<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/NCT03790189</url>
  </required_header>
  <id_info>
    <org_study_id>172797</org_study_id>
    <nct_id>NCT03790189</nct_id>
  </id_info>
  <brief_title>Subchondral and Intra-articular Application of Bone Marrow Concentrate for Knee Unicompartmental OA</brief_title>
  <acronym>MarrowMule</acronym>
  <official_title>Subchondral and Intra-articular Application of Bone Marrow Concentrate as a Treatment Strategy for Knee Unicompartmental Osteoarthritis (OA): a Pilot Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istituto Clinico Humanitas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Istituto Clinico Humanitas</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>
      Unicompartmental knee osteoarthritis (OA) is a common finding especially in patients with&#xD;
      lower limb malalignment and previous meniscectomy. Among the various treatment options, in&#xD;
      recent years there has been an increasing attention towards the use of biologic agents, such&#xD;
      as platelet rich plasma and mesenchymal stem cells, as intra-articular injective approaches&#xD;
      to relieve pain and restore joint function. Anyway, the sole intra-articular administration&#xD;
      of these agents may not lead to satisfactory outcome in a relevant percentage of patients. In&#xD;
      fact, unicompartmental osteoarthritis is not only characterized by degeneration of the&#xD;
      articular cartilage, but also by pathologic changes in the subchondral bone, both at the&#xD;
      tibial plateaux and in the femoral condyle. Magnetic resonance imaging reveals, in many&#xD;
      cases, alterations of the subchondral tissue known as &quot;bone marrow edema&quot;, which is a sign of&#xD;
      bone overload and play a significant role in the progression of unicompartmental OA and is&#xD;
      responsible of OA-related symptoms. Therefore, concurrent treatment of both the subchondral&#xD;
      bone damage and intra-articular degeneration could led to better outcome for patients&#xD;
      affected by unicompartmental OA: the aim of the present pilot trial is to assess the safety&#xD;
      and describe the clinical outcome following concurrent intra-articular and subchondral bone&#xD;
      application of Bone Marrow Concentrate (BMC). BMC is an autologous product rich in&#xD;
      mesenchymal stem cells, which have immuno-modulatory and throfic properties and are able to&#xD;
      restore the joint homeostasis by reducing the inflammatory distress traditionally associated&#xD;
      to OA.&#xD;
&#xD;
      BMC will be collected directly in the operating room from the anterior iliac crest or the&#xD;
      tibia by using the MARROW CELLUTION kit (Geistlich, Switzerland), which allows to obtain BMC&#xD;
      without the need of centrifugation processes. Approximately 9-10 ml of BMC will be harvested:&#xD;
      6 ml will be injected, under fluoroscopic guidance, in the tibial emiplateaux (approx 3 ml)&#xD;
      and in the femoral condyle (approx 3 ml) presenting MRI evidence of bone marrow edema. The&#xD;
      remaining amount of BMC will be administered intra-articularly to address articular tissues&#xD;
      (cartilage, menisci and synovium). Twenty-five patients affected by unicompartmental knee OA&#xD;
      will be included in the present pilot trial and treated in a &quot;Day-Surgery&quot; regimen. They will&#xD;
      be followed up at 3, 6, and 12 months' after treatment by clinical questionnaires and&#xD;
      radiographic evaluations (x-rays at 6 and 12 months, MRI at 12 months' f-up). Any intra-op&#xD;
      and post-op adverse events will be documented.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">January 2019</start_date>
  <completion_date type="Anticipated">November 2021</completion_date>
  <primary_completion_date type="Anticipated">July 2021</primary_completion_date>
  <phase>N/A</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>Change in IKDC (International Knee Documentation Committee) subjective score</measure>
    <time_frame>baseline vs 12 months' follow-up</time_frame>
    <description>IKDC subjective score is a validated clinical questionnaire (available also in Italian) designed to assess the functional status of the knee by a series of 10 items. The IKDC subjective score assess the overall function of the knee as subjectively evaluated by the patient who needs to answer a series of questions concerning symptoms and his/her activity level. It ranges from 0 to 100 points, with higher values representing a better knee status.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Variation in KOOS (Knee Injury and Osteoarthritis Outcome) Score</measure>
    <time_frame>baseline vs 12 months' follow-up</time_frame>
    <description>KOOS score is a validated clinical questionnaire (available also in Italian) designed to assess the functional status of the knee by a series of 42 items. KOOS score consists of five sub-scales (Pain, Symptoms, Activity of Daily life, Sport, Quality of Life). The total score is obtained by summing the score of each sub-scale (max 21 point for Pain, 17 points for Symptoms, 41 points for Activity of daily life, 12 points for Sport, 9 points for Quality of Life). The total score's range is 0-100 and higher values represents better knee status.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VAS (Visual Analogue Scale) for pain</measure>
    <time_frame>baseline vs 12 months' after treatment</time_frame>
    <description>Visual Analogue Scale to evaluate average knee pain during daily life. Range is from 0 to 100 and higher values represent higher pain perceived by the patient.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRI (Magnetic Resonance Imaging) Changes in subchondral bone edema and cartilage status from basal to 12 months' follow-up</measure>
    <time_frame>baseline vs 12 months' follow-up</time_frame>
    <description>MRI of the index knee will be performed to assess if the bone marrow concentrate was able to produce any effect on the subchondral bone edema and/or articular cartilage. To this purpose, the WORMS (Whole Organ Magnetic Resonance Imaging Score) will be adopted. This score allows to evaluate: 1) the amount of bone marrow edema (0-3 scale based on the extension of the bone marrow edema in the anatomical region considered, with higher value representing bigger bone marrow edema); 2) the cartilage damage (0 to 6 scale with higher values representing worse cartilage status)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Osteoarthritis, Knee</condition>
  <condition>Cartilage Degeneration</condition>
  <arm_group>
    <arm_group_label>Bone Marrow Concentrate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Bone Marrow concentrate will be injected intra-articularly and at the bone-cartilage interface both in the tibia and femur of patients affected by unicompartmental knee osteoarthritis</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Subchondral and intra-articular injection of BMC</intervention_name>
    <description>Bone Marrow concentrate will be injected intra-articularly and at the bone-cartilage interface both in the tibia and femur of patients affected by unicompartmental knee osteoarthritis</description>
    <arm_group_label>Bone Marrow Concentrate</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  chronic symptomatic (at least 6 months) medial or lateral unicompartmental OA of the&#xD;
             knee, with Kellgren-Lawrence Score evaluated at x-rays= 2 or 3;&#xD;
&#xD;
          -  MRI evidence of &quot;bone marrow edema&quot; affecting the subchondral bone of the tibial&#xD;
             emiplateaux and femoral condyle;&#xD;
&#xD;
          -  failure of previous conservative treatments in the same knee (e.g: pharmacological&#xD;
             therapy, physiotherapy, previous intra-articular injections, etc..);&#xD;
&#xD;
          -  willingness to participate in the trial, including all follow-up visits and&#xD;
             radiographic examinations.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  medial or lateral unicompartmental OA with Kellgren-Lawrence score= 1 or 4 (i.e. early&#xD;
             osteoarthritis or end-stage osteoarthritis);&#xD;
&#xD;
          -  no MRI evidence of bone marrow edema in the affected knee compartment;&#xD;
&#xD;
          -  concurrent rheumatic or other immunological diseases;&#xD;
&#xD;
          -  concurrent malignancies;&#xD;
&#xD;
          -  bilateral symptomatic knee OA;&#xD;
&#xD;
          -  concurrent patello-femoral OA;&#xD;
&#xD;
          -  BMI&gt;35&#xD;
&#xD;
          -  any surgical treatment in the index knee within 12 months from the screening visit.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizaveta Kon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Istituto Clinico Humanitas, Rozzano, Italy</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Berardo Di Matteo, MD</last_name>
    <role>Study Director</role>
    <affiliation>Istituto Clinico Humanitas, Rozzano, Italy</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Berardo Di Matteo, MD</last_name>
    <phone>+390282245425</phone>
    <email>berardo.dimatteo@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Laura Lovato, MS</last_name>
    <email>laura.lovato@hunimed.eu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Istituto Clinico Humanitas</name>
      <address>
        <city>Rozzano</city>
        <state>Milano</state>
        <zip>20089</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Berardo Di Matteo</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Sanchez M, Delgado D, Sanchez P, Muinos-Lopez E, Paiva B, Granero-Molto F, Prosper F, Pompei O, Perez JC, Azofra J, Padilla S, Fiz N. Combination of Intra-Articular and Intraosseous Injections of Platelet Rich Plasma for Severe Knee Osteoarthritis: A Pilot Study. Biomed Res Int. 2016;2016:4868613. doi: 10.1155/2016/4868613. Epub 2016 Jul 4.</citation>
    <PMID>27462609</PMID>
  </reference>
  <reference>
    <citation>Kwan Tat S, Lajeunesse D, Pelletier JP, Martel-Pelletier J. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol. 2010 Feb;24(1):51-70. doi: 10.1016/j.berh.2009.08.004.</citation>
    <PMID>20129200</PMID>
  </reference>
  <reference>
    <citation>Dray A, Read SJ. Arthritis and pain. Future targets to control osteoarthritis pain. Arthritis Res Ther. 2007;9(3):212. doi: 10.1186/ar2178.</citation>
    <PMID>17561993</PMID>
  </reference>
  <reference>
    <citation>Pan J, Wang B, Li W, Zhou X, Scherr T, Yang Y, Price C, Wang L. Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints. Bone. 2012 Aug;51(2):212-7. doi: 10.1016/j.bone.2011.11.030. Epub 2011 Dec 16.</citation>
    <PMID>22197997</PMID>
  </reference>
  <reference>
    <citation>Sanchez M, Fiz N, Guadilla J, Padilla S, Anitua E, Sanchez P, Delgado D. Intraosseous infiltration of platelet-rich plasma for severe knee osteoarthritis. Arthrosc Tech. 2014 Dec 15;3(6):e713-7. doi: 10.1016/j.eats.2014.09.006. eCollection 2014 Dec.</citation>
    <PMID>25685680</PMID>
  </reference>
  <reference>
    <citation>Pretzel D, Linss S, Rochler S, Endres M, Kaps C, Alsalameh S, Kinne RW. Relative percentage and zonal distribution of mesenchymal progenitor cells in human osteoarthritic and normal cartilage. Arthritis Res Ther. 2011 Apr 15;13(2):R64. doi: 10.1186/ar3320.</citation>
    <PMID>21496249</PMID>
  </reference>
  <reference>
    <citation>Hernigou P, Auregan JC, Dubory A, Flouzat-Lachaniette CH, Chevallier N, Rouard H. Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. Int Orthop. 2018 Nov;42(11):2563-2571. doi: 10.1007/s00264-018-3916-9. Epub 2018 Mar 27.</citation>
    <PMID>29589086</PMID>
  </reference>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 22, 2018</study_first_submitted>
  <study_first_submitted_qc>December 28, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 31, 2018</study_first_posted>
  <last_update_submitted>December 28, 2018</last_update_submitted>
  <last_update_submitted_qc>December 28, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 31, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>knee</keyword>
  <keyword>unicompartmental osteoarthritis</keyword>
  <keyword>injection</keyword>
  <keyword>subchondroplasty</keyword>
  <keyword>bone marrow concentrate</keyword>
  <keyword>mesenchymal stem cells</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Osteoarthritis, Knee</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03790189
org study id: 172797
nct id: NCT03790189
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Unicompartmental knee osteoarthritis (OA) is a common finding especially in patients with
      lower limb malalignment and previous meniscectomy. Among the various treatment options, in
      recent years there has been an increasing attention towards the use of biologic agents, such
      as platelet rich plasma and mesenchymal stem cells, as intra-articular injective approaches
      to relieve pain and restore joint function. Anyway, the sole intra-articular administration
      of these agents may not lead to satisfactory outcome in a relevant percentage of patients. In
      fact, unicompartmental osteoarthritis is not only characterized by degeneration of the
      articular cartilage, but also by pathologic changes in the subchondral bone, both at the
      tibial plateaux and in the femoral condyle. Magnetic resonance imaging reveals, in many
      cases, alterations of the subchondral tissue known as "bone marrow edema", which is a sign of
      bone overload and play a significant role in the progression of unicompartmental OA and is
      responsible of OA-related symptoms. Therefore, concurrent treatment of both the subchondral
      bone damage and intra-articular degeneration could led to better outcome for patients
      affected by unicompartmental OA: the aim of the present pilot trial is to assess the safety
      and describe the clinical outcome following concurrent intra-articular and subchondral bone
      application of Bone Marrow Concentrate (BMC). BMC is an autologous product rich in
      mesenchymal stem cells, which have immuno-modulatory and throfic properties and are able to
      restore the joint homeostasis by reducing the inflammatory distress traditionally associated
      to OA.

      BMC will be collected directly in the operating room from the anterior iliac crest or the
      tibia by using the MARROW CELLUTION kit (Geistlich, Switzerland), which allows to obtain BMC
      without the need of centrifugation processes. Approximately 9-10 ml of BMC will be harvested:
      6 ml will be injected, under fluoroscopic guidance, in the tibial emiplateaux (approx 3 ml)
      and in the femoral condyle (approx 3 ml) presenting MRI evidence of bone marrow edema. The
      remaining amount of BMC will be administered intra-articularly to address articular tissues
      (cartilage, menisci and synovium). Twenty-five patients affected by unicompartmental knee OA
      will be included in the present pilot trial and treated in a "Day-Surgery" regimen. They will
      be followed up at 3, 6, and 12 months' after treatment by clinical questionnaires and
      radiographic evaluations (x-rays at 6 and 12 months, MRI at 12 months' f-up). Any intra-op
      and post-op adverse events will be documented.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in IKDC (International Knee Documentation Committee) subjective score
time frame: baseline vs 12 months' follow-up
description: IKDC subjective score is a validated clinical questionnaire (available also in Italian) designed to assess the functional status of the knee by a series of 10 items. The IKDC subjective score assess the overall function of the knee as subjectively evaluated by the patient who needs to answer a series of questions concerning symptoms and his/her activity level. It ranges from 0 to 100 points, with higher values representing a better knee status.
measure: Variation in KOOS (Knee Injury and Osteoarthritis Outcome) Score
time frame: baseline vs 12 months' follow-up
description: KOOS score is a validated clinical questionnaire (available also in Italian) designed to assess the functional status of the knee by a series of 42 items. KOOS score consists of five sub-scales (Pain, Symptoms, Activity of Daily life, Sport, Quality of Life). The total score is obtained by summing the score of each sub-scale (max 21 point for Pain, 17 points for Symptoms, 41 points for Activity of daily life, 12 points for Sport, 9 points for Quality of Life). The total score's range is 0-100 and higher values represents better knee status.
measure: VAS (Visual Analogue Scale) for pain
time frame: baseline vs 12 months' after treatment
description: Visual Analogue Scale to evaluate average knee pain during daily life. Range is from 0 to 100 and higher values represent higher pain perceived by the patient.
measure: MRI (Magnetic Resonance Imaging) Changes in subchondral bone edema and cartilage status from basal to 12 months' follow-up
time frame: baseline vs 12 months' follow-up
description: MRI of the index knee will be performed to assess if the bone marrow concentrate was able to produce any effect on the subchondral bone edema and/or articular cartilage. To this purpose, the WORMS (Whole Organ Magnetic Resonance Imaging Score) will be adopted. This score allows to evaluate: 1) the amount of bone marrow edema (0-3 scale based on the extension of the bone marrow edema in the anatomical region considered, with higher value representing bigger bone marrow edema); 2) the cartilage damage (0 to 6 scale with higher values representing worse cartilage status)
arm group label: Bone Marrow Concentrate
arm group type: Experimental
description: Bone Marrow concentrate will be injected intra-articularly and at the bone-cartilage interface both in the tibia and femur of patients affected by unicompartmental knee osteoarthritis
intervention type: Biological
intervention name: Subchondral and intra-articular injection of BMC
description: Bone Marrow concentrate will be injected intra-articularly and at the bone-cartilage interface both in the tibia and femur of patients affected by unicompartmental knee osteoarthritis
arm group label: Bone Marrow Concentrate
criteria: 
gender: All
minimum age: 35 Years
maximum age: 75 Years
healthy volunteers: No
last name: Elizaveta Kon, MD
role: Principal Investigator
affiliation: Istituto Clinico Humanitas, Rozzano, Italy
last name: Berardo Di Matteo, MD
role: Study Director
affiliation: Istituto Clinico Humanitas, Rozzano, Italy
last name: Berardo Di Matteo, MD
phone: +390282245425
email: berardo.dimatteo@gmail.com
last name: Laura Lovato, MS
email: laura.lovato@hunimed.eu
facility: 
status: Recruiting
contact: 
country: Italy
citation: Sanchez M, Delgado D, Sanchez P, Muinos-Lopez E, Paiva B, Granero-Molto F, Prosper F, Pompei O, Perez JC, Azofra J, Padilla S, Fiz N. Combination of Intra-Articular and Intraosseous Injections of Platelet Rich Plasma for Severe Knee Osteoarthritis: A Pilot Study. Biomed Res Int. 2016;2016:4868613. doi: 10.1155/2016/4868613. Epub 2016 Jul 4.
PMID: 27462609
citation: Kwan Tat S, Lajeunesse D, Pelletier JP, Martel-Pelletier J. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol. 2010 Feb;24(1):51-70. doi: 10.1016/j.berh.2009.08.004.
PMID: 20129200
citation: Dray A, Read SJ. Arthritis and pain. Future targets to control osteoarthritis pain. Arthritis Res Ther. 2007;9(3):212. doi: 10.1186/ar2178.
PMID: 17561993
citation: Pan J, Wang B, Li W, Zhou X, Scherr T, Yang Y, Price C, Wang L. Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints. Bone. 2012 Aug;51(2):212-7. doi: 10.1016/j.bone.2011.11.030. Epub 2011 Dec 16.
PMID: 22197997
citation: Sanchez M, Fiz N, Guadilla J, Padilla S, Anitua E, Sanchez P, Delgado D. Intraosseous infiltration of platelet-rich plasma for severe knee osteoarthritis. Arthrosc Tech. 2014 Dec 15;3(6):e713-7. doi: 10.1016/j.eats.2014.09.006. eCollection 2014 Dec.
PMID: 25685680
citation: Pretzel D, Linss S, Rochler S, Endres M, Kaps C, Alsalameh S, Kinne RW. Relative percentage and zonal distribution of mesenchymal progenitor cells in human osteoarthritic and normal cartilage. Arthritis Res Ther. 2011 Apr 15;13(2):R64. doi: 10.1186/ar3320.
PMID: 21496249
citation: Hernigou P, Auregan JC, Dubory A, Flouzat-Lachaniette CH, Chevallier N, Rouard H. Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. Int Orthop. 2018 Nov;42(11):2563-2571. doi: 10.1007/s00264-018-3916-9. Epub 2018 Mar 27.
PMID: 29589086
responsible party type: Sponsor
mesh term: Osteoarthritis
mesh term: Osteoarthritis, Knee
sharing ipd: No