<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/NCT04425863</url>
  </required_header>
  <id_info>
    <org_study_id>IDEA</org_study_id>
    <nct_id>NCT04425863</nct_id>
  </id_info>
  <brief_title>Ivermectin, Aspirin, Dexamethasone and Enoxaparin as Treatment of Covid 19</brief_title>
  <acronym>IDEA</acronym>
  <official_title>Evaluation of Ivermectin, Aspirin, Dexamethasone and Enoxaparin as Treatment of covid19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Eurnekian Public Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Eurnekian Public Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The associated use of Ivermectin, aspirin, dexamethasone, and enoxaparin (in different&#xD;
      combinations and doses) will reduce the impact of COVID infection 19, the need of admission&#xD;
      to the intensive care unit, and mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Between 30 and 50% of patients who contract COVID 19 will be asymptomatic or&#xD;
      oligosymptomatic. This fact will not give rise to the consult, and will directly affect a&#xD;
      notorious sub-registration of the cases.&#xD;
&#xD;
      The second, even more disturbing, premise is that these patients are as contagious as the&#xD;
      moderate and severe cases.&#xD;
&#xD;
      The virus incubation period has been calculated at 5.1 days (95% CI, 4.5 to 5.8 days), and&#xD;
      97.5% of patients are said to have symptoms at 11 days (95% CI 8.2 to 15.6 days).&#xD;
&#xD;
      A mortality of 5.7% has been calculated. The average COVID patient presents with fever (78%),&#xD;
      cough (60-79%) and myalgias or fatigue (35.8 to 44%).&#xD;
&#xD;
      55% develop dyspnea, which appears on average 8 days after the onset of symptoms.&#xD;
&#xD;
      To the manifestations expressed above, the presence of bilateral conjunctival injection&#xD;
      should be added, without associated secretions, hypogeusia, skin rash and hyposmia.&#xD;
&#xD;
      Diagnostic confirmation is made through laboratory studies, which can be performed on a wide&#xD;
      variety of biological samples.&#xD;
&#xD;
      Bronchoalveolar lavage samples showed the highest sensitivity (93%), followed by sputum&#xD;
      samples (72%), nasal swabs (63%), fiberoptic brush biopsy (46%), pharyngeal swabs (32%),&#xD;
      feces ( 29%) and, finally, blood (1%). A sensitivity of 91% is reported in saliva samples.&#xD;
&#xD;
      Evidence suggests that a subgroup of patients with severe forms of COVID 19 may have cytokine&#xD;
      storm syndrome.&#xD;
&#xD;
      Therefore, we recommend the identification and treatment of hyperinflammation using existing&#xD;
      approved therapies with proven safety profiles to address the immediate need to reduce&#xD;
      increasing mortality (see Therapeutic Proposal).&#xD;
&#xD;
      Secondary hemophagocytic lymphohistiocytosis (SHLH) is a poorly recognized hyperinflammatory&#xD;
      syndrome characterized by fatal and fulminant hypercytokinemia with multiple organ failure.&#xD;
&#xD;
      In adults, SHLH is most often triggered by viral infections, and occurs in 3.7-4.3% of sepsis&#xD;
      cases.&#xD;
&#xD;
      The cardinal features of sHLH include constant fever, cytopenias, and hyperferritinemia;&#xD;
      Pulmonary involvement (including ARDS) occurs in approximately 50% of patients.&#xD;
&#xD;
      A cytokine profile that resembles sHLH is associated with the severity of COVID-19 disease,&#xD;
      characterized by an increase in interleukin (IL) -2, IL-7, granulocyte colony stimulating&#xD;
      factor, protein 10 inducible by interferon-γ, monocyte chemoattractant protein, macrophage&#xD;
      inflammatory protein 1-α and tumor necrosis factor-α.&#xD;
&#xD;
      Mortality predictors from a recent multicenter retrospective study of 150 confirmed cases of&#xD;
      COVID-19 in Wuhan, China included elevated ferritin (mean 1297.6 ng / ml in non-survivors&#xD;
      versus 614.0 ng / ml in survivors; p &lt;0.001) and IL-6 (p &lt;0.0001), suggesting that mortality&#xD;
      could be due to viral hyperinflammation.&#xD;
&#xD;
      However, cases have been reported where tissue and organ involvement has been found whose&#xD;
      concentration of ACE receptors is very dissimilar (myocardium, brain). In all of them, the&#xD;
      common denominator was small vessel thrombosis, as seen in entities such as Catastrophic&#xD;
      Antiphospholidic Syndrome.&#xD;
&#xD;
      Currently the Virchow triad factors have been narrowed down in more detail:&#xD;
&#xD;
      Circulatory stasis: abnormalities of hemorrheology and turbulence in vascular bifurcations&#xD;
      and stenotic regions.&#xD;
&#xD;
      Injury to the vascular wall: abnormalities in the endothelium, such as atherosclerosis and&#xD;
      associated vascular inflammation.&#xD;
&#xD;
      Hypercoagulable state: abnormalities in the coagulation and fibrinolytic pathways and in&#xD;
      platelet function associated with an increased risk of VTE and other cardiovascular diseases&#xD;
      (such as coronary artery disease [CPA], heart failure and stroke in patients with AF). All&#xD;
      lead to a state of hypercoagulability, which could explain the formation of microthrombosis&#xD;
      in different locations, as has been repeatedly reported in patients with COVID 19.&#xD;
&#xD;
      BASES OF THE PROPOSED THERAPEUTICS They rest on four pillars: Ivermectin, Aspirin,&#xD;
      Dexamentasone and Enoxaparin. IVERMECTIN Ivermectin is a broad-spectrum antiparasitic, with&#xD;
      vermicidal and ectoparasiticidal properties. It was discovered and marketed for animal use in&#xD;
      the early 1980s.&#xD;
&#xD;
      Approved in 1997 by the FDA for single-dose strongyllidiasis of 200 mcg / kg and crusted&#xD;
      scabies (Scabies Norway) in patients with AIDS at a dose of 200 mcg / kg, every week for 2&#xD;
      weeks.&#xD;
&#xD;
      In Argentina, it has been available for human use for almost 20 years. But, much more&#xD;
      recently, its viricidal effects have been compiled on different varieties of flavivirus,&#xD;
      dengue, Zica, Chikunguña, etc.&#xD;
&#xD;
      Ivermectin has been reported to be a SARS-CoV-2 inhibitor. This activity is believed to be&#xD;
      due to the dependence of many different RNA viruses on IMPα / β1 during infection. These&#xD;
      reports suggested that the inhibitory activity of ivermectin nuclear transport may be&#xD;
      effective against SARS-CoV-2, since they demonstrate that ivermectin has antiviral action&#xD;
      against the clinical isolate of SARS-CoV-2 in vitro, with a single dose capable to control&#xD;
      viral replication in 24-48 hours. in vitro.&#xD;
&#xD;
      Although in vitro studies have used doses that -extrapolated to those recommended in the&#xD;
      treatment of ectoparasitosis in humans- might seem high, the truth is that studies carried&#xD;
      out in healthy volunteers, more than two decades ago, proved that the usual doses they can be&#xD;
      increased tenfold, without significant side and / or adverse effects.&#xD;
&#xD;
      ASPIRIN Aspirin is the common name for acetylsalicylic acid. The chemical production is based&#xD;
      on the salicylic acid obtained by synthesis. Its most common uses and for what it was first&#xD;
      used was as an analgesic (for pain), antipyretic (to lower fever) and anti-inflammatory. It&#xD;
      is classified as a non-steroidal anti-inflammatory drug (NSAID). In 1989 the first large&#xD;
      study was published that proved that Aspirin reduces cardiovascular risk, acting as an&#xD;
      antiplatelet agent.&#xD;
&#xD;
      These were low-dose Aspirin, and the risk of myocardial infarction was found to decrease by&#xD;
      44% when the previously named dose of Aspirin was administered.&#xD;
&#xD;
      HEPARIN AND ENOXAPARIN Heparins are injectable anticoagulant substances. A distinction should&#xD;
      be made between standard heparin or unfractionated heparin (HNF) and low molecular weight&#xD;
      heparins (LMWH).&#xD;
&#xD;
      HNF is made up of a heterogeneous mixture of polysaccharide chains of variable length.&#xD;
&#xD;
      LMWHs are the result of fragmentation of HNF by different methods to achieve products with&#xD;
      lower and more homogeneous molecular weights. They are also made up of a mixture of&#xD;
      polysaccharide chains and their average molecular weight is much lower. The antithrombotic&#xD;
      and anticoagulant activity of HNF is related to the ability to inhibit factor Xa and factor&#xD;
      IIa respectively. LMWHs have less inhibitory activity to thrombin or factor IIa but maintain&#xD;
      the same potency with respect to factor Xa, so it is expected that they present a lower risk&#xD;
      of bleeding but the same antithrombotic activity.&#xD;
&#xD;
      CORTICOSTEROIDS Systemic corticosteroids are powerful anti-inflammatory and immunosuppressive&#xD;
      agents. They can be administered intravenously, intramuscularly, orally, intralesionally, and&#xD;
      topically. Its side effects increase with high, long and frequent doses. Corticosteroids are&#xD;
      drugs frequently used in various clinical situations, because they are powerful&#xD;
      anti-inflammatories and immunomodulators. Glucocorticoids passively diffuse through the cell&#xD;
      membrane, then join soluble receptor proteins in the cytoplasm. They are used, among others,&#xD;
      for the treatment of some rheumatic diseases. A separate case, well known but not studied in&#xD;
      the current contingency, is acute adrenal insufficiency.&#xD;
&#xD;
      CURRENT IDEA TRIAL Based on the precedent data, we started a Clinical Trial based on the&#xD;
      above-mentioned four drugs, on a gradual scale, and according the severity of each case. In&#xD;
      order to determine the dose and combination, we developed our own Severity Score.&#xD;
&#xD;
      INTERPRETATION:&#xD;
&#xD;
      Mild cases Only minor criteria findings Moderate cases 3 major crit. findings, or 2 major + 2&#xD;
      minor Severe cases 4 major crit. Findings or 3 major + 2/3 minor&#xD;
&#xD;
      Based on the previous criteria, we used the following combinations and doses:&#xD;
&#xD;
      DISEASE SEVERITY Firm Suspicious Case or Confirmed case 24 mg orally at a dose of 200 ug / kg&#xD;
      in a single dose, to be repeated a week later Aspirin 250 mg orally Moderate clinical stage&#xD;
      36 mg orally at a dose of 400 ug / kg in a single dose, to be repeated a week later&#xD;
      Dexamethasone 4 mg/day (parenteral) Aspirin 250 mg orally Low Flow Washed Oxygen or Oxygen&#xD;
      Concentrator Severe case with bilateral pneumonia 48 mg via gastric cannulae, to be repeated&#xD;
      a week later Dexamethasone 4 mg/day (parenteral) Enoxaparin100 UI/kg (1 mg/kg) Mechanical&#xD;
      Ventilation&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 1, 2020</start_date>
  <completion_date type="Actual">August 30, 2020</completion_date>
  <primary_completion_date type="Actual">August 30, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Patients Who Improved Their Condition or Did Not Worsen it</measure>
    <time_frame>7 days</time_frame>
    <description>Number of patients who did not go to a more severe stage of disease or die (i.e. they neither go from mild to moderate or severe, nor go from moderate to severe or die, if they had been already enrolled in a severe condition)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>ICU-treated Patients After 2-week Treatment</measure>
    <time_frame>14 days</time_frame>
    <description>Number of patients needing ICU-treatment including mechanical ventilation after 2-week treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>30 days</time_frame>
    <description>Patients who died within 30 days after enrollment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Patients Needing Drug Dose Adjustment</measure>
    <time_frame>14 days</time_frame>
    <description>Patients who needed dose adjustment of any of the drugs involved in the treatment protocol</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>14 days</time_frame>
    <description>Patient presenting serious adverse events</description>
  </primary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">167</enrollment>
  <condition>Severe Acute Respiratory Syndrome</condition>
  <condition>Ventilation Pneumonitis</condition>
  <arm_group>
    <arm_group_label>Mild cases</arm_group_label>
    <description>This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting only mild symptoms such as: fever not above 38.5 °C; isolated diarrheal episodes, hyposmia or hypogeusia, mild desaturation (93 - 96 %), dyspnea without matter, polymyoarthralgias, persistent headache, abdominal pain.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate cases</arm_group_label>
    <description>This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting either: 3 severe symptoms (i.e. fever above 38.5 °C, diarrhea with more than 3 daily depositions, flictenular conjunctivitis, strong desaturation (92% or less), tachypnea (FR&gt; 25 / minute) or 2 severe symptoms + 2 mild symptoms (fever not above 38.5 °C; isolated diarrheal episodes, hyposmia or hypogeusia, mild desaturation (93 - 96 %), dyspnea without matter, polymyoarthralgias, persistent headache, abdominal pain)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Severe cases</arm_group_label>
    <description>This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting either: 4 severe symptoms or 3 severe symptoms and not less than 2 mild symptoms or clinical signs of bilateral viral pneumonia</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ivermectin 5 MG/ML oral solution, Aspirin 250 mg tablets</intervention_name>
    <description>24 mg oral Ivermectin on days 0 and 7 and 1 Aspirin tablet daily for 30 days. Outpatient treatment.</description>
    <arm_group_label>Mild cases</arm_group_label>
    <other_name>Outpatient treatment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Ivermectin 5 mg/mL oral solution, Dexamethasone 4-mg injection, Aspirin 250 mg tablets</intervention_name>
    <description>36 mg oral Ivermectin on days 0 and 7; 1 daily injection of 4-mg Dexamethasone until discharge, 1 Aspirin tablet daily for 30 days. Inpatient treatment in ward care, including Low flow washed oxygen or oxygen concentrator</description>
    <arm_group_label>Moderate cases</arm_group_label>
    <other_name>Inpatient treatment in ward care</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Ivermectin 5 MG/ML oral solution, Dexamethasone 4-mg injection, Enoxaparin injection. Inpatient treatment with mechanical ventilation in ICU.</intervention_name>
    <description>48 mg oral Ivermectin on days 0 and 7; 1 daily injection of 4-mg Dexamethasone until discharge, Enoxaparin 100 IU/kg (ca. 1 mg/kg) daily until transfer to ward care. Then continue with inpatient treatment in ward care.</description>
    <arm_group_label>Severe cases</arm_group_label>
    <other_name>Inpatient treatment in ICU</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients bothe genders, ages 5 or up, non pregnant, capable of accepting participation in&#xD;
        trial (granted by signed premission), and affected by COVID 19&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        patients with positive oral/nasal swabs&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Children under 5 years old Pregnant women Previous reports of allergy to any of the drugs&#xD;
        used in the clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alfredo Secchi, M.D.</last_name>
    <role>Study Chair</role>
    <affiliation>President Ethical Commitee, Hospital Eurnekian</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Eurnekian</name>
      <address>
        <city>Buenos Aires</city>
        <zip>1802</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
  </location_countries>
  <reference>
    <citation>Rizzo E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn Schmiedebergs Arch Pharmacol. 2020 Jul;393(7):1153-1156. doi: 10.1007/s00210-020-01902-5. Epub 2020 May 27.</citation>
    <PMID>32462282</PMID>
  </reference>
  <reference>
    <citation>Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.</citation>
    <PMID>32251768</PMID>
  </reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>June 8, 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>August 13, 2020</results_first_submitted>
  <results_first_submitted_qc>October 8, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 19, 2020</results_first_posted>
  <last_update_submitted>October 8, 2020</last_update_submitted>
  <last_update_submitted_qc>October 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 19, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Eurnekian Public Hospital</investigator_affiliation>
    <investigator_full_name>Hector E Carvallo</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>COVID 19 IVERMECTIN ASPIRIN DEXAMETASONE ENOXAPARIN</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Severe Acute Respiratory Syndrome</mesh_term>
    <mesh_term>Pneumonia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
    <mesh_term>Ivermectin</mesh_term>
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Dexamethasone acetate</mesh_term>
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Pharmaceutical Solutions</mesh_term>
    <mesh_term>BB 1101</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Personal data will remain secret. Only clinical descriptions (age, gender, co-morbidities, evolution, outcomes will be released</ipd_description>
  </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>May 29, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/63/NCT04425863/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment at Eurnekian Public Hospital</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Mild Cases</title>
          <description>This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting only mild symptoms such as: fever not above 38.5 °C; isolated diarrheal episodes, hyposmia or hypogeusia, mild desaturation (93 - 96 %), dyspnea without matter, polymyoarthralgias, persistent headache, abdominal pain.</description>
        </group>
        <group group_id="P2">
          <title>Moderate Cases</title>
          <description>This group includes patients diagnosed positive for COVID-19 via rtPCR an presenting either: 3 severe symptoms (i.e. fever above 38.5 °C, diarrhea with more than 3 daily depositions, flictenular conjuntivitis, strong desaturation of 92 % or less, tachypnea with FR higher than 25/minute) or 2 severe symptoms + 2 mild symptoms (as already described for mild cases).</description>
        </group>
        <group group_id="P3">
          <title>Severe Cases</title>
          <description>This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting either: 4 severe symptoms or 3 severe symptoms and not less than 2 mild symptoms or clinical signs of bilateral viral pneumonia.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="135"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="135"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Mild Cases</title>
          <description>Patients diagnosed positive for COVID-19 and presenting only mild symptoms.</description>
        </group>
        <group group_id="B2">
          <title>Moderate Cases</title>
          <description>Patients diagnosed positive for COVID-19 and presenting either 3 severe symptoms or 2 severe symptoms + 2 mild symptoms</description>
        </group>
        <group group_id="B3">
          <title>Severe Cases</title>
          <description>Patients diagnosed positive for COVID-19 and presenting either 4 severe symptoms or 3 severe symptoms + not less than 2 mild symptoms or clinical symptoms of bilateral viral pneumonia</description>
        </group>
        <group group_id="B4">
          <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="135"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="20"/>
            <count group_id="B4" value="167"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55.7" lower_limit="41" upper_limit="88"/>
                    <measurement group_id="B2" value="59.7" lower_limit="41" upper_limit="88"/>
                    <measurement group_id="B3" value="59.7" lower_limit="41" upper_limit="88"/>
                    <measurement group_id="B4" value="56.5" lower_limit="41" upper_limit="88"/>
                  </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="66"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="84"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="69"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="135"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="20"/>
                    <measurement group_id="B4" value="167"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="135"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="20"/>
                    <measurement group_id="B4" value="167"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Argentina</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="135"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="20"/>
                    <measurement group_id="B4" value="167"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Patients Who Improved Their Condition or Did Not Worsen it</title>
        <description>Number of patients who did not go to a more severe stage of disease or die (i.e. they neither go from mild to moderate or severe, nor go from moderate to severe or die, if they had been already enrolled in a severe condition)</description>
        <time_frame>7 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mild Cases</title>
            <description>Patients diagnosed positive for COVID-19 via rtPCR and presenting only mild symptoms. No clinical signs of viral pneumonia.</description>
          </group>
          <group group_id="O2">
            <title>Moderate Cases</title>
            <description>Patients diagnosed positive for COVID-19 and presenting either 3 severe symptoms or 2 severe symptoms + 2 mild symptoms. Clinical sign of viral pneumonia.</description>
          </group>
          <group group_id="O3">
            <title>Severe Cases</title>
            <description>Patient diagnosed positive for COVID-19 presenting 4 severe symptoms or 3 severe symptoms and not less than 2 mild symptoms. Clinical signs of bilateral viral pneumonia.</description>
          </group>
        </group_list>
        <measure>
          <title>Patients Who Improved Their Condition or Did Not Worsen it</title>
          <description>Number of patients who did not go to a more severe stage of disease or die (i.e. they neither go from mild to moderate or severe, nor go from moderate to severe or die, if they had been already enrolled in a severe condition)</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="135"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="135"/>
                    <measurement group_id="O2" value="12"/>
                    <measurement group_id="O3" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>ICU-treated Patients After 2-week Treatment</title>
        <description>Number of patients needing ICU-treatment including mechanical ventilation after 2-week treatment</description>
        <time_frame>14 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mild Cases</title>
            <description>Patients diagnosed positive for COVID-19 via rtPCR, presenting only mild symptoms and no clinical sign of viral pneumonia.</description>
          </group>
          <group group_id="O2">
            <title>Moderate Cases</title>
            <description>Patients diagnosed positive for COVID-19 via rtPCR, presenting either 3 severe symptoms or 2 mild severe symptoms + 2 mild symptoms or clinical signs of viral pneumonia.</description>
          </group>
          <group group_id="O3">
            <title>Severe Cases</title>
            <description>Patients diagnosed positive for COVID-19, presenting either 4 severe symptoms or 3 severe symptoms + at least 2 mild symptoms or clinical signs of bilateral viral pneumonia</description>
          </group>
        </group_list>
        <measure>
          <title>ICU-treated Patients After 2-week Treatment</title>
          <description>Number of patients needing ICU-treatment including mechanical ventilation after 2-week treatment</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="135"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Mortality</title>
        <description>Patients who died within 30 days after enrollment</description>
        <time_frame>30 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mild Cases</title>
            <description>Patients diagnosed positive for COVID-19 presenting only mild symptoms and no clinical signs of viral pneumonia.</description>
          </group>
          <group group_id="O2">
            <title>Moderate Cases</title>
            <description>Patients diagnosed positive for COVID-19 and presenting either 3 severe symptoms or 2 severe + 2 mild symptoms and showing clinical signs of viral pneumonia.</description>
          </group>
          <group group_id="O3">
            <title>Severe Cases</title>
            <description>Patients diagnosed positive for COVID-19 and presenting either 4 severe symptoms or 3 severe symptoms + 2 mild symptoms or clinical signs of bilateral viral pneumonia.</description>
          </group>
        </group_list>
        <measure>
          <title>Mortality</title>
          <description>Patients who died within 30 days after enrollment</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="135"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>A chi-squared test is used to find out whether there is a statistically significant decrease in mortality rate when the IDEA treatment protocol is used in hospitalized patients in comparison with other treatments in the same hospital in the same period of time (3 out of 12 inpatients died)</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0246</p_value>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Overall mortality rate of patients treated according to IDEA protocol is compared by a chi-squared test against overall mortality rate in Argentina (the same region where the hospital is located). Data used for overall mortality in Argentina correspond to June 30th according to the website of the Ministry of Health of Argentina</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0475</p_value>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>A chi-square test was applied to compare the mortality rate of patients treated with IDEA protocol as compared with data published (26.84 %) in Bertsimas D, Lukin G, Mingardi L, Nohadani O, Orfanoudaki A, Stellato B et al. (2020), COVID-19 Mortality Risk Assessment: An International Multi-Center Study doi: 10.1101/2020.07.07.20148304</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0025</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Patients Needing Drug Dose Adjustment</title>
        <description>Patients who needed dose adjustment of any of the drugs involved in the treatment protocol</description>
        <time_frame>14 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mild Cases</title>
            <description>Patients diagnosed positive for COVID-19 presenting only mild symptoms and no clinical sign of viral pneumonia.</description>
          </group>
          <group group_id="O2">
            <title>Moderate Cases</title>
            <description>Patients diagnosed positive for COVID-19 by rtPCR and presenting 3 severe symptoms or 2 mild + 2 severe symptoms or clinical signs of viral pneumonia.</description>
          </group>
          <group group_id="O3">
            <title>Severe Cases</title>
            <description>Patients diagnosed positive for COVID-19 by rtPCR and presenting 4 severe symptoms or 3 severe symptoms + 2 mild symptoms or clinical signs of bilateral viral pneumonia.</description>
          </group>
        </group_list>
        <measure>
          <title>Patients Needing Drug Dose Adjustment</title>
          <description>Patients who needed dose adjustment of any of the drugs involved in the treatment protocol</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="135"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Adverse Events</title>
        <description>Patient presenting serious adverse events</description>
        <time_frame>14 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mild Cases</title>
            <description>Patients diagnosed positive for COVID-19 by rtPCR and presenting only mild symptoms and no clinical sign of viral pneumonia.</description>
          </group>
          <group group_id="O2">
            <title>Moderate Cases</title>
            <description>Patients diagnosed positive for COVID-19 by rtPCR and presenting either 3 severe symptoms or 2 severe symptoms + 2 mild symptoms or clinical signs of viral pneumonia.</description>
          </group>
          <group group_id="O3">
            <title>Severe Cases</title>
            <description>Patients diagnosed positive for COVID-19 by rtPCR, presenting 4 sever symptoms, or 3 severe symptoms + 2 mild symptoms or clinical signs of bilateral viral pneumonia.</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events</title>
          <description>Patient presenting serious adverse events</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="135"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Mild Cases</title>
          <description>Patients diagnosed positive for COVID-19 presenting only mild symptoms and no clinical signs of viral pneumonia.</description>
        </group>
        <group group_id="E2">
          <title>Moderate Cases</title>
          <description>Patients diagnosed positive for COVID-19 by rtPCR presenting 3 severe symptoms or 2 severe symptoms + 2 mild symptoms or clinical signs of viral pneumonia</description>
        </group>
        <group group_id="E3">
          <title>Severe Cases</title>
          <description>Patients diagnosed positive for COVID-19 by rtPCR presenting 4 severe symptoms or 3 severe symptoms + 2 mild symptoms or clinical signs of bilateral viral pneumonia</description>
        </group>
      </group_list>
      <serious_events>
        <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="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>multiple organ failure</sub_title>
                <description>Multiple organ failure and respiratory defficiency leading to death</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-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="0" subjects_at_risk="135"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hemorrhage</sub_title>
                <description>Required only minor intervention. The patient had an ulcer at enrollment.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="135"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" 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>
    <point_of_contact>
      <name_or_title>Dr. Héctor Carvallo</name_or_title>
      <organization>Eurnekian Public Hospital</organization>
      <phone>54144800949</phone>
      <email>hymcarvallo@hotmail.com</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/NCT04425863
org study id: IDEA
nct id: NCT04425863
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The associated use of Ivermectin, aspirin, dexamethasone, and enoxaparin (in different
      combinations and doses) will reduce the impact of COVID infection 19, the need of admission
      to the intensive care unit, and mortality.
Between 30 and 50% of patients who contract COVID 19 will be asymptomatic or
      oligosymptomatic. This fact will not give rise to the consult, and will directly affect a
      notorious sub-registration of the cases.

      The second, even more disturbing, premise is that these patients are as contagious as the
      moderate and severe cases.

      The virus incubation period has been calculated at 5.1 days (95% CI, 4.5 to 5.8 days), and
      97.5% of patients are said to have symptoms at 11 days (95% CI 8.2 to 15.6 days).

      A mortality of 5.7% has been calculated. The average COVID patient presents with fever (78%),
      cough (60-79%) and myalgias or fatigue (35.8 to 44%).

      55% develop dyspnea, which appears on average 8 days after the onset of symptoms.

      To the manifestations expressed above, the presence of bilateral conjunctival injection
      should be added, without associated secretions, hypogeusia, skin rash and hyposmia.

      Diagnostic confirmation is made through laboratory studies, which can be performed on a wide
      variety of biological samples.

      Bronchoalveolar lavage samples showed the highest sensitivity (93%), followed by sputum
      samples (72%), nasal swabs (63%), fiberoptic brush biopsy (46%), pharyngeal swabs (32%),
      feces ( 29%) and, finally, blood (1%). A sensitivity of 91% is reported in saliva samples.

      Evidence suggests that a subgroup of patients with severe forms of COVID 19 may have cytokine
      storm syndrome.

      Therefore, we recommend the identification and treatment of hyperinflammation using existing
      approved therapies with proven safety profiles to address the immediate need to reduce
      increasing mortality (see Therapeutic Proposal).

      Secondary hemophagocytic lymphohistiocytosis (SHLH) is a poorly recognized hyperinflammatory
      syndrome characterized by fatal and fulminant hypercytokinemia with multiple organ failure.

      In adults, SHLH is most often triggered by viral infections, and occurs in 3.7-4.3% of sepsis
      cases.

      The cardinal features of sHLH include constant fever, cytopenias, and hyperferritinemia;
      Pulmonary involvement (including ARDS) occurs in approximately 50% of patients.

      A cytokine profile that resembles sHLH is associated with the severity of COVID-19 disease,
      characterized by an increase in interleukin (IL) -2, IL-7, granulocyte colony stimulating
      factor, protein 10 inducible by interferon-γ, monocyte chemoattractant protein, macrophage
      inflammatory protein 1-α and tumor necrosis factor-α.

      Mortality predictors from a recent multicenter retrospective study of 150 confirmed cases of
      COVID-19 in Wuhan, China included elevated ferritin (mean 1297.6 ng / ml in non-survivors
      versus 614.0 ng / ml in survivors; p <0.001) and IL-6 (p <0.0001), suggesting that mortality
      could be due to viral hyperinflammation.

      However, cases have been reported where tissue and organ involvement has been found whose
      concentration of ACE receptors is very dissimilar (myocardium, brain). In all of them, the
      common denominator was small vessel thrombosis, as seen in entities such as Catastrophic
      Antiphospholidic Syndrome.

      Currently the Virchow triad factors have been narrowed down in more detail:

      Circulatory stasis: abnormalities of hemorrheology and turbulence in vascular bifurcations
      and stenotic regions.

      Injury to the vascular wall: abnormalities in the endothelium, such as atherosclerosis and
      associated vascular inflammation.

      Hypercoagulable state: abnormalities in the coagulation and fibrinolytic pathways and in
      platelet function associated with an increased risk of VTE and other cardiovascular diseases
      (such as coronary artery disease [CPA], heart failure and stroke in patients with AF). All
      lead to a state of hypercoagulability, which could explain the formation of microthrombosis
      in different locations, as has been repeatedly reported in patients with COVID 19.

      BASES OF THE PROPOSED THERAPEUTICS They rest on four pillars: Ivermectin, Aspirin,
      Dexamentasone and Enoxaparin. IVERMECTIN Ivermectin is a broad-spectrum antiparasitic, with
      vermicidal and ectoparasiticidal properties. It was discovered and marketed for animal use in
      the early 1980s.

      Approved in 1997 by the FDA for single-dose strongyllidiasis of 200 mcg / kg and crusted
      scabies (Scabies Norway) in patients with AIDS at a dose of 200 mcg / kg, every week for 2
      weeks.

      In Argentina, it has been available for human use for almost 20 years. But, much more
      recently, its viricidal effects have been compiled on different varieties of flavivirus,
      dengue, Zica, Chikunguña, etc.

      Ivermectin has been reported to be a SARS-CoV-2 inhibitor. This activity is believed to be
      due to the dependence of many different RNA viruses on IMPα / β1 during infection. These
      reports suggested that the inhibitory activity of ivermectin nuclear transport may be
      effective against SARS-CoV-2, since they demonstrate that ivermectin has antiviral action
      against the clinical isolate of SARS-CoV-2 in vitro, with a single dose capable to control
      viral replication in 24-48 hours. in vitro.

      Although in vitro studies have used doses that -extrapolated to those recommended in the
      treatment of ectoparasitosis in humans- might seem high, the truth is that studies carried
      out in healthy volunteers, more than two decades ago, proved that the usual doses they can be
      increased tenfold, without significant side and / or adverse effects.

      ASPIRIN Aspirin is the common name for acetylsalicylic acid. The chemical production is based
      on the salicylic acid obtained by synthesis. Its most common uses and for what it was first
      used was as an analgesic (for pain), antipyretic (to lower fever) and anti-inflammatory. It
      is classified as a non-steroidal anti-inflammatory drug (NSAID). In 1989 the first large
      study was published that proved that Aspirin reduces cardiovascular risk, acting as an
      antiplatelet agent.

      These were low-dose Aspirin, and the risk of myocardial infarction was found to decrease by
      44% when the previously named dose of Aspirin was administered.

      HEPARIN AND ENOXAPARIN Heparins are injectable anticoagulant substances. A distinction should
      be made between standard heparin or unfractionated heparin (HNF) and low molecular weight
      heparins (LMWH).

      HNF is made up of a heterogeneous mixture of polysaccharide chains of variable length.

      LMWHs are the result of fragmentation of HNF by different methods to achieve products with
      lower and more homogeneous molecular weights. They are also made up of a mixture of
      polysaccharide chains and their average molecular weight is much lower. The antithrombotic
      and anticoagulant activity of HNF is related to the ability to inhibit factor Xa and factor
      IIa respectively. LMWHs have less inhibitory activity to thrombin or factor IIa but maintain
      the same potency with respect to factor Xa, so it is expected that they present a lower risk
      of bleeding but the same antithrombotic activity.

      CORTICOSTEROIDS Systemic corticosteroids are powerful anti-inflammatory and immunosuppressive
      agents. They can be administered intravenously, intramuscularly, orally, intralesionally, and
      topically. Its side effects increase with high, long and frequent doses. Corticosteroids are
      drugs frequently used in various clinical situations, because they are powerful
      anti-inflammatories and immunomodulators. Glucocorticoids passively diffuse through the cell
      membrane, then join soluble receptor proteins in the cytoplasm. They are used, among others,
      for the treatment of some rheumatic diseases. A separate case, well known but not studied in
      the current contingency, is acute adrenal insufficiency.

      CURRENT IDEA TRIAL Based on the precedent data, we started a Clinical Trial based on the
      above-mentioned four drugs, on a gradual scale, and according the severity of each case. In
      order to determine the dose and combination, we developed our own Severity Score.

      INTERPRETATION:

      Mild cases Only minor criteria findings Moderate cases 3 major crit. findings, or 2 major + 2
      minor Severe cases 4 major crit. Findings or 3 major + 2/3 minor

      Based on the previous criteria, we used the following combinations and doses:

      DISEASE SEVERITY Firm Suspicious Case or Confirmed case 24 mg orally at a dose of 200 ug / kg
      in a single dose, to be repeated a week later Aspirin 250 mg orally Moderate clinical stage
      36 mg orally at a dose of 400 ug / kg in a single dose, to be repeated a week later
      Dexamethasone 4 mg/day (parenteral) Aspirin 250 mg orally Low Flow Washed Oxygen or Oxygen
      Concentrator Severe case with bilateral pneumonia 48 mg via gastric cannulae, to be repeated
      a week later Dexamethasone 4 mg/day (parenteral) Enoxaparin100 UI/kg (1 mg/kg) Mechanical
      Ventilation
observational model: Cohort
time perspective: Prospective
measure: Patients Who Improved Their Condition or Did Not Worsen it
time frame: 7 days
description: Number of patients who did not go to a more severe stage of disease or die (i.e. they neither go from mild to moderate or severe, nor go from moderate to severe or die, if they had been already enrolled in a severe condition)
measure: ICU-treated Patients After 2-week Treatment
time frame: 14 days
description: Number of patients needing ICU-treatment including mechanical ventilation after 2-week treatment
measure: Mortality
time frame: 30 days
description: Patients who died within 30 days after enrollment
measure: Patients Needing Drug Dose Adjustment
time frame: 14 days
description: Patients who needed dose adjustment of any of the drugs involved in the treatment protocol
measure: Adverse Events
time frame: 14 days
description: Patient presenting serious adverse events
arm group label: Mild cases
description: This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting only mild symptoms such as: fever not above 38.5 °C; isolated diarrheal episodes, hyposmia or hypogeusia, mild desaturation (93 - 96 %), dyspnea without matter, polymyoarthralgias, persistent headache, abdominal pain.
arm group label: Moderate cases
description: This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting either: 3 severe symptoms (i.e. fever above 38.5 °C, diarrhea with more than 3 daily depositions, flictenular conjunctivitis, strong desaturation (92% or less), tachypnea (FR> 25 / minute) or 2 severe symptoms + 2 mild symptoms (fever not above 38.5 °C; isolated diarrheal episodes, hyposmia or hypogeusia, mild desaturation (93 - 96 %), dyspnea without matter, polymyoarthralgias, persistent headache, abdominal pain)
arm group label: Severe cases
description: This group includes patients diagnosed positive for COVID-19 via rtPCR and presenting either: 4 severe symptoms or 3 severe symptoms and not less than 2 mild symptoms or clinical signs of bilateral viral pneumonia
intervention type: Drug
intervention name: Ivermectin 5 MG/ML oral solution, Aspirin 250 mg tablets
description: 24 mg oral Ivermectin on days 0 and 7 and 1 Aspirin tablet daily for 30 days. Outpatient treatment.
arm group label: Mild cases
other name: Outpatient treatment
intervention type: Other
intervention name: Ivermectin 5 mg/mL oral solution, Dexamethasone 4-mg injection, Aspirin 250 mg tablets
description: 36 mg oral Ivermectin on days 0 and 7; 1 daily injection of 4-mg Dexamethasone until discharge, 1 Aspirin tablet daily for 30 days. Inpatient treatment in ward care, including Low flow washed oxygen or oxygen concentrator
arm group label: Moderate cases
other name: Inpatient treatment in ward care
intervention type: Other
intervention name: Ivermectin 5 MG/ML oral solution, Dexamethasone 4-mg injection, Enoxaparin injection. Inpatient treatment with mechanical ventilation in ICU.
description: 48 mg oral Ivermectin on days 0 and 7; 1 daily injection of 4-mg Dexamethasone until discharge, Enoxaparin 100 IU/kg (ca. 1 mg/kg) daily until transfer to ward care. Then continue with inpatient treatment in ward care.
arm group label: Severe cases
other name: Inpatient treatment in ICU
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 5 Years
maximum age: N/A
healthy volunteers: No
last name: Alfredo Secchi, M.D.
role: Study Chair
affiliation: President Ethical Commitee, Hospital Eurnekian
facility: 
country: Argentina
citation: Rizzo E. Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action. Naunyn Schmiedebergs Arch Pharmacol. 2020 Jul;393(7):1153-1156. doi: 10.1007/s00210-020-01902-5. Epub 2020 May 27.
PMID: 32462282
citation: Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.
PMID: 32251768
responsible party type: Principal Investigator
investigator affiliation: Eurnekian Public Hospital
investigator full name: Hector E Carvallo
investigator title: Principal investigator
mesh term: COVID-19
mesh term: Severe Acute Respiratory Syndrome
mesh term: Pneumonia
mesh term: Aspirin
mesh term: Ivermectin
mesh term: Dexamethasone
mesh term: Dexamethasone acetate
mesh term: Enoxaparin
mesh term: Pharmaceutical Solutions
mesh term: BB 1101
sharing ipd: Undecided
ipd description: Personal data will remain secret. Only clinical descriptions (age, gender, co-morbidities, evolution, outcomes will be released
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 