<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/NCT04457609</url>
  </required_header>
  <id_info>
    <org_study_id>ISMMSCCOVID19</org_study_id>
    <nct_id>NCT04457609</nct_id>
  </id_info>
  <brief_title>Administration of Allogenic UC-MSCs as Adjuvant Therapy for Critically-Ill COVID-19 Patients</brief_title>
  <official_title>Application of Umbilical Cord Mesenchymal Stem Cells as Adjuvant Therapy for Critically-Ill COVID-19 Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Indonesia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Indonesia University</source>
  <oversight_info>
    <has_dmc>No</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>
      Novel Coronavirus (2019nCoV) or Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)&#xD;
      that causes Coronavirus Disease 2019, or known as Covid-19 has recently become a global&#xD;
      health emergency since it was first detected in Wuhan, the People Republic of China in&#xD;
      December 2019. Since then, the prevalence has rapidly increased worldwide. In Indonesia, by&#xD;
      the end of April 2020, around 10,000 patients have been tested positive for Covid-19&#xD;
      infection, with a case fatality rate of around 8%.&#xD;
&#xD;
      The pathogenesis of Covid-19 is still under investigation and to our understanding, ACE2&#xD;
      receptors in the alveoli serve as the binding site of the S-protein of envelope spike virus&#xD;
      of SARS-CoV-2. TMPRSS2 enzyme aids the fusion between cell membrane and capsid of the virus,&#xD;
      allowing penetration of virus into the cell. Vesicles containing virion fuse with cell&#xD;
      membrane and released as new virions. Cytopathic effect of the virus and its ability to&#xD;
      overcome immune response determines the degree of infection.&#xD;
&#xD;
      Differences in immunological profile among degrees of severity of Covid-19 may vary&#xD;
      especially for the number of pro-inflammatory cytokines such as tumor necrosis factor alpha&#xD;
      (TNF-α), interleukin (IL)-1, IL-6, IL-8, leukemia-inhibiting factors (LIF), immunological&#xD;
      markers such as CXCR3+CD4+, CXCR3+CD8+ T cell and CXCR3+ NK cells, implying the ongoing&#xD;
      cytokine storm. The previous studies also found increasing number for infection markers such&#xD;
      as procalcitonin, ferritin, and C-reactive protein. The decreasing number of&#xD;
      anti-inflammatory cytokines in such as IL-10 also supports this finding.&#xD;
&#xD;
      Previous studies have shown immunomodulating and anti-inflammatory capacity of the&#xD;
      mesenchymal stem cells (MSCs). MSCs contributed to the shifting of pro-inflammatory Th2 into&#xD;
      anti-inflammatory Th2. One of the most recent study on the usage of MSCs on Covid-19 patients&#xD;
      showed increased expression of leukemia inhibitory factor (LIF), which give rise to&#xD;
      inhibitory effect of T lymphocyte and natural killer (NK) cell population. Vascular&#xD;
      epithelial growth factor (VEGF) is found increasing following MSCs administration, which&#xD;
      indicates the ability to improve the disrupted capillaries due to SARS-Cov-2 infection. The&#xD;
      ability of MSCs in differentiating to alveolar cells is proven by the presence of SPM and&#xD;
      SPC2, surfactant proteins produced by type II alveolar cells. MSCs are unable to be infected&#xD;
      by SARS-CoV-2 since they don't have ACE2 receptors and TMPRSS2 enzyme.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a double blind, randomized control trial (RCT). This study will be concluded in&#xD;
      2 months, from May to July 2020, from subject selection to the end of follow up. Research&#xD;
      subjects are obtained consecutively from Covid-19 patients who receive care in the intensive&#xD;
      care unit (ICU) across four Covid-19 referral hospitals, including Persahabatan Hospital,&#xD;
      Sulianti Saroso Center for Infectious Disease, Cipto Mangunkusumo General Hospital, and&#xD;
      Universitas Indonesia Hospital, with 10 subjects obtained from each hospital and total 40&#xD;
      subjects for this RCT. Subjects from each hospitals are divided into control and experimental&#xD;
      groups. Subject belongs to the control group will receive standardized therapy (consisting of&#xD;
      oseltamivir and azithromycin), whereas subjects in the experimental group will receive MSCs&#xD;
      infusion, in addition to standardized therapy.&#xD;
&#xD;
      Subject Criteria Inclusion Criteria for MSC Donor from Umbilical Cord:&#xD;
&#xD;
      Umbilical cord is collected from elective caesarean section from a fullterm pregnancies&#xD;
      without any complication and free from HIV, Hepatitis B, C, D virus, Cytomegalovirus, Rubella&#xD;
      Virus, and free from fungal and bacterial contamination.&#xD;
&#xD;
      Informed consent all of the subjects must be filled and signed up before ruled in this study.&#xD;
&#xD;
      As soon as after delivery, the umbilical cord is collected and processed in sterile specimen&#xD;
      0,9% NaCl at 4oC for 8 hours. The umbilical cord transported to the laboratory and cultured&#xD;
      in GMP lab, at Stem Cells Medical Technology Integrated Service Unit Cipto Mangunkusumo&#xD;
      Hospital. Cellular viability and proliferation are evaluated after cell characterization test&#xD;
      by flow cytometer.&#xD;
&#xD;
      Sterility tests are done three times to ensure cellular sterility. Subjects will receive MSCs&#xD;
      through infusion through intravenous for 1 hour, following the administration of&#xD;
      diphenhydramine and anticoagulant to prevent clotting.&#xD;
&#xD;
      Following the MSCs administration, monitoring at the patients is carried out every day,&#xD;
      whereas laboratory testing for basic parameters (complete blood count, differential count,&#xD;
      blood gas analysis, C-reactive protein, SGOT/SGPT (AST/ALT), Ureum/Creatinine, eGFR,&#xD;
      electrolyte, procalcitonin, albumin, total bilirubin, D-Dimer, fibrinogen, troponin I and&#xD;
      proBNP) are carried out every three days. Cytokine levels are measured before the&#xD;
      administration and 7th day after the administration. Chest radiography is carried out every&#xD;
      three days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">July 2020</start_date>
  <completion_date type="Anticipated">September 2020</completion_date>
  <primary_completion_date type="Anticipated">August 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical improvement: Presence of dyspnea</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing whether the patients still have dyspnea, one of cardinal symptoms of Covid-19, assessed from the respiratory rate</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical improvement: presence of sputum</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing whether the patients still have productive cough, one of cardinal symptoms of Covid-19, assessed from lung auscultation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical improvement: fever</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the presence of fever from measurement of body temperature checking, assessed on daily basis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical improvement: ventilation status</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing whether the patients still require ventilation, one of cardinal symptoms of ARDS in Covid-19, assessed from patients' ability during ventilation weaning phase</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical improvement: blood pressure</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the patients' blood pressure on daily basis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical improvement: heart rate</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the patients' heart rate on daily basis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical improvement: respiratory rate</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the patients' respiratory rate on daily basis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical improvement: oxygen saturation</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the patients' oxygen saturation on daily basis</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from leukocyte level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in total leukocyte upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from lymphocytes level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in lymphocytes level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from blood pH</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in blood pH level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from blood level of CO2</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in blood pH level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from blood base excess level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in blood base excess level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from blood oxygen partial pressure</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in blood oxygen partial pressure upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from blood level of HCO3</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in blood level of HCO3 upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from blood level of O2 saturation</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in blood level of O2 saturation upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from level of CRP</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in level of CRP, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from level of SGOT/SGPT (AST/ALT)</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in laboratory parameter, consist of SGOT/SGPT (AST/ALT) level, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from the level of ureum/creatinine level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in laboratory parameter, consist of ureum/creatinine level, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from the level of eGFR</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in laboratory parameter, consist of eGFR, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from the level of sodium</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in level of sodium, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from the level of potassium</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in level of potassium, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from the level of chloride</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in level of chloride, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in procalcitonin level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in procalcitonin level to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from albumin level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in albumin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General laboratory outcome from total bilirubin level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in total bilirubin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in D-Dimer level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in D-Dimer to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in fibrinogen level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in fibrinogen to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac changes from troponin level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in troponin level to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac changes from NT proBNP level</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in NT proBNP to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Leukemia Inhibiting Factor</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in leukemia inhibiting factor (LIF) to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of IL-6</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in level of IL-6 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of IL-10</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in level of IL-10 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of vascular endothelial growth factor (VEGF)</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in vascular endothelial growth factor (VEGF) to assess the effect of growth factors in the MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of ferritin</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in level of ferritin to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of CXCR3</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in level of CXCR3 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of CD4</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in level of CD4 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of CD8</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in level of CD8 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in level of CD56</measure>
    <time_frame>7 days</time_frame>
    <description>Assessing the changes in CD56 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiologic Improvement from Chest X-Ray/CT Scan</measure>
    <time_frame>15 days</time_frame>
    <description>Assessing the changes in radiology examination (Chest X-Ray/CT Scan) for any increased in lung infiltration or ground glass opacity, assessed prior to implantation and once every 3 days post-implantation</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>COVID</condition>
  <condition>Pulmonary Infection</condition>
  <condition>Sars-CoV2</condition>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients receive standardized treatment, consisting of Oseltamivir and Azithromycin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Experiment Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive intravenous infusion of 1x10^6 unit of umbilical-cord derived mesenchymal stem cells (UC-MSCs)/kgBW in 100 cc of 0.9% NaCl for 1 hour, in addition to standardized treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oseltamivir</intervention_name>
    <description>Current standardized treatment for Covid-19</description>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_label>Experiment Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azithromycin</intervention_name>
    <description>Current standardized treatment for Covid-19</description>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_label>Experiment Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Umbilical Cord Mesenchymal Stem Cells</intervention_name>
    <description>Adjuvant therapy on top of current standardized treatment (Oseltamivir + Azithromycin)</description>
    <arm_group_label>Experiment Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients aged 18-95 years old&#xD;
&#xD;
          -  Confirmed for diagnosis of Covid-19 through RT-PCR from nasopharyngeal swab and/or&#xD;
             bronchoalveolar lavage for patients under intubation&#xD;
&#xD;
          -  Laboratory results showed leukopenia and lymphopenic&#xD;
&#xD;
          -  Chest radiography shows pneumonia appearance and/or ground-glass opacity on chest&#xD;
             CT-Scan&#xD;
&#xD;
          -  Patients/their families are willing to sign the informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of malignancy&#xD;
&#xD;
          -  Pregnant, or show positive result on pregnancy test&#xD;
&#xD;
          -  Patients was/are currently participating in other clinical trials within the last 3&#xD;
             months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>95 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ismail H Dilogo, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Indonesia University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ismail H Dilogo, MD, PhD</last_name>
    <phone>+621500135</phone>
    <email>ismailortho@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tri Kurniawati, BSc</last_name>
    <phone>+621500135</phone>
    <email>selpuncarscm@yahoo.co.id</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Cipto Mangunkusumo General Hospital</name>
      <address>
        <city>Jakarta Pusat</city>
        <state>DKI Jakarta</state>
        <country>Indonesia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ismail H Dilogo, MD, PhD</last_name>
      <phone>+62211500135</phone>
    </contact>
    <investigator>
      <last_name>Ismail H Dilogo, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Cleopas M Rumende, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ceva W Pitoyo, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Telly Kamelia, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dita Aditianingsih, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Adhrie Sugiarto, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Isabella K Liem, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Radiana D Antarianto, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Persahabatan General Hospital</name>
      <address>
        <city>Jakarta</city>
        <state>DKI Jakarta</state>
        <country>Indonesia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Erlina Burhan, MD, PhD</last_name>
      <phone>+62214891708</phone>
      <email>erlina_burhan@yahoo.com</email>
    </contact>
    <contact_backup>
      <last_name>Triya Damayanti, MD, PhD</last_name>
      <phone>+62214891708</phone>
    </contact_backup>
    <investigator>
      <last_name>Erlina Burhan, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Triya Damayanti, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Navy GHM Lolong Wulung, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Wahju Aniwidyaningsih, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sulianti Saroso Center for Infectious Disease</name>
      <address>
        <city>Jakarta</city>
        <state>DKI Jakarta</state>
        <country>Indonesia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pompini A Sitompul, MD</last_name>
      <phone>+62216506559</phone>
    </contact>
    <investigator>
      <last_name>Pompini A Sitompul, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Faisal Matondang, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Rosa Marlina, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Titi Sundari, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitas Indonesia Hospital</name>
      <address>
        <city>Depok</city>
        <state>West Java</state>
        <country>Indonesia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dita Aditianingsih, MD, PhD</last_name>
      <phone>+622150829292</phone>
    </contact>
    <investigator>
      <last_name>Dita Aditianingsih, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>RR D Handayani, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Indonesia</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>May 27, 2020</study_first_submitted>
  <study_first_submitted_qc>July 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>July 2, 2020</last_update_submitted>
  <last_update_submitted_qc>July 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Indonesia University</investigator_affiliation>
    <investigator_full_name>Ismail Hadisoebroto Dilogo</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Covid-19 Pneumonia</keyword>
  <keyword>SARS-CoV-2</keyword>
  <keyword>Mesenchymal Stem Cells</keyword>
  <keyword>Umbilical Cord</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azithromycin</mesh_term>
    <mesh_term>Oseltamivir</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04457609
org study id: ISMMSCCOVID19
nct id: NCT04457609
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Novel Coronavirus (2019nCoV) or Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)
      that causes Coronavirus Disease 2019, or known as Covid-19 has recently become a global
      health emergency since it was first detected in Wuhan, the People Republic of China in
      December 2019. Since then, the prevalence has rapidly increased worldwide. In Indonesia, by
      the end of April 2020, around 10,000 patients have been tested positive for Covid-19
      infection, with a case fatality rate of around 8%.

      The pathogenesis of Covid-19 is still under investigation and to our understanding, ACE2
      receptors in the alveoli serve as the binding site of the S-protein of envelope spike virus
      of SARS-CoV-2. TMPRSS2 enzyme aids the fusion between cell membrane and capsid of the virus,
      allowing penetration of virus into the cell. Vesicles containing virion fuse with cell
      membrane and released as new virions. Cytopathic effect of the virus and its ability to
      overcome immune response determines the degree of infection.

      Differences in immunological profile among degrees of severity of Covid-19 may vary
      especially for the number of pro-inflammatory cytokines such as tumor necrosis factor alpha
      (TNF-α), interleukin (IL)-1, IL-6, IL-8, leukemia-inhibiting factors (LIF), immunological
      markers such as CXCR3+CD4+, CXCR3+CD8+ T cell and CXCR3+ NK cells, implying the ongoing
      cytokine storm. The previous studies also found increasing number for infection markers such
      as procalcitonin, ferritin, and C-reactive protein. The decreasing number of
      anti-inflammatory cytokines in such as IL-10 also supports this finding.

      Previous studies have shown immunomodulating and anti-inflammatory capacity of the
      mesenchymal stem cells (MSCs). MSCs contributed to the shifting of pro-inflammatory Th2 into
      anti-inflammatory Th2. One of the most recent study on the usage of MSCs on Covid-19 patients
      showed increased expression of leukemia inhibitory factor (LIF), which give rise to
      inhibitory effect of T lymphocyte and natural killer (NK) cell population. Vascular
      epithelial growth factor (VEGF) is found increasing following MSCs administration, which
      indicates the ability to improve the disrupted capillaries due to SARS-Cov-2 infection. The
      ability of MSCs in differentiating to alveolar cells is proven by the presence of SPM and
      SPC2, surfactant proteins produced by type II alveolar cells. MSCs are unable to be infected
      by SARS-CoV-2 since they don't have ACE2 receptors and TMPRSS2 enzyme.
This study is a double blind, randomized control trial (RCT). This study will be concluded in
      2 months, from May to July 2020, from subject selection to the end of follow up. Research
      subjects are obtained consecutively from Covid-19 patients who receive care in the intensive
      care unit (ICU) across four Covid-19 referral hospitals, including Persahabatan Hospital,
      Sulianti Saroso Center for Infectious Disease, Cipto Mangunkusumo General Hospital, and
      Universitas Indonesia Hospital, with 10 subjects obtained from each hospital and total 40
      subjects for this RCT. Subjects from each hospitals are divided into control and experimental
      groups. Subject belongs to the control group will receive standardized therapy (consisting of
      oseltamivir and azithromycin), whereas subjects in the experimental group will receive MSCs
      infusion, in addition to standardized therapy.

      Subject Criteria Inclusion Criteria for MSC Donor from Umbilical Cord:

      Umbilical cord is collected from elective caesarean section from a fullterm pregnancies
      without any complication and free from HIV, Hepatitis B, C, D virus, Cytomegalovirus, Rubella
      Virus, and free from fungal and bacterial contamination.

      Informed consent all of the subjects must be filled and signed up before ruled in this study.

      As soon as after delivery, the umbilical cord is collected and processed in sterile specimen
      0,9% NaCl at 4oC for 8 hours. The umbilical cord transported to the laboratory and cultured
      in GMP lab, at Stem Cells Medical Technology Integrated Service Unit Cipto Mangunkusumo
      Hospital. Cellular viability and proliferation are evaluated after cell characterization test
      by flow cytometer.

      Sterility tests are done three times to ensure cellular sterility. Subjects will receive MSCs
      through infusion through intravenous for 1 hour, following the administration of
      diphenhydramine and anticoagulant to prevent clotting.

      Following the MSCs administration, monitoring at the patients is carried out every day,
      whereas laboratory testing for basic parameters (complete blood count, differential count,
      blood gas analysis, C-reactive protein, SGOT/SGPT (AST/ALT), Ureum/Creatinine, eGFR,
      electrolyte, procalcitonin, albumin, total bilirubin, D-Dimer, fibrinogen, troponin I and
      proBNP) are carried out every three days. Cytokine levels are measured before the
      administration and 7th day after the administration. Chest radiography is carried out every
      three days.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Clinical improvement: Presence of dyspnea
time frame: 15 days
description: Assessing whether the patients still have dyspnea, one of cardinal symptoms of Covid-19, assessed from the respiratory rate
measure: Clinical improvement: presence of sputum
time frame: 15 days
description: Assessing whether the patients still have productive cough, one of cardinal symptoms of Covid-19, assessed from lung auscultation
measure: Clinical improvement: fever
time frame: 15 days
description: Assessing the presence of fever from measurement of body temperature checking, assessed on daily basis
measure: Clinical improvement: ventilation status
time frame: 15 days
description: Assessing whether the patients still require ventilation, one of cardinal symptoms of ARDS in Covid-19, assessed from patients' ability during ventilation weaning phase
measure: Clinical improvement: blood pressure
time frame: 15 days
description: Assessing the patients' blood pressure on daily basis
measure: Clinical improvement: heart rate
time frame: 15 days
description: Assessing the patients' heart rate on daily basis
measure: Clinical improvement: respiratory rate
time frame: 15 days
description: Assessing the patients' respiratory rate on daily basis
measure: Clinical improvement: oxygen saturation
time frame: 15 days
description: Assessing the patients' oxygen saturation on daily basis
measure: General laboratory outcome from leukocyte level
time frame: 15 days
description: Assessing the changes in total leukocyte upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from lymphocytes level
time frame: 15 days
description: Assessing the changes in lymphocytes level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from blood pH
time frame: 15 days
description: Assessing the changes in blood pH level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from blood level of CO2
time frame: 15 days
description: Assessing the changes in blood pH level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from blood base excess level
time frame: 15 days
description: Assessing the changes in blood base excess level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from blood oxygen partial pressure
time frame: 15 days
description: Assessing the changes in blood oxygen partial pressure upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from blood level of HCO3
time frame: 15 days
description: Assessing the changes in blood level of HCO3 upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from blood level of O2 saturation
time frame: 15 days
description: Assessing the changes in blood level of O2 saturation upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from level of CRP
time frame: 15 days
description: Assessing the changes in level of CRP, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from level of SGOT/SGPT (AST/ALT)
time frame: 15 days
description: Assessing the changes in laboratory parameter, consist of SGOT/SGPT (AST/ALT) level, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from the level of ureum/creatinine level
time frame: 15 days
description: Assessing the changes in laboratory parameter, consist of ureum/creatinine level, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from the level of eGFR
time frame: 15 days
description: Assessing the changes in laboratory parameter, consist of eGFR, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from the level of sodium
time frame: 15 days
description: Assessing the changes in level of sodium, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from the level of potassium
time frame: 15 days
description: Assessing the changes in level of potassium, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from the level of chloride
time frame: 15 days
description: Assessing the changes in level of chloride, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: Changes in procalcitonin level
time frame: 15 days
description: Assessing the changes in procalcitonin level to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from albumin level
time frame: 15 days
description: Assessing the changes in albumin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: General laboratory outcome from total bilirubin level
time frame: 15 days
description: Assessing the changes in total bilirubin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: Changes in D-Dimer level
time frame: 15 days
description: Assessing the changes in D-Dimer to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: Changes in fibrinogen level
time frame: 15 days
description: Assessing the changes in fibrinogen to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: Cardiac changes from troponin level
time frame: 15 days
description: Assessing the changes in troponin level to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: Cardiac changes from NT proBNP level
time frame: 15 days
description: Assessing the changes in NT proBNP to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation
measure: Changes in Leukemia Inhibiting Factor
time frame: 7 days
description: Assessing the changes in leukemia inhibiting factor (LIF) to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of IL-6
time frame: 7 days
description: Assessing the changes in level of IL-6 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of IL-10
time frame: 7 days
description: Assessing the changes in level of IL-10 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of vascular endothelial growth factor (VEGF)
time frame: 7 days
description: Assessing the changes in vascular endothelial growth factor (VEGF) to assess the effect of growth factors in the MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of ferritin
time frame: 7 days
description: Assessing the changes in level of ferritin to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of CXCR3
time frame: 7 days
description: Assessing the changes in level of CXCR3 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of CD4
time frame: 7 days
description: Assessing the changes in level of CD4 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of CD8
time frame: 7 days
description: Assessing the changes in level of CD8 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Changes in level of CD56
time frame: 7 days
description: Assessing the changes in CD56 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation
measure: Radiologic Improvement from Chest X-Ray/CT Scan
time frame: 15 days
description: Assessing the changes in radiology examination (Chest X-Ray/CT Scan) for any increased in lung infiltration or ground glass opacity, assessed prior to implantation and once every 3 days post-implantation
arm group label: Control Group
arm group type: Placebo Comparator
description: Patients receive standardized treatment, consisting of Oseltamivir and Azithromycin
arm group label: Experiment Group
arm group type: Experimental
description: Patients receive intravenous infusion of 1x10^6 unit of umbilical-cord derived mesenchymal stem cells (UC-MSCs)/kgBW in 100 cc of 0.9% NaCl for 1 hour, in addition to standardized treatment
intervention type: Drug
intervention name: Oseltamivir
description: Current standardized treatment for Covid-19
arm group label: Control Group
arm group label: Experiment Group
intervention type: Drug
intervention name: Azithromycin
description: Current standardized treatment for Covid-19
arm group label: Control Group
arm group label: Experiment Group
intervention type: Biological
intervention name: Umbilical Cord Mesenchymal Stem Cells
description: Adjuvant therapy on top of current standardized treatment (Oseltamivir + Azithromycin)
arm group label: Experiment Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 95 Years
healthy volunteers: No
last name: Ismail H Dilogo, MD, PhD
role: Principal Investigator
affiliation: Indonesia University
last name: Ismail H Dilogo, MD, PhD
phone: +621500135
email: ismailortho@gmail.com
last name: Tri Kurniawati, BSc
phone: +621500135
email: selpuncarscm@yahoo.co.id
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Indonesia
responsible party type: Principal Investigator
investigator affiliation: Indonesia University
investigator full name: Ismail Hadisoebroto Dilogo
investigator title: Principal Investigator
mesh term: COVID-19
mesh term: Azithromycin
mesh term: Oseltamivir