<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/NCT02239393</url>
  </required_header>
  <id_info>
    <org_study_id>20140368</org_study_id>
    <nct_id>NCT02239393</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Intravenous Autologous Mesenchymal Stem Cells for MS: a Phase 2 Proof of Concept Study</brief_title>
  <acronym>MESCAMS</acronym>
  <official_title>MEsenchymal Stem Cell Therapy for CAnadian MS Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ottawa Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ottawa Hospital Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The mechanism of action of MSC relies on their ability to modulate pathogenic immune&#xD;
      responses and provide neuroprotection through the release of anti-apoptotic, anti-oxidant and&#xD;
      trophic factors as demonstrated by in-vitro and in-vivo preclinical studies.&#xD;
&#xD;
      Patients will be randomized to receive immediate vs. delayed treatment with either a dose&#xD;
      equal to 1-2 millions/kg of body weight of autologous MSC, or equivalent volume of suspension&#xD;
      media at baseline. At week 24 treatments will be reversed.&#xD;
&#xD;
      The primary outcome of this study is to evaluate:&#xD;
&#xD;
        -  Treatment's safety within one year from MSC administration by measuring the number,&#xD;
           time-frame and severity of adverse events and&#xD;
&#xD;
        -  Treatment's activity in terms of reduction in total number of gadolinium-enhancing&#xD;
           lesions (GEL) by magnetic resonance imaging (MRI) scans.&#xD;
&#xD;
      Secondary outcomes are to gain preliminary information on the efficacy of the experimental&#xD;
      treatment in terms of combined MRI activity and clinical efficacy (incidence of relapses and&#xD;
      disability progression).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The mechanism of action of Mesenchymal Stem Cells (MSCs) relies on their ability to modulate&#xD;
      pathogenic immune responses and provide neuroprotection through the release of&#xD;
      anti-apoptotic, anti-oxidant and trophic factors as demonstrated by in vitro and in vivo&#xD;
      preclinical studies.&#xD;
&#xD;
      Patients will be randomized to receive immediate vs. delayed treatment with either a dose&#xD;
      equal to 1-2 millions/kg of body weight of autologous MSC, or equivalent volume of suspension&#xD;
      media at baseline. At 6 months treatments will be reversed.&#xD;
&#xD;
      The primary outcome of this study is to evaluate&#xD;
&#xD;
        -  treatment's safety within one year from MSC administration by measuring the the number,&#xD;
           time-frame and severity of adverse event and&#xD;
&#xD;
        -  treatment's activity in terms of reduction in the total number of contrast-gadolinium&#xD;
           enhancing lesions (GEL) by magnetic resonance imaging (MRI) scans.&#xD;
&#xD;
      Secondary outcomes are to gain preliminary information on the efficacy of the experimental&#xD;
      treatment in terms of combined MRI activity and clinical efficacy (incidence of relapses and&#xD;
      disability progression).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2015</start_date>
  <completion_date type="Actual">December 2019</completion_date>
  <primary_completion_date type="Actual">December 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety</measure>
    <time_frame>24 weeks from first infusion</time_frame>
    <description>Incidence and severity of adverse events in MSC treatment group compared to placebo group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Efficacy</measure>
    <time_frame>24 weeks from first infusion</time_frame>
    <description>Total number of gadolinium-enhancing lesions (GEL) on MRI scan</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>48 weeks from first infusion</time_frame>
    <description>Number of gadolinium-enhancing lesions (GEL) counted over week 28, 36, 48 compared with the number of GEL counted over 4, 12, 24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>24 weeks from first infusion</time_frame>
    <description>Combined unique magnetic resonance imaging (MRI) activity (number of new or enlarging T2, or enhancing or re-enhancing lesions), volume of gadolinium-enhancing lesions (GEL) and volume of black holes (BH) over 4, 12, 24 weeks compared between treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>48 weeks from first infusion</time_frame>
    <description>Combined unique magnetic resonance imaging (MRI) activity, volume of gadolinium-enhancing lesions (GEL) and volume of black holes (BH) over week 28, 36, 48 compared with the same outcomes over 4, 12 and 24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>48 weeks from first infusion</time_frame>
    <description>Number of relapses in MSC treatment group vs. placebo group in the first 24 weeks and after cross-over re-treatment in the two groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>48 weeks from first infusion</time_frame>
    <description>Time to sustained progression of disability and proportion of progression-free patients compared between treatment groups during the first 24 weeks and after cross-over.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">31</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Autologous Mesenchymal Stem Cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1 to 2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Suspension media</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1 to 2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mesenchymal Stem Cells</intervention_name>
    <description>Mesenchymal Stem Cells in Plasma-Lyte A (Baxter) suspension media, containing 5% Human Albumin and 10% dimethylsulfoxide (DMSO, total volume of 5mL DMSO in final cell product) and autologous MSCs at a dose of 1 to 2 x 106 MSC/Kg participant's body weight at randomization.&#xD;
Matching placebo Plasma-Lyte A (Baxter) suspension media, containing 5% Human Albumin and 10% DMSO (total volume of 5mL DMSO in final cell product).</description>
    <arm_group_label>Autologous Mesenchymal Stem Cells</arm_group_label>
    <arm_group_label>Suspension media</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1) Males and females with a diagnosis of MS&#xD;
&#xD;
               1. Relapsing remitting MS (RRMS) not responding to at least 1 year of attempted&#xD;
                  therapy with one or more of the approved therapies (beta-interferon, glatiramer&#xD;
                  acetate, natalizumab, mitoxantrone, fingolimod, dimethyl fumarate, teriflunomide,&#xD;
                  alemtuzumab) as evidenced by at least one of the following:&#xD;
&#xD;
                    -  i) ≥1 clinically documented relapse in past 12 months&#xD;
&#xD;
                    -  ii) ≥2 clinically documented relapses in past 24 months&#xD;
&#xD;
                    -  iii) ≥1 gadolinium-enhancing lesion (GEL) at MRI performed within the past&#xD;
                       12 months&#xD;
&#xD;
               2. Secondary progressive MS (SPMS) not responding to at least a year of attempted&#xD;
                  therapy with one or more of the approved therapies (beta-interferon, glatiramer&#xD;
                  acetate, natalizumab, mitoxantrone, fingolimod, dimethylfumarate, teriflunomide,&#xD;
                  alemtuzumab) as evidenced by both:&#xD;
&#xD;
                    -  i) an increase of ≥1 EDSS point (if at randomization EDSS ≤ 5.0) or 0.5 EDSS&#xD;
                       point (if at randomization EDSS ≥ 5.5) in the past 12 months&#xD;
&#xD;
                    -  ii) ≥1 clinically documented relapse or ≥ 1 gadolinium-enhancing lesion&#xD;
                       (GEL) at MRI within the past 12 months&#xD;
&#xD;
               3. Primary progressive MS (PPMS) patients with all the following features:&#xD;
&#xD;
                    -  i) an increase of ≥1 EDSS point (if at randomization EDSS ≤ 5.0) or 0.5 EDSS&#xD;
                       point (if at randomization EDSS ≥5.5), in the past 12 months&#xD;
&#xD;
                    -  ii) ≥ 1 gadolinium-enhancing lesion (GEL) at MRI performed within the past&#xD;
                       12 months&#xD;
&#xD;
                    -  iii) positive cerebrospinal fluid (CSF) (oligoclonal banding)&#xD;
&#xD;
          -  2) Age 18 to 50 years old, inclusive at time of informed consent&#xD;
&#xD;
          -  3) Disease duration 2 to 15 years (inclusive)&#xD;
&#xD;
          -  4) EDSS 2.5 to 6.5&#xD;
&#xD;
          -  5) Able and willing to sign informed consent prior to any study-related activities&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1) RRMS not fulfilling inclusion criteria&#xD;
&#xD;
          -  2) SPMS not fulfilling inclusion criteria&#xD;
&#xD;
          -  3) PPMS not fulfilling inclusion criteria&#xD;
&#xD;
          -  4) A history of active or chronic infection including infection with HIV1-2, chronic&#xD;
             Hepatitis B or Hepatitis C&#xD;
&#xD;
          -  5) Treatment with any immunosuppressive therapy, including natalizumab and fingolimod,&#xD;
             within the 3 months prior to randomization&#xD;
&#xD;
          -  6) Previous treatment with cladribine or alemtuzumab&#xD;
&#xD;
          -  7) Treatment with interferon-beta, glatiramer acetate, teriflunomide or dimethyl&#xD;
             fumarate within the 30 days prior to randomization (all teriflunomide patients will be&#xD;
             required to have followed a wash-out with either cholestyramine or activated charcoal&#xD;
             as indicated in the product monograph)&#xD;
&#xD;
          -  8) Treatment with corticosteroids within the 30 days prior to randomization&#xD;
&#xD;
          -  9) Relapse occurred during the 60 days prior to randomization&#xD;
&#xD;
          -  10) Previous history of a malignancy (patient reported) other than basal cell&#xD;
             carcinoma of the skin or carcinoma in situ that has been in remission for more than&#xD;
             one year&#xD;
&#xD;
          -  11) Severely limited life expectancy by any other co-morbid illness&#xD;
&#xD;
          -  12) History of previous diagnosis of myelodysplasia or previous hematologic disease&#xD;
             (patient reported) or current clinically relevant abnormalities of white blood cell&#xD;
             counts&#xD;
&#xD;
          -  13) Pregnancy or risk of pregnancy (this includes participants that are not willing to&#xD;
             practice active contraception for the duration of the study)&#xD;
&#xD;
          -  14) eGFR &lt; 60 mL/min/1.73m2 or known renal failure or inability to undergo MRI&#xD;
             examination&#xD;
&#xD;
          -  15) Known allergy to gentamicin or related aminoglycosides&#xD;
&#xD;
          -  16) Inability to give written informed consent in accordance with research ethics&#xD;
             board guidelines&#xD;
&#xD;
          -  17) Concomitant participation in another clinical trial&#xD;
&#xD;
          -  18) Inability to adhere to protocol according to the investigator's medical judgement&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark S. Freedman, MSc MD FRCPC</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ottawa Hospital Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Health Sciences Centre</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R3A 1R9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ottawa Hospital - General Campus</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>September 10, 2014</study_first_submitted>
  <study_first_submitted_qc>September 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2014</study_first_posted>
  <last_update_submitted>March 3, 2020</last_update_submitted>
  <last_update_submitted_qc>March 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Multiple Sclerosis</keyword>
  <keyword>Mesenchymal Stem Cells</keyword>
  <keyword>MSC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>April 3, 2023</submitted>
  </pending_results>
  <!-- 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/NCT02239393
org study id: 20140368
nct id: NCT02239393
lead sponsor: 
has dmc: Yes
The mechanism of action of MSC relies on their ability to modulate pathogenic immune
      responses and provide neuroprotection through the release of anti-apoptotic, anti-oxidant and
      trophic factors as demonstrated by in-vitro and in-vivo preclinical studies.

      Patients will be randomized to receive immediate vs. delayed treatment with either a dose
      equal to 1-2 millions/kg of body weight of autologous MSC, or equivalent volume of suspension
      media at baseline. At week 24 treatments will be reversed.

      The primary outcome of this study is to evaluate:

        -  Treatment's safety within one year from MSC administration by measuring the number,
           time-frame and severity of adverse events and

        -  Treatment's activity in terms of reduction in total number of gadolinium-enhancing
           lesions (GEL) by magnetic resonance imaging (MRI) scans.

      Secondary outcomes are to gain preliminary information on the efficacy of the experimental
      treatment in terms of combined MRI activity and clinical efficacy (incidence of relapses and
      disability progression).
The mechanism of action of Mesenchymal Stem Cells (MSCs) relies on their ability to modulate
      pathogenic immune responses and provide neuroprotection through the release of
      anti-apoptotic, anti-oxidant and trophic factors as demonstrated by in vitro and in vivo
      preclinical studies.

      Patients will be randomized to receive immediate vs. delayed treatment with either a dose
      equal to 1-2 millions/kg of body weight of autologous MSC, or equivalent volume of suspension
      media at baseline. At 6 months treatments will be reversed.

      The primary outcome of this study is to evaluate

        -  treatment's safety within one year from MSC administration by measuring the the number,
           time-frame and severity of adverse event and

        -  treatment's activity in terms of reduction in the total number of contrast-gadolinium
           enhancing lesions (GEL) by magnetic resonance imaging (MRI) scans.

      Secondary outcomes are to gain preliminary information on the efficacy of the experimental
      treatment in terms of combined MRI activity and clinical efficacy (incidence of relapses and
      disability progression).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Safety
time frame: 24 weeks from first infusion
description: Incidence and severity of adverse events in MSC treatment group compared to placebo group
measure: Efficacy
time frame: 24 weeks from first infusion
description: Total number of gadolinium-enhancing lesions (GEL) on MRI scan
measure: Efficacy
time frame: 48 weeks from first infusion
description: Number of gadolinium-enhancing lesions (GEL) counted over week 28, 36, 48 compared with the number of GEL counted over 4, 12, 24 weeks.
measure: Efficacy
time frame: 24 weeks from first infusion
description: Combined unique magnetic resonance imaging (MRI) activity (number of new or enlarging T2, or enhancing or re-enhancing lesions), volume of gadolinium-enhancing lesions (GEL) and volume of black holes (BH) over 4, 12, 24 weeks compared between treatment groups.
measure: Efficacy
time frame: 48 weeks from first infusion
description: Combined unique magnetic resonance imaging (MRI) activity, volume of gadolinium-enhancing lesions (GEL) and volume of black holes (BH) over week 28, 36, 48 compared with the same outcomes over 4, 12 and 24 weeks.
measure: Efficacy
time frame: 48 weeks from first infusion
description: Number of relapses in MSC treatment group vs. placebo group in the first 24 weeks and after cross-over re-treatment in the two groups.
measure: Efficacy
time frame: 48 weeks from first infusion
description: Time to sustained progression of disability and proportion of progression-free patients compared between treatment groups during the first 24 weeks and after cross-over.
arm group label: Autologous Mesenchymal Stem Cells
arm group type: Experimental
description: At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1 to 2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0.
arm group label: Suspension media
arm group type: Experimental
description: At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1 to 2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0.
intervention type: Biological
intervention name: Mesenchymal Stem Cells
description: Mesenchymal Stem Cells in Plasma-Lyte A (Baxter) suspension media, containing 5% Human Albumin and 10% dimethylsulfoxide (DMSO, total volume of 5mL DMSO in final cell product) and autologous MSCs at a dose of 1 to 2 x 106 MSC/Kg participant's body weight at randomization.
Matching placebo Plasma-Lyte A (Baxter) suspension media, containing 5% Human Albumin and 10% DMSO (total volume of 5mL DMSO in final cell product).
arm group label: Autologous Mesenchymal Stem Cells
arm group label: Suspension media
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
last name: Mark S. Freedman, MSc MD FRCPC
role: Principal Investigator
affiliation: Ottawa Hospital Research Institute
facility: 
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Sclerosis
sharing ipd: No
submitted: April 3, 2023