<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/NCT04424901</url>
  </required_header>
  <id_info>
    <org_study_id>20-192-2.F</org_study_id>
    <nct_id>NCT04424901</nct_id>
  </id_info>
  <brief_title>Trial of Open Label Dipyridamole- In Hospitalized Patients With COVID-19</brief_title>
  <acronym>TOLD</acronym>
  <official_title>A Randomized, Open-label Study of the Vascular and Microbiologic Efficacy of Dipyridamole Plus Standard Care vs. Standard Care in Hospitalized COVID19 Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UConn Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>UConn Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Brief Summary:&#xD;
&#xD;
      The goal here is to evaluate dipyridamole in treating respiratory tract infection and&#xD;
      circulatory dysfunction due to SARS-CoV-2 coronavirus in hospitalized CVID-19 patients.&#xD;
&#xD;
      Infection with SARS-CoV-2 causes human COVID-19 (HCoV-19). The infection is associated with a&#xD;
      deleterious inflammatory response and a prothrombotic state in addition to tissue damage from&#xD;
      direct viral entry and proliferation. Dipyridamole has anti-platelet and anti-inflammatory&#xD;
      effects. The drug was recently demonstrated to have anti-SARS-Cov-2 effect primarily in&#xD;
      vitro. The concentration causing anti-viral effect in vitro is within that in the blood of&#xD;
      humans taking this drug. As an oral tablet, it has the advantage of easy administration.&#xD;
&#xD;
      Anti thrombotic, anti viral and anti inflammatory actions of this drug may be efficacious and&#xD;
      safe in hospitalized subjects&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The original protocol stipulated an enrollment of 100 patients, randomized in a 1 to 1&#xD;
      distribution of treatment versus control [placebo] group. However, the study was terminated&#xD;
      because of insufficient enrollment due to the dramatic reduction in the number of&#xD;
      hospitalized COVID patients.&#xD;
&#xD;
      A total of 41 patients were randomized prior to study termination. Detailed reports and&#xD;
      overall results were reviewed for all patients.&#xD;
&#xD;
      Adverse event occurrences were similar in groups. Given the severity of COVID, these numbers&#xD;
      were not unexpected.&#xD;
&#xD;
      The DSMC concluded that all the AEs seen in study subjects are either unrelated or probably&#xD;
      unrelated to the TOLD study intervention.&#xD;
&#xD;
      The DSMC reviewed the primary outcome results. No statistically significant change in either&#xD;
      the platelet count or the D-dimer results.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    reduction of Hospitalized COVID patients at UConnHealth&#xD;
  </why_stopped>
  <start_date type="Actual">May 3, 2020</start_date>
  <completion_date type="Actual">April 24, 2022</completion_date>
  <primary_completion_date type="Actual">March 22, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomized Open Label Study Standard Care vs. Standard Care with Dipyridamole</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>D-dimer</measure>
    <time_frame>up to 9 days</time_frame>
    <description>Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Platelet Count</measure>
    <time_frame>up to 9 days</time_frame>
    <description>Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Viral Detection</measure>
    <time_frame>9 days</time_frame>
    <description>Evaluate for a non-detection from nasopharyngeal swab and in stool</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Survival</measure>
    <time_frame>9 days</time_frame>
    <description>Survival Status Alive</description>
  </other_outcome>
  <other_outcome>
    <measure>Inflammatory Markers</measure>
    <time_frame>9 days</time_frame>
    <description>Change in the markers CRP/Ferritin</description>
  </other_outcome>
  <other_outcome>
    <measure>Blood Markers</measure>
    <time_frame>9 days</time_frame>
    <description>Change in Lymphocyte Count/ Fibrinogen/Cardiac Troponin</description>
  </other_outcome>
  <other_outcome>
    <measure>PT PTT</measure>
    <time_frame>9 days</time_frame>
    <description>Coagulation System</description>
  </other_outcome>
  <other_outcome>
    <measure>Pulmonary Status</measure>
    <time_frame>9 days</time_frame>
    <description>Change in SpO2/ imaging</description>
  </other_outcome>
  <other_outcome>
    <measure>Clinical Status</measure>
    <time_frame>9 days</time_frame>
    <description>Change in fever, cough, sputum</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>COVID-19 Pneumonia</condition>
  <condition>Vascular Complications</condition>
  <arm_group>
    <arm_group_label>Standard Care</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Care with Dipyridamole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Daily dose while hospitalized up to 9 days</description>
    <arm_group_label>Standard Care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dipyridamole Tablets</intervention_name>
    <description>Daily dose while hospitalized up to 9 days</description>
    <arm_group_label>Standard Care with Dipyridamole</arm_group_label>
    <other_name>Persantine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adults ≥18 years of age.&#xD;
&#xD;
          2. COVID-19 positive by PCR and hospitalized for respiratory infection with a range of&#xD;
             respiratory severity as follows.&#xD;
&#xD;
             Moderate ● Diagnosed with SARS-CoV-2 infection by standard RT-PCR assay or equivalent&#xD;
             testing&#xD;
&#xD;
             ● Symptoms of moderate illness with COVID-19, which could include:&#xD;
&#xD;
             o Fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal&#xD;
             symptoms; shortness of breath with exertion&#xD;
&#xD;
               -  Clinical signs suggestive of moderate illness with COVID-19, such as:&#xD;
&#xD;
                  o RR ≥ 20, HR ≥ 90, SaO2 ≥93% on room air or requires ≤2L oxygen by nasal cannula&#xD;
                  (NC) in order maintain SaO2 ≥93%, fever &gt;38.3 Celsius&#xD;
&#xD;
               -  No clinical signs indicative of Severe or Critical Illness Severity&#xD;
&#xD;
             Severe&#xD;
&#xD;
               -  Diagnosed with SARS-CoV-2 infection by standard RT-PCR assay or equivalent&#xD;
                  testing&#xD;
&#xD;
               -  Symptoms suggestive of severe systemic illness with COVID-19, which could&#xD;
                  include:&#xD;
&#xD;
                  o any symptom of Moderate Illness; shortness of breath at rest or respiratory&#xD;
                  distress&#xD;
&#xD;
               -  Clinical signs indicative of severe systemic illness with COVID-19, such as&#xD;
&#xD;
                  o RR ≥ 30, HR ≥ 125, requires &gt; 2L oxygen by NC in order maintain SaO2 ≥93%,&#xD;
                  PaO2/FiO2 &lt;300&#xD;
&#xD;
               -  No criteria for Critical Severity&#xD;
&#xD;
             Critical ● Diagnosed with SARS-CoV-2 infection by standard RT-PCR assay or equivalent&#xD;
             testing&#xD;
&#xD;
               -  Evidence of critical illness, defined by at least 1 of the following:&#xD;
&#xD;
                    -  Respiratory failure defined based on resource utilization requiring at least&#xD;
                       1 of the following:&#xD;
&#xD;
                       ◙, Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen&#xD;
                       delivered via reinforced nasal cannula at flow rates &gt;20L/min with fraction&#xD;
                       of delivered oxygen ≥0.5), noninvasive positive pressure ventilation, ECMO,&#xD;
                       or clinical diagnosis of respiratory failure (i.e., clinical need for one of&#xD;
                       the preceding therapies, but preceding therapies not able to be administered&#xD;
                       in setting of resource limitation)&#xD;
&#xD;
                    -  Shock (defined by SBP &lt; 90 mm Hg, or Diastolic BP &lt; 60 mm Hg or requiring&#xD;
                       vasopressors)&#xD;
&#xD;
                    -  Multiple organ dysfunction/failure&#xD;
&#xD;
          3. Able to give written informed consent in English to participate in the study by&#xD;
             patient.&#xD;
&#xD;
             -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Exclusion Criteria:&#xD;
&#xD;
               1. Inability to swallow or ingest oral medication in either tablet form or in&#xD;
                  suspension form.&#xD;
&#xD;
               2. Patient is known to be pregnant&#xD;
&#xD;
               3. Patients with a history of allergy or hypersensitivity to dipyridamole&#xD;
&#xD;
               4. Patient is unable to consent -intubated, on mechanical ventilation&#xD;
&#xD;
               5. Bleeding disorders (e.g. thrombocytopenia with platelet counts &lt; 50,000)&#xD;
&#xD;
               6. Existing severe medical illnesses unrelated to Covid-19 infection such as end&#xD;
                  stage heart, kidney, liver disorders;&#xD;
&#xD;
                  or hepatic insufficiency defined as liver enzymes ≥5 times upper limit normal if&#xD;
                  baseline is normal or 5 times baseline if baseline is abnormal.&#xD;
&#xD;
                  Metastatic cancer as well as those with severe coronary artery disease, unstable&#xD;
                  angina, STEMI, NSTEMI, hypotension (systolic blood pressure &lt;90mmHg),&#xD;
                  myocarditis, bradycardia with resting heart rate less than 60 bpm,&#xD;
                  atrioventricular block without pacemaker.&#xD;
&#xD;
                  Those with myasthenia gravis and those treated with cholinesterase inhibitors&#xD;
&#xD;
               7. Patient is enrolled in a clinical trial for another investigational drug designed&#xD;
                  to test for efficacy for SARS-CoV-2&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bruce Liang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UConn Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UConn Health</name>
      <address>
        <city>Farmington</city>
        <state>Connecticut</state>
        <zip>06030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <results_first_submitted>February 24, 2023</results_first_submitted>
  <results_first_submitted_qc>April 20, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">April 21, 2023</results_first_posted>
  <last_update_submitted>April 20, 2023</last_update_submitted>
  <last_update_submitted_qc>April 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UConn Health</investigator_affiliation>
    <investigator_full_name>Bruce Liang</investigator_full_name>
    <investigator_title>Professor of Medicine School of Medicine</investigator_title>
  </responsible_party>
  <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>Dipyridamole</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 30, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/01/NCT04424901/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>July 21, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/01/NCT04424901/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment from Acute Care University Hospital Units May 2020 to March 2022</recruitment_details>
      <pre_assignment_details>At Consent, subjects are randomized to Placebo or Dipyridamole group.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Standard Care</title>
          <description>Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.</description>
        </group>
        <group group_id="P2">
          <title>Standard Care With Dipyridamole</title>
          <description>For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.&#xD;
Dipyridamole: Dipyridamole-100mg taken 3 times a day by mouth for 7 days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>patients were discharged prior to Hospital Day 9</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Standard Care</title>
          <description>Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.</description>
        </group>
        <group group_id="B2">
          <title>Standard Care With Dipyridamole</title>
          <description>For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.&#xD;
Dipyridamole: Dipyridamole-100mg taken 3 times a day by mouth for 7 days.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="21"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="41"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.62" spread="14.06"/>
                    <measurement group_id="B2" value="60.75" spread="13.89"/>
                    <measurement group_id="B3" value="60.17" spread="13.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race</title>
              <category_list>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black/African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Hispanic/Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>COVID-19 -moderate or severe</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>D-dimer</title>
        <description>Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)</description>
        <time_frame>up to 9 days</time_frame>
        <population>Percent Change from Baseline</population>
        <group_list>
          <group group_id="O1">
            <title>Standard Care</title>
            <description>Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.</description>
          </group>
          <group group_id="O2">
            <title>Standard Care With Dipyridamole</title>
            <description>For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.&#xD;
Dipyridamole: Dipyridamole-100mg taken 3 times a day by mouth for 7 days.</description>
          </group>
        </group_list>
        <measure>
          <title>D-dimer</title>
          <description>Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)</description>
          <population>Percent Change from Baseline</population>
          <units>Percent Change of D-Dimer (ng/mL)</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.99" lower_limit="-17.12" upper_limit="85.63"/>
                    <measurement group_id="O2" value="-10.09" lower_limit="-22.06" upper_limit="6.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Platelet Count</title>
        <description>Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)</description>
        <time_frame>up to 9 days</time_frame>
        <population>Percent Change (%) from Baseline</population>
        <group_list>
          <group group_id="O1">
            <title>Standard Care</title>
            <description>Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.</description>
          </group>
          <group group_id="O2">
            <title>Standard Care With Dipyridamole</title>
            <description>For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.&#xD;
Dipyridamole: Dipyridamole-100mg taken 3 times a day by mouth for 7 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Platelet Count</title>
          <description>Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)</description>
          <population>Percent Change (%) from Baseline</population>
          <units>Percent Change of 10^3 Platelets/uL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.45" spread="34.94"/>
                    <measurement group_id="O2" value="35.48" spread="37.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Viral Detection</title>
        <description>Evaluate for a non-detection from nasopharyngeal swab and in stool</description>
        <time_frame>9 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Survival</title>
        <description>Survival Status Alive</description>
        <time_frame>9 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Inflammatory Markers</title>
        <description>Change in the markers CRP/Ferritin</description>
        <time_frame>9 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Blood Markers</title>
        <description>Change in Lymphocyte Count/ Fibrinogen/Cardiac Troponin</description>
        <time_frame>9 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>PT PTT</title>
        <description>Coagulation System</description>
        <time_frame>9 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Pulmonary Status</title>
        <description>Change in SpO2/ imaging</description>
        <time_frame>9 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Clinical Status</title>
        <description>Change in fever, cough, sputum</description>
        <time_frame>9 days</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Mortality assessed up to 30 days beyond date of enrollment</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Standard Care</title>
          <description>Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.</description>
        </group>
        <group group_id="E2">
          <title>Standard Care With Dipyridamole</title>
          <description>For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.&#xD;
Day 3,6 &amp; 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.&#xD;
Data collection ends on day 9.&#xD;
Dipyridamole: Dipyridamole-100mg taken 3 times a day by mouth for 7 days.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE V 5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death NOS</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine Aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute Kidney Injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE V 5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus Tachycardia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" events="6" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Sinus Bradycardia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Atrial Fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Increase Alanine Aminotransferase</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Increase Aspartate Aminotransferase</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Platelet Count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>No data obtained beyond 9 days of enrollment. If discharged from care, phone follow up limited to data provided by subject report, up to day 9.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Ellen Ciesielski</name_or_title>
      <organization>UConnHealth</organization>
      <phone>860-679-6004</phone>
      <email>eciesielski@uchc.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT04424901
org study id: 20-192-2.F
nct id: NCT04424901
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Brief Summary:

      The goal here is to evaluate dipyridamole in treating respiratory tract infection and
      circulatory dysfunction due to SARS-CoV-2 coronavirus in hospitalized CVID-19 patients.

      Infection with SARS-CoV-2 causes human COVID-19 (HCoV-19). The infection is associated with a
      deleterious inflammatory response and a prothrombotic state in addition to tissue damage from
      direct viral entry and proliferation. Dipyridamole has anti-platelet and anti-inflammatory
      effects. The drug was recently demonstrated to have anti-SARS-Cov-2 effect primarily in
      vitro. The concentration causing anti-viral effect in vitro is within that in the blood of
      humans taking this drug. As an oral tablet, it has the advantage of easy administration.

      Anti thrombotic, anti viral and anti inflammatory actions of this drug may be efficacious and
      safe in hospitalized subjects
The original protocol stipulated an enrollment of 100 patients, randomized in a 1 to 1
      distribution of treatment versus control [placebo] group. However, the study was terminated
      because of insufficient enrollment due to the dramatic reduction in the number of
      hospitalized COVID patients.

      A total of 41 patients were randomized prior to study termination. Detailed reports and
      overall results were reviewed for all patients.

      Adverse event occurrences were similar in groups. Given the severity of COVID, these numbers
      were not unexpected.

      The DSMC concluded that all the AEs seen in study subjects are either unrelated or probably
      unrelated to the TOLD study intervention.

      The DSMC reviewed the primary outcome results. No statistically significant change in either
      the platelet count or the D-dimer results.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized Open Label Study Standard Care vs. Standard Care with Dipyridamole
primary purpose: Treatment
masking: None (Open Label)
measure: D-dimer
time frame: up to 9 days
description: Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)
measure: Platelet Count
time frame: up to 9 days
description: Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)
measure: Viral Detection
time frame: 9 days
description: Evaluate for a non-detection from nasopharyngeal swab and in stool
measure: Survival
time frame: 9 days
description: Survival Status Alive
measure: Inflammatory Markers
time frame: 9 days
description: Change in the markers CRP/Ferritin
measure: Blood Markers
time frame: 9 days
description: Change in Lymphocyte Count/ Fibrinogen/Cardiac Troponin
measure: PT PTT
time frame: 9 days
description: Coagulation System
measure: Pulmonary Status
time frame: 9 days
description: Change in SpO2/ imaging
measure: Clinical Status
time frame: 9 days
description: Change in fever, cough, sputum
arm group label: Standard Care
arm group type: Placebo Comparator
description: Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.
Day 3,6 & 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.
Data collection ends on day 9.
arm group label: Standard Care with Dipyridamole
arm group type: Experimental
description: For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.
Day 3,6 & 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.
Data collection ends on day 9.
intervention type: Drug
intervention name: Placebo
description: Daily dose while hospitalized up to 9 days
arm group label: Standard Care
intervention type: Drug
intervention name: Dipyridamole Tablets
description: Daily dose while hospitalized up to 9 days
arm group label: Standard Care with Dipyridamole
other name: Persantine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bruce Liang, MD
role: Principal Investigator
affiliation: UConn Health
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: UConn Health
investigator full name: Bruce Liang
investigator title: Professor of Medicine School of Medicine
mesh term: COVID-19
mesh term: Dipyridamole
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: No data obtained beyond 9 days of enrollment. If discharged from care, phone follow up limited to data provided by subject report, up to day 9.
point of contact: 