<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/NCT03771989</url>
  </required_header>
  <id_info>
    <org_study_id>TOMAT</org_study_id>
    <nct_id>NCT03771989</nct_id>
  </id_info>
  <brief_title>Treatment of Osteoarthritis With Autologous, Microfragmented Adipose Tissue.</brief_title>
  <official_title>Treatment of Osteoarthritis With Autologous, Microfragmented Adipose Tissue. A Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hvidovre University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hvidovre University Hospital</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 study is a blinded, multicenter, randomized, controlled trial with participants&#xD;
      individually randomized to one of two parallel groups:&#xD;
&#xD;
        1. The intervention group: Participants receive one intra articular injection with&#xD;
           autologous, microfragmented adipose tissue.&#xD;
&#xD;
        2. The control group: Participants receive one intra articular injection with Saline&#xD;
           (placebo).&#xD;
&#xD;
      The objective of the study is to investigate if intra-articular injection with autologous,&#xD;
      microfragmented adipose tissue prepared using the Lipogems system affects the patient&#xD;
      reported outcome in patients with osteoarthritis of the knee.&#xD;
&#xD;
      The primary endpoint is KOOS4 evaluated at 6 months after the intervention. Secondary&#xD;
      endpoints are the KOOS including all five subscales evaluated after 6months, 1 and 2 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      2 Study Objective To investigate if intra-articular injection with autologous,&#xD;
      microfragmented adipose tissue prepared using the Lipogems system affects the patient&#xD;
      reported outcome in patients with osteoarthritis of the knee.&#xD;
&#xD;
      Hypothesis Treatment with autologous, microfragmented adipose tissue has the potential to&#xD;
      reverse degenerative changes in knees with osteoarthritis. The patient will experience a&#xD;
      better patient reported health in comparison with placebo treatment.&#xD;
&#xD;
      Null hypothesis There is no difference in patient reported outcome when treatment with&#xD;
      autologous, microfragmented adipose tissue is compared to placebo treatment.&#xD;
&#xD;
      3 Background Osteoarthritis (OA) of the knee is a destructive joint disease, causing&#xD;
      degeneration of cartilage, damage to the underlying bone and morphological changes to the&#xD;
      joint1. It is a major public health concern due to the increased life expectancy of the&#xD;
      ageing population2,3. No approved medical treatment that reverses the morphological changes&#xD;
      currently exists. Conventional treatment includes physiotherapy, pain killers, braces and in&#xD;
      end-stage OA surgical knee replacement4.&#xD;
&#xD;
      During the past decade researchers have started to explore the regenerative potential of&#xD;
      mesenchymal stem cells (MSC) in OA5. MSCs are multipotent progenitor cells able to give rise&#xD;
      to osteocytes, adipocytes, chondrocytes, myoblasts and tenocytes6. MSCs were first used to&#xD;
      treat Chondral defects in 19987 and to treat OA in 20028. Since then, a number of case&#xD;
      reports and prospective series have been published showing significant short term and long&#xD;
      term effect on pain and cartilage thickness5. Latest a prospective case-series of 1128&#xD;
      patients involving 1856 joints showed an improvement of at least 50% in 86% of patients at 3&#xD;
      months and 91% of patients at 12 months using a modified Knee/Hip Osteoarthritis Outcome&#xD;
      Score (KOOS/HOOS) questionnaire9. Only 0.9% of patients did not show improvement after&#xD;
      treatment. However, when interpreting these studies one should bear in mind that they are all&#xD;
      level four evidence and as such prone to bias.&#xD;
&#xD;
      No serious adverse effects like infection or neoplastic formation have been observed in&#xD;
      treatment with MSC of OA9,10. Non-manipulated or minimally manipulated cell therapies have&#xD;
      been used within a wide range of medical conditions including: stroke, myocardial infarction,&#xD;
      Crohn's disease, rheumatoid arthritis and breast augmentation. More than 17.000 scientific&#xD;
      articles have been published reporting treatment of more than 320.000 patients11. No severe&#xD;
      safety issues have been raised12.&#xD;
&#xD;
      Mesenchymal stem cells can be derived from bone marrow or adipose tissue5. Most research has&#xD;
      been performed on bone marrow-derived stem cells. Studies have shown promising results, but&#xD;
      in 2016 a randomized study found no effect of active treatment with bone marrow aspirate&#xD;
      concentrate compared to placebo with saline in the treatment of arthritic knees13. The past&#xD;
      years a series of studies have been published showing promising effect of Adipose-derived&#xD;
      mesenchymal stem cells (AMSCs). By using AMSC a large amount of cells can be harvested from a&#xD;
      small volume of tissue thereby avoiding the costly and time consuming process of expanding&#xD;
      the cells in culture5,9.&#xD;
&#xD;
      Mesenchymal stem cells are thought to be able to activate and influence the microenvironment&#xD;
      by serving as &quot;a site-regulated drug store&quot; 14. The use of adipose-derived mesenchymal stem&#xD;
      cells in treatment of OA has had a huge interest the past years15,16, and the complex&#xD;
      regulatory issues applying for enzymatic treated and/or expanded cells have led to the&#xD;
      development of minimally manipulated tissue17. The Lipogems system is one such system where&#xD;
      the adipose tissue is microfragmented and washed free of blood residues. The resulting&#xD;
      product is safe (FDA approval in 2016) and is said to be effective in the treatment of&#xD;
      different pathologies18, but level one evidence is lacking.&#xD;
&#xD;
      In a pilot study of 20 patients with knee OA performed by the research group behind the&#xD;
      present project the Lipogems system showed promising results (submitted). No safety issues&#xD;
      were raised and the patients improved from 13 to 21 in the five sub scales of KOOS at 3 and&#xD;
      12 months follow up. The Lipogems system is introduced at the Danish market in 2018. There is&#xD;
      a pressing need to perform a state of the art RCT comparing the Lipogems system with placebo&#xD;
      in the treatment of knee OA.&#xD;
&#xD;
      4 Design of the study 4.1 Patient involvement in the study design In order to secure the&#xD;
      highest degree of relevance of the study qualitative interviews were conducted with 10&#xD;
      patients suffering from OA of the knee who would be considered eligible for inclusion. They&#xD;
      were asked the following two questions: 1) What is your biggest problem in concern to your&#xD;
      knee(s)? 2) What are your most important criteria of success after a procedure to your&#xD;
      knee(s)? Based on the answers endpoints were developed and chosen.&#xD;
&#xD;
      4.5 Time schedule Inclusion of patients is planned to begin 15th of November 2018. The&#xD;
      expected study period is 4 years; the recruitment itself is expected to span 1½ year,&#xD;
      provided that an average of 8 patients is included per month.&#xD;
&#xD;
      4.6 Termination of the trial If a critical adverse event is considered to have a causal&#xD;
      relationship with the treatment the project manager is responsible to initiate a discussion&#xD;
      with the other investigators on whether the trial should be terminated.&#xD;
&#xD;
      4.7 Follow up Follow up investigations are performed after 3, 6, 12 and 24 months. Study&#xD;
      nurse 1 performs follow up in the outpatient clinic. If patients do not show for follow up&#xD;
      investigation they will be contacted by phone up to three times and will be asked to return&#xD;
      fulfilled questionnaires by mail.&#xD;
&#xD;
      4.8 Data registration All relevant data is recorded RedCap in a database specifically&#xD;
      designed for the trial. The data registration will be reported to the Danish Data Protection&#xD;
      Agency.&#xD;
&#xD;
      The following data is registered:&#xD;
&#xD;
      4.8.1 Inclusion Date of examination. Social security number Demographic parameters: Age,&#xD;
      gender. Risk parameters: ASA score, smoking, diabetes, coronary heart disease, rheumatic&#xD;
      disease (RA or connective tissue disease).&#xD;
&#xD;
      Type of work Sports activity KOOS Tegner Activity Scale Kellgren-Lawrence score&#xD;
&#xD;
      4.8.2 Follow up at 3, 6 and 12 months Date of examination. Change in work status Sports&#xD;
      activity KOOS Tegner Activity Scale Donor site morbidity&#xD;
&#xD;
      4.9 Biological material&#xD;
&#xD;
      A research biobank is created for storage of tissue. The following tissue will be stored:&#xD;
&#xD;
      Samle of the graft.&#xD;
&#xD;
      5 Population Patients who are suffering from pain and functional impairment due to&#xD;
      osteoarthritis of the knee and referred to one of the participating departments are eligible&#xD;
      for inclusion. Patients who fulfil the inclusion criteria but do not wish to participate are&#xD;
      treated according the standard regimen of the department.&#xD;
&#xD;
      5.1 Inclusion procedure Patients referred to the orthopaedic department at the involved&#xD;
      hospitals are seen in the outpatient clinic. If they fulfil the inclusion criteria they will&#xD;
      be verbally informed of the study, given written patient information, and offered an&#xD;
      appointment with study nurse 1 and an investigating surgeon.&#xD;
&#xD;
      At this appointment it is re-assessed whether the patient meets the inclusion criteria. If so&#xD;
      the patient will once again be verbally informed of the study and given the opportunity - on&#xD;
      informed basis without any pressure - to decide whether he/she wants to participate in the&#xD;
      trial. The patient is informed of his/her right to 24 hours of reflection.&#xD;
&#xD;
      All patients assessed for eligibility are registered according to the consort requirements.&#xD;
&#xD;
      7 Safety 7.1 Risks and side effects The project team has performed a pilot study raising no&#xD;
      major safety issues (the resulting manuscript is submitted for publication). Non-manipulated&#xD;
      or minimally manipulated cell therapies have been used within a wide range of medical&#xD;
      conditions including: stroke, myocardial infarction, Crohn's disease, rheumatoid arthritis&#xD;
      and breast augmentation. More than 17,000 scientific articles have been published reporting&#xD;
      treatment of more than 320,000 patients11. No severe safety issues have been raised12.&#xD;
      However, there is always the risk of unknown side effects.&#xD;
&#xD;
      7.2 Education and training Trained personnel at the investigation sites will carry out&#xD;
      treatment, observations and measurements.&#xD;
&#xD;
      7.3 Adverse events In this context adverse events are defined as any unintended, unfavourable&#xD;
      finding, symptom or disease that occurs, whether it is considered to be related to the study&#xD;
      or not. Adverse events will be recorded.&#xD;
&#xD;
      8 Statistics 8.1 Sample Size 120 patients will be included; 60 patients in each group. The&#xD;
      sample size calculation is based on a clinical relevant difference of 10 point in KOOS, a&#xD;
      standard deviation (SD) of 15 and power of 0.90 (two sided). 98 patients are required; due to&#xD;
      the risk of drop out 120 patients will be included; 60 in each group. The used SD and&#xD;
      clinical relevant difference are recommended at KOOS.NU&#xD;
&#xD;
      . 8.2 Analysis of endpoints The two groups are described descriptively regarding demographic&#xD;
      parameters as well as primary and secondary endpoints. Comparison of the primary and&#xD;
      secondary outcomes of both groups is done by use of relevant statistics according to the&#xD;
      characteristics and distribution of the variables. The change of the outcomes over a period&#xD;
      of time is described within each group.&#xD;
&#xD;
      All statistical testing will be performed at the two-sided 5% significance level, and 95%&#xD;
      confidence intervals will be presented where appropriate. No formal interim analyses are&#xD;
      planned, and hence no statistical testing will take place until the one-year analysis. The&#xD;
      one year analysis will take place after all participants have completed their one year&#xD;
      follow-up and sufficient time has been allowed for data entry and validation.&#xD;
&#xD;
      Prior to any analysis, missing data pattern will be investigated and reasons for missing data&#xD;
      obtained and summarized where possible. The primary analysis will be conducted as an&#xD;
      intention-to-treat analysis, which includes all participants with missing outcome data,&#xD;
      unless there is clear evidence that its underlying assumption is inappropriate. Sensitivity&#xD;
      analysis will be performed to assess the robustness of the results by imputing missing data&#xD;
      using multiple imputations under both missing at random and missing not at random&#xD;
      assumptions. Per protocol analyses will also be performed.&#xD;
&#xD;
      11 Ethics 11.1 Ethical considerations The study is carried out in accordance with the&#xD;
      principles of the Helsinki Declaration.&#xD;
&#xD;
      11.2 Declaration of consent All patients will receive verbal and written information&#xD;
      concerning the study. The inclusion will take place after a declaration of consent has been&#xD;
      obtained. It is the responsibility of the investigators to provide patients with&#xD;
      comprehensive verbal and written information concerning the course of the study, purpose,&#xD;
      potential risks and benefits.&#xD;
&#xD;
      12 Data processing All Data will be stored in RedCap. The patients will be identified by an&#xD;
      assigned number. At the completion of the study all identifiable data will be destroyed. The&#xD;
      project will be reported to the Danish Data Protection Agency. The project will follow the&#xD;
      Danish act concerning storage and handling of personal data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 1, 2019</start_date>
  <completion_date type="Anticipated">March 30, 2024</completion_date>
  <primary_completion_date type="Actual">February 28, 2022</primary_completion_date>
  <phase>N/A</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>
    <intervention_model_description>The study is performed as a blinded, multicenter, randomized, controlled trial with participants individually randomized to one of two parallel groups:&#xD;
The intervention group: Participants receive one intra articular injection with autologous, microfragmented adipose tissue.&#xD;
The control group: Participants receive one intra articular injection with Saline (placebo).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>4.4.1 Randomization Randomization is computer based, performed in blocks of twelve.&#xD;
4.4.2 Blinding Blinding of the patient is secured as follows: The liposuction and microfragmentation of the fatty tissue is performed in the operating theatre. When the graft is ready for use the randomization envelope is opened by the project nurse; if the patient is allocated to active treatment syringes containing the microfragmented fatty tissue are prepared; if the patient is allocated to placebo syringes containing saline are prepared. The 10ml syringe is placed in the hand of the treating surgeon. Injection is performed with a 21G cannula. Due to the difference in viscosity of the graft and saline, the surgeon cannot be blinded.&#xD;
In order to investigate if the blinding is working the patients will be asked at 6 months follow up which group he/she believe he/she was assigned to.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>KOOS4</measure>
    <time_frame>6 months</time_frame>
    <description>The Knee injury and Osteoarthritis Outcome Score. The KOOS questionnaire was developed in the 1990s as an instrument to assess the patient's opinion about their knee and associated problems. Since the first publication in 1998, the psychometric properties of the KOOS have been assessed in more than twenty individual studies from all over the world. Furthermore, KOOS has been evaluated and compared to other instruments in several reviews measured after one year19,20 ,21,22.&#xD;
KOOS4 constructs an average score for four out of the five KOOS subscale scores. It was first used by Frobell et al in 201023. The reason for not including all five subscale scores is that in active patients, very few difficulties with activities of daily living (ADL) exists. Including the subscale ADL would then add unwanted 'noise' to the constructed outcome22.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>KOOS</measure>
    <time_frame>6 months</time_frame>
    <description>The Knee injury and Osteoarthritis Outcome Score (including all five subscales) The KOOS holds 42 items in five separately scored subscales: KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and knee-related Quality of Life (KOOS QOL)22,24.&#xD;
The five patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved22.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>KOOS</measure>
    <time_frame>12 months</time_frame>
    <description>The Knee injury and Osteoarthritis Outcome Score (including all five subscales) The KOOS holds 42 items in five separately scored subscales: KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and knee-related Quality of Life (KOOS QOL)22,24.&#xD;
The five patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved22.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>KOOS</measure>
    <time_frame>24 months</time_frame>
    <description>The Knee injury and Osteoarthritis Outcome Score (including all five subscales) The KOOS holds 42 items in five separately scored subscales: KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and knee-related Quality of Life (KOOS QOL)22,24.&#xD;
The five patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved22.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Failure</measure>
    <time_frame>6 months</time_frame>
    <description>If the patients do not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure. A clinical relevant difference is estimated to be 10points (please see section 8 Statistics). The number of patients experiencing failure of the treatment is recorded at each follow up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Failure</measure>
    <time_frame>12 months</time_frame>
    <description>If the patients do not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure. A clinical relevant difference is estimated to be 10points (please see section 8 Statistics). The number of patients experiencing failure of the treatment is recorded at each follow up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Failure</measure>
    <time_frame>24 months</time_frame>
    <description>If the patients do not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure. A clinical relevant difference is estimated to be 10points (please see section 8 Statistics). The number of patients experiencing failure of the treatment is recorded at each follow up.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Osteoarthritis, Knee</condition>
  <arm_group>
    <arm_group_label>Intervention</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients are treated with an intra articular injection with autologous, micro-fragmented adipose tissue.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients are treated with an intra articular injection with saline (placebo).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>autologous, micro-fragmented adipose tissue</intervention_name>
    <description>The active treatment is an intra-articular injection with autologous, microfragmented adipose tissue prepared using the Lipogems system.&#xD;
Implantation of the graft is performed with the patient supine using two injections sites in order to reduce the risk of extra-articular injection.</description>
    <arm_group_label>Intervention</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>The placebo is an injection with saline</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        5.2 Inclusion criteria&#xD;
&#xD;
          -  Age 18-70 years.&#xD;
&#xD;
          -  Kellgren-Lawrence grade 2 - 3 in the tibiofemoral joint&#xD;
&#xD;
          -  The patient must be expected to be able to attend follow up examinations&#xD;
&#xD;
          -  The patient must be able to speak and understand Danish&#xD;
&#xD;
          -  The patient must be able to give informed consent&#xD;
&#xD;
        5.3 Exclusion criteria&#xD;
&#xD;
          -  Smoking (the patient must consent to being non-smoking 6 weeks pre and post the&#xD;
             procedure)&#xD;
&#xD;
          -  Varus or valgus malalignment of the knee &gt; 5 degrees&#xD;
&#xD;
          -  Laxity of the MCL or LCL of 10 degrees or more compared to the opposite knee&#xD;
&#xD;
          -  Knee instability and anterior-posterior laxity of 3mm or above&#xD;
&#xD;
          -  Preceding open surgery to the knee or fracture in the proximal tibia or distal femur&#xD;
&#xD;
          -  Extension deficit of the knee&#xD;
&#xD;
          -  Kellgren-Lawrence grade 4 in any of the three compartments&#xD;
&#xD;
          -  BMI &gt; 40&#xD;
&#xD;
          -  Terminal illness or severe medical illness: ASA score higher than or equal to 3&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kristoffer W Barfod</last_name>
    <role>Principal Investigator</role>
    <affiliation>Copenhagen University Hospital Hviovre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Copenhagen University Hospital Hvidovre</name>
      <address>
        <city>Hvidovre</city>
        <zip>2650</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>December 9, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <last_update_submitted>April 4, 2022</last_update_submitted>
  <last_update_submitted_qc>April 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 5, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hvidovre University Hospital</investigator_affiliation>
    <investigator_full_name>Kristoffer Barfod</investigator_full_name>
    <investigator_title>Associate Professor, MD PhD</investigator_title>
  </responsible_party>
  <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>Undecided</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/NCT03771989
org study id: TOMAT
nct id: NCT03771989
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The study is a blinded, multicenter, randomized, controlled trial with participants
      individually randomized to one of two parallel groups:

        1. The intervention group: Participants receive one intra articular injection with
           autologous, microfragmented adipose tissue.

        2. The control group: Participants receive one intra articular injection with Saline
           (placebo).

      The objective of the study is to investigate if intra-articular injection with autologous,
      microfragmented adipose tissue prepared using the Lipogems system affects the patient
      reported outcome in patients with osteoarthritis of the knee.

      The primary endpoint is KOOS4 evaluated at 6 months after the intervention. Secondary
      endpoints are the KOOS including all five subscales evaluated after 6months, 1 and 2 years.
2 Study Objective To investigate if intra-articular injection with autologous,
      microfragmented adipose tissue prepared using the Lipogems system affects the patient
      reported outcome in patients with osteoarthritis of the knee.

      Hypothesis Treatment with autologous, microfragmented adipose tissue has the potential to
      reverse degenerative changes in knees with osteoarthritis. The patient will experience a
      better patient reported health in comparison with placebo treatment.

      Null hypothesis There is no difference in patient reported outcome when treatment with
      autologous, microfragmented adipose tissue is compared to placebo treatment.

      3 Background Osteoarthritis (OA) of the knee is a destructive joint disease, causing
      degeneration of cartilage, damage to the underlying bone and morphological changes to the
      joint1. It is a major public health concern due to the increased life expectancy of the
      ageing population2,3. No approved medical treatment that reverses the morphological changes
      currently exists. Conventional treatment includes physiotherapy, pain killers, braces and in
      end-stage OA surgical knee replacement4.

      During the past decade researchers have started to explore the regenerative potential of
      mesenchymal stem cells (MSC) in OA5. MSCs are multipotent progenitor cells able to give rise
      to osteocytes, adipocytes, chondrocytes, myoblasts and tenocytes6. MSCs were first used to
      treat Chondral defects in 19987 and to treat OA in 20028. Since then, a number of case
      reports and prospective series have been published showing significant short term and long
      term effect on pain and cartilage thickness5. Latest a prospective case-series of 1128
      patients involving 1856 joints showed an improvement of at least 50% in 86% of patients at 3
      months and 91% of patients at 12 months using a modified Knee/Hip Osteoarthritis Outcome
      Score (KOOS/HOOS) questionnaire9. Only 0.9% of patients did not show improvement after
      treatment. However, when interpreting these studies one should bear in mind that they are all
      level four evidence and as such prone to bias.

      No serious adverse effects like infection or neoplastic formation have been observed in
      treatment with MSC of OA9,10. Non-manipulated or minimally manipulated cell therapies have
      been used within a wide range of medical conditions including: stroke, myocardial infarction,
      Crohn's disease, rheumatoid arthritis and breast augmentation. More than 17.000 scientific
      articles have been published reporting treatment of more than 320.000 patients11. No severe
      safety issues have been raised12.

      Mesenchymal stem cells can be derived from bone marrow or adipose tissue5. Most research has
      been performed on bone marrow-derived stem cells. Studies have shown promising results, but
      in 2016 a randomized study found no effect of active treatment with bone marrow aspirate
      concentrate compared to placebo with saline in the treatment of arthritic knees13. The past
      years a series of studies have been published showing promising effect of Adipose-derived
      mesenchymal stem cells (AMSCs). By using AMSC a large amount of cells can be harvested from a
      small volume of tissue thereby avoiding the costly and time consuming process of expanding
      the cells in culture5,9.

      Mesenchymal stem cells are thought to be able to activate and influence the microenvironment
      by serving as "a site-regulated drug store" 14. The use of adipose-derived mesenchymal stem
      cells in treatment of OA has had a huge interest the past years15,16, and the complex
      regulatory issues applying for enzymatic treated and/or expanded cells have led to the
      development of minimally manipulated tissue17. The Lipogems system is one such system where
      the adipose tissue is microfragmented and washed free of blood residues. The resulting
      product is safe (FDA approval in 2016) and is said to be effective in the treatment of
      different pathologies18, but level one evidence is lacking.

      In a pilot study of 20 patients with knee OA performed by the research group behind the
      present project the Lipogems system showed promising results (submitted). No safety issues
      were raised and the patients improved from 13 to 21 in the five sub scales of KOOS at 3 and
      12 months follow up. The Lipogems system is introduced at the Danish market in 2018. There is
      a pressing need to perform a state of the art RCT comparing the Lipogems system with placebo
      in the treatment of knee OA.

      4 Design of the study 4.1 Patient involvement in the study design In order to secure the
      highest degree of relevance of the study qualitative interviews were conducted with 10
      patients suffering from OA of the knee who would be considered eligible for inclusion. They
      were asked the following two questions: 1) What is your biggest problem in concern to your
      knee(s)? 2) What are your most important criteria of success after a procedure to your
      knee(s)? Based on the answers endpoints were developed and chosen.

      4.5 Time schedule Inclusion of patients is planned to begin 15th of November 2018. The
      expected study period is 4 years; the recruitment itself is expected to span 1½ year,
      provided that an average of 8 patients is included per month.

      4.6 Termination of the trial If a critical adverse event is considered to have a causal
      relationship with the treatment the project manager is responsible to initiate a discussion
      with the other investigators on whether the trial should be terminated.

      4.7 Follow up Follow up investigations are performed after 3, 6, 12 and 24 months. Study
      nurse 1 performs follow up in the outpatient clinic. If patients do not show for follow up
      investigation they will be contacted by phone up to three times and will be asked to return
      fulfilled questionnaires by mail.

      4.8 Data registration All relevant data is recorded RedCap in a database specifically
      designed for the trial. The data registration will be reported to the Danish Data Protection
      Agency.

      The following data is registered:

      4.8.1 Inclusion Date of examination. Social security number Demographic parameters: Age,
      gender. Risk parameters: ASA score, smoking, diabetes, coronary heart disease, rheumatic
      disease (RA or connective tissue disease).

      Type of work Sports activity KOOS Tegner Activity Scale Kellgren-Lawrence score

      4.8.2 Follow up at 3, 6 and 12 months Date of examination. Change in work status Sports
      activity KOOS Tegner Activity Scale Donor site morbidity

      4.9 Biological material

      A research biobank is created for storage of tissue. The following tissue will be stored:

      Samle of the graft.

      5 Population Patients who are suffering from pain and functional impairment due to
      osteoarthritis of the knee and referred to one of the participating departments are eligible
      for inclusion. Patients who fulfil the inclusion criteria but do not wish to participate are
      treated according the standard regimen of the department.

      5.1 Inclusion procedure Patients referred to the orthopaedic department at the involved
      hospitals are seen in the outpatient clinic. If they fulfil the inclusion criteria they will
      be verbally informed of the study, given written patient information, and offered an
      appointment with study nurse 1 and an investigating surgeon.

      At this appointment it is re-assessed whether the patient meets the inclusion criteria. If so
      the patient will once again be verbally informed of the study and given the opportunity - on
      informed basis without any pressure - to decide whether he/she wants to participate in the
      trial. The patient is informed of his/her right to 24 hours of reflection.

      All patients assessed for eligibility are registered according to the consort requirements.

      7 Safety 7.1 Risks and side effects The project team has performed a pilot study raising no
      major safety issues (the resulting manuscript is submitted for publication). Non-manipulated
      or minimally manipulated cell therapies have been used within a wide range of medical
      conditions including: stroke, myocardial infarction, Crohn's disease, rheumatoid arthritis
      and breast augmentation. More than 17,000 scientific articles have been published reporting
      treatment of more than 320,000 patients11. No severe safety issues have been raised12.
      However, there is always the risk of unknown side effects.

      7.2 Education and training Trained personnel at the investigation sites will carry out
      treatment, observations and measurements.

      7.3 Adverse events In this context adverse events are defined as any unintended, unfavourable
      finding, symptom or disease that occurs, whether it is considered to be related to the study
      or not. Adverse events will be recorded.

      8 Statistics 8.1 Sample Size 120 patients will be included; 60 patients in each group. The
      sample size calculation is based on a clinical relevant difference of 10 point in KOOS, a
      standard deviation (SD) of 15 and power of 0.90 (two sided). 98 patients are required; due to
      the risk of drop out 120 patients will be included; 60 in each group. The used SD and
      clinical relevant difference are recommended at KOOS.NU

      . 8.2 Analysis of endpoints The two groups are described descriptively regarding demographic
      parameters as well as primary and secondary endpoints. Comparison of the primary and
      secondary outcomes of both groups is done by use of relevant statistics according to the
      characteristics and distribution of the variables. The change of the outcomes over a period
      of time is described within each group.

      All statistical testing will be performed at the two-sided 5% significance level, and 95%
      confidence intervals will be presented where appropriate. No formal interim analyses are
      planned, and hence no statistical testing will take place until the one-year analysis. The
      one year analysis will take place after all participants have completed their one year
      follow-up and sufficient time has been allowed for data entry and validation.

      Prior to any analysis, missing data pattern will be investigated and reasons for missing data
      obtained and summarized where possible. The primary analysis will be conducted as an
      intention-to-treat analysis, which includes all participants with missing outcome data,
      unless there is clear evidence that its underlying assumption is inappropriate. Sensitivity
      analysis will be performed to assess the robustness of the results by imputing missing data
      using multiple imputations under both missing at random and missing not at random
      assumptions. Per protocol analyses will also be performed.

      11 Ethics 11.1 Ethical considerations The study is carried out in accordance with the
      principles of the Helsinki Declaration.

      11.2 Declaration of consent All patients will receive verbal and written information
      concerning the study. The inclusion will take place after a declaration of consent has been
      obtained. It is the responsibility of the investigators to provide patients with
      comprehensive verbal and written information concerning the course of the study, purpose,
      potential risks and benefits.

      12 Data processing All Data will be stored in RedCap. The patients will be identified by an
      assigned number. At the completion of the study all identifiable data will be destroyed. The
      project will be reported to the Danish Data Protection Agency. The project will follow the
      Danish act concerning storage and handling of personal data.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The study is performed as a blinded, multicenter, randomized, controlled trial with participants individually randomized to one of two parallel groups:
The intervention group: Participants receive one intra articular injection with autologous, microfragmented adipose tissue.
The control group: Participants receive one intra articular injection with Saline (placebo).
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: 4.4.1 Randomization Randomization is computer based, performed in blocks of twelve.
4.4.2 Blinding Blinding of the patient is secured as follows: The liposuction and microfragmentation of the fatty tissue is performed in the operating theatre. When the graft is ready for use the randomization envelope is opened by the project nurse; if the patient is allocated to active treatment syringes containing the microfragmented fatty tissue are prepared; if the patient is allocated to placebo syringes containing saline are prepared. The 10ml syringe is placed in the hand of the treating surgeon. Injection is performed with a 21G cannula. Due to the difference in viscosity of the graft and saline, the surgeon cannot be blinded.
In order to investigate if the blinding is working the patients will be asked at 6 months follow up which group he/she believe he/she was assigned to.
measure: KOOS4
time frame: 6 months
description: The Knee injury and Osteoarthritis Outcome Score. The KOOS questionnaire was developed in the 1990s as an instrument to assess the patient's opinion about their knee and associated problems. Since the first publication in 1998, the psychometric properties of the KOOS have been assessed in more than twenty individual studies from all over the world. Furthermore, KOOS has been evaluated and compared to other instruments in several reviews measured after one year19,20 ,21,22.
KOOS4 constructs an average score for four out of the five KOOS subscale scores. It was first used by Frobell et al in 201023. The reason for not including all five subscale scores is that in active patients, very few difficulties with activities of daily living (ADL) exists. Including the subscale ADL would then add unwanted 'noise' to the constructed outcome22.
measure: KOOS
time frame: 6 months
description: The Knee injury and Osteoarthritis Outcome Score (including all five subscales) The KOOS holds 42 items in five separately scored subscales: KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and knee-related Quality of Life (KOOS QOL)22,24.
The five patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved22.
measure: KOOS
time frame: 12 months
description: The Knee injury and Osteoarthritis Outcome Score (including all five subscales) The KOOS holds 42 items in five separately scored subscales: KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and knee-related Quality of Life (KOOS QOL)22,24.
The five patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved22.
measure: KOOS
time frame: 24 months
description: The Knee injury and Osteoarthritis Outcome Score (including all five subscales) The KOOS holds 42 items in five separately scored subscales: KOOS Pain, KOOS Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and knee-related Quality of Life (KOOS QOL)22,24.
The five patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as is common in orthopedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved22.
measure: Failure
time frame: 6 months
description: If the patients do not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure. A clinical relevant difference is estimated to be 10points (please see section 8 Statistics). The number of patients experiencing failure of the treatment is recorded at each follow up.
measure: Failure
time frame: 12 months
description: If the patients do not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure. A clinical relevant difference is estimated to be 10points (please see section 8 Statistics). The number of patients experiencing failure of the treatment is recorded at each follow up.
measure: Failure
time frame: 24 months
description: If the patients do not experience a clinically relevant improvement in KOOS4 the treatment is considered a failure. A clinical relevant difference is estimated to be 10points (please see section 8 Statistics). The number of patients experiencing failure of the treatment is recorded at each follow up.
arm group label: Intervention
arm group type: Active Comparator
description: Patients are treated with an intra articular injection with autologous, micro-fragmented adipose tissue.
arm group label: Control
arm group type: Placebo Comparator
description: Patients are treated with an intra articular injection with saline (placebo).
intervention type: Biological
intervention name: autologous, micro-fragmented adipose tissue
description: The active treatment is an intra-articular injection with autologous, microfragmented adipose tissue prepared using the Lipogems system.
Implantation of the graft is performed with the patient supine using two injections sites in order to reduce the risk of extra-articular injection.
arm group label: Intervention
intervention type: Other
intervention name: Saline
description: The placebo is an injection with saline
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Kristoffer W Barfod
role: Principal Investigator
affiliation: Copenhagen University Hospital Hviovre
facility: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: Hvidovre University Hospital
investigator full name: Kristoffer Barfod
investigator title: Associate Professor, MD PhD
mesh term: Osteoarthritis
mesh term: Osteoarthritis, Knee
sharing ipd: Undecided