of Stem
      Regenerative Medicine according to the inclusion and exclusion criteria and verified in the
      academic committee.

      The administration will be intravenously, with a concentration of 2 X 10^6 mesenchymal cells
      per kilogram of patient weight. The infusions will be carried out nested at cyclophosphamide
      application cycles ten days after each application of the cyclophosphamide schedule for each
      patient. To assess safety and therapeutic effects, the occurrence of any adverse event will
      be described from start of infusion until the conclusion of the trial in six months.

      To assess the response, a pre-infusion and sixth-month post-infusion instrument will be
      applied that includes clinical variables, paraclinical and hemodynamic tests to evaluate skin
      involvement using the modified RODNAN score, changes in nail capillaroscopy, lung function
      and structural involvement by high-resolution chest tomography (hrCT), diffusion capacity for
      carbon monoxide (DLCO) and a 6-minute walk. As part of the cardiovascular assessment,
      cerebral natriuretic peptide (BNP), transthoracic echocardiogramwill be performed; The
      Cambridge Pulmonary Hypertension Outcome Review(CAMPHOR) and Sysq will be used as tools for
      the assessment of pulmonary hypertension. A comparison of these tests before initiation of
      therapy and after completion of 24 weeks of infusion scheme should be performed.
expanded access type intermediate: Yes
intervention type: Biological
intervention name: Mesenchymal Stem Cells from Wharton ́s jellyintravenous infusion of Mesenchymal Stem Cells from Wharton ́s jelly
description: Mesenchymal Stem Cells from Wharton ́s jellyintravenous infusion of Mesenchymal Stem Cells from Wharton ́s jelly
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: John Londono, MD,PhD
role: Principal Investigator
affiliation: Universidad de la Sabana
last name: John Londono, MD,PhD
phone: +573187114885
email: john.londono@unisabana.edu.co
last name: Mabel Avila, MD,PhD
phone: +573114747335
email: dircientifica@bancodecelulas.com
facility: 
status: Available
contact: 
contact backup: 
country: Colombia
citation: Jaeger VK, Wirz EG, Allanore Y, Rossbach P, Riemekasten G, Hachulla E, Distler O, Airo P, Carreira PE, Balbir Gurman A, Tikly M, Vettori S, Damjanov N, Muller-Ladner U, Distler JH, Li M, Walker UA; EUSTAR co-authors. Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study. PLoS One. 2016 Oct 5;11(10):e0163894. doi: 10.1371/journal.pone.0163894. eCollection 2016.
PMID: 27706206
citation: McNearney TA, Reveille JD, Fischbach M, Friedman AW, Lisse JR, Goel N, Tan FK, Zhou X, Ahn C, Feghali-Bostwick CA, Fritzler M, Arnett FC, Mayes MD. Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheum. 2007 Mar 15;57(2):318-26. doi: 10.1002/art.22532.
PMID: 17330281
citation: Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE; SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. 2018 Jan 4;378(1):35-47. doi: 10.1056/nejmoa1703327.
PMID: 29298160
citation: van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV, Matucci-Cerinic M, Voskuyl AE, van de Loosdrecht AA, Daikeler T, Kotter I, Schmalzing M, Martin T, Lioure B, Weiner SM, Kreuter A, Deligny C, Durand JM, Emery P, Machold KP, Sarrot-Reynauld F, Warnatz K, Adoue DF, Constans J, Tony HP, Del Papa N, Fassas A, Himsel A, Launay D, Lo Monaco A, Philippe P, Quere I, Rich E, Westhovens R, Griffiths B, Saccardi R, van den Hoogen FH, Fibbe WE, Socie G, Gratwohl A, Tyndall A; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368.
PMID: 25058083
responsible party type: Sponsor
mesh term: Hypertension, Pulmonary
mesh term: Pulmonary Fibrosis
mesh term: Hypertension
mesh term: Scleroderma, Systemic
mesh term: Scleroderma, Diffuse
mesh term: Sclerosis