<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/NCT04453371</url>
  </required_header>
  <id_info>
    <org_study_id>tPA-2020</org_study_id>
    <nct_id>NCT04453371</nct_id>
  </id_info>
  <brief_title>Impact of Tissue Plasminogen Activator (tPA) Treatment for an Atypical Acute Respiratory Distress Syndrome (COVID-19)</brief_title>
  <acronym>AtTAC</acronym>
  <official_title>Tissue Plasminogen Activator (tPA) Treatment for an Atypical Acute Respiratory Distress Syndrome (Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome (MicroCLOTS): A Multicentral Randomized Trial (AtTAC-trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Negovsky Reanimatology Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Demikhov Municipal Clinical Hospital 68</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Negovsky Reanimatology Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      At the beginning COVID-associated lung injury was considered as typical ARDS, hence&#xD;
      respiratory and nonrespiratory treatments were delivered according to general principles for&#xD;
      this kind of illness. There is hypothesis that in predisposed individuals, alveolar viral&#xD;
      damage is followed by an inflammatory reaction and by microvascular pulmonary thrombosis. The&#xD;
      investigators suggest that thrombolytic therapy may be beneficial when compared to standard&#xD;
      care in patients with SARS-CoV-2 and severe respiratory failure.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      COVID 19 pandemic is a serious challenge for International medical community. There is lack&#xD;
      of knowledge about the nature and character of the lung injury caused by this kind of&#xD;
      infection. At the beginning COVID-associated lung injury was considered as typical ARDS,&#xD;
      hence respiratory and nonrespiratory treatments were delivered according to general&#xD;
      principles for this kind of illness. There is hypothesis that in predisposed individuals,&#xD;
      alveolar viral damage is followed by an inflammatory reaction and by microvascular pulmonary&#xD;
      thrombosis. This progressive endothelial thromboinflammatory syndrome may also involve the&#xD;
      microvascular bed of the brain and other vital organs, leading to multiple organ failure and&#xD;
      death. Understanding the crucial role of microthrombosis in the genesis of SARS-2-CoV led to&#xD;
      a widespread anticoagulant use. Moreover, there is evidence about a possible benefit of&#xD;
      thrombolysis in patients with severe COVID-19 pulmonary disease. For Instance, some&#xD;
      investigators reported about three patients with COVID 19 lung injury treated with alteplase&#xD;
      (tPA). Authors oversaw positive changes in P/F ratio in 3/3 patients, even if in two of these&#xD;
      patients changes lasted for a short period. Another investigators reported about the&#xD;
      improvements in alveolar ventilation, arterial oxygenation and diminishing in vasopressor's&#xD;
      support in 4 patients with SARS-2CoV after thrombolysis. Encouraging results were obtained&#xD;
      also by another team in case series of 5 patients who received alteplase. Thus, there is&#xD;
      evidence suggesting that thrombolytic therapy may be beneficial when compared to standard&#xD;
      care in patients with SARS-CoV-2 and severe respiratory failure. This hypothesis is based on&#xD;
      a well-established pathophysiological concept of the occurrence of pulmonary damage as a&#xD;
      result of microthrombosis of the lung vessels. Hence, it seems crucial to conduct a&#xD;
      randomized clinical trial to test the effectiveness of this treatment.&#xD;
&#xD;
      Objective: To establish whether plasminogen activator (tPA) treatment improves alveolar&#xD;
      ventilation P/F (PaO2/FiO2) ratio will be calculated each 6 hours during first 3 days after&#xD;
      the end of thrombolysis procedure in patients with an Atypical Acute Respiratory Distress&#xD;
      Syndrome (Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome&#xD;
      (MicroCLOTS).&#xD;
&#xD;
      Methods: Research assistants and/or clinician screen all mechanically ventilated patients for&#xD;
      eligibility. Patients satisfying all of the Inclusion and Exclusion Criteria are classified&#xD;
      as 'Eligible'. With informed consent from a substitute decision maker or under the decision&#xD;
      of Concilium of three independent physicians, Eligible patients are 'Enrolled' into the&#xD;
      study. Eligible patients Qualify for Randomization to one of the 2 groups: with or without&#xD;
      thrombolytic therapy. In summary, patients are consented and Enrolled prior to Randomization.&#xD;
      To enroll or randomize Eligible patients, research coordinators obtain informed consent and&#xD;
      access the automated web-based system through Internet based program (available 24&#xD;
      hours/day). Each participating center has a separate computer-generated randomization&#xD;
      schedule, with 1:1 (control to intervention) assignment, stratified by center, and using&#xD;
      random variable block sizes.&#xD;
&#xD;
      The thrombolysis procedure: In the study group, tPA (Alteplase) 25 mg i/v over 2 hours,&#xD;
      followed by a 25 mg tPA infusion over the subsequent 22 hours. After the end of thrombolytic&#xD;
      therapy, unfractionated heparin is administered i/v at a starting dose of 10 units / kg per&#xD;
      hour. The target value of PTT is 40C-50C. In the control group, an equivalent amount of&#xD;
      Ringer's solution is administered. After 24 hours, the heparin infusion gets started, similar&#xD;
      the described for study group.&#xD;
&#xD;
      In both groups patient's transfer from the heparin infusion to the introduction of&#xD;
      low-molecular-weight heparins is performed after normalization of the D-dimer level.&#xD;
&#xD;
      Statistical analysis: Primary data analysis will be based on intention to treat (ITT)&#xD;
      analysis.&#xD;
&#xD;
      Data will be analyzed also on a modified ITT approach (mITT). Will be included in this&#xD;
      analysis only patients with evidence of an Atypical Acute Respiratory Distress Syndrome&#xD;
      (Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome (MicroCLOTS).&#xD;
&#xD;
      Subgroups analysis: Some pre-defined subgroups analysis will be performed:&#xD;
&#xD;
        1. Patients with with P/F &lt;200 mmHg&gt;100 mmHg;&#xD;
&#xD;
        2. Patients with with P/F &lt;100 mmHg;&#xD;
&#xD;
        3. Patient 65+ group;&#xD;
&#xD;
        4. Patients under 65 years old. Interim analyses: Interim analyses will not be performed&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Our local committee has denied the approval request&#xD;
  </why_stopped>
  <start_date type="Anticipated">October 15, 2020</start_date>
  <completion_date type="Anticipated">February 15, 2021</completion_date>
  <primary_completion_date type="Anticipated">January 15, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>P/F (PaO2/FiO2) change during the first 72hrs after the end of the procedure in adult patients with severe atypical ARDS caused by SARS-2-CoV.</measure>
    <time_frame>Each 6 hours during first 3 days after the end of thrombolysis procedure.</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Ventilator-free time (days free from MV) for 28 days of observation.</measure>
    <time_frame>28 days</time_frame>
    <description>Calculated as 28 days - number of days when patient receive any kind of ventilatory support (MV + SV + NIV).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Mortality in 28 days and 1 year after randomization despite of the reason.</measure>
    <time_frame>28 days, 1 year after randomization</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Length of stay in the ICU</measure>
    <time_frame>28 days</time_frame>
    <description>Number of days when patient was in ICU</description>
  </other_outcome>
  <other_outcome>
    <measure>Length of stay in hospital</measure>
    <time_frame>28 days</time_frame>
    <description>Number of days when patient was in hospital</description>
  </other_outcome>
  <other_outcome>
    <measure>The time needed for &quot;improvement of 2 points&quot; according to WHO &quot;Ordinal Scale for Clinical Improvement&quot;</measure>
    <time_frame>From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 month</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Chest radiographs on a daily basis and define barotrauma as the presence of new pneumothorax, pneumomediastinum, pneumoperitoneum, or subcutaneous emphysema.</measure>
    <time_frame>Daily up to extubation than once a week/or on attending intensivist's discretion up to 1 month</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Blood Pressure in millimetres of mercury</measure>
    <time_frame>Each 4 hours during first 2 weeks after the end of thrombolysis procedure.</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Heart Rate in beats per minute</measure>
    <time_frame>Each 4 hours during first 2 weeks after the end of thrombolysis procedure.</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Blood Oxygen Saturation</measure>
    <time_frame>Each 4 hours during first 2 weeks after the end of thrombolysis procedure.</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>ECG Q-wave</measure>
    <time_frame>Each 24 hours during first 2 weeks after the end of thrombolysis procedure.</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>ECG ST-segment</measure>
    <time_frame>Each 24 hours during first 2 weeks after the end of thrombolysis procedure.</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Acute Respiratory Distress Syndrome</condition>
  <arm_group>
    <arm_group_label>Study group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Thrombolysis</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Ringer's solution infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tissue plasminogen activator</intervention_name>
    <description>In the study group, tPA (Alteplase) 25 mg i/v over 2 hours, followed by a 25 mg tPA infusion over the subsequent 22 hours. After the end of thrombolytic therapy, unfractionated heparin is administered i/v at a starting dose of 10 units / kg per hour. The target value of PTT is 40C-50C.&#xD;
In both groups patient's transfer from the heparin infusion to the introduction of low-molecular-weight heparins is performed after normalization of the D-dimer level.</description>
    <arm_group_label>Study group</arm_group_label>
    <other_name>Alteplase</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ringer solution</intervention_name>
    <description>In the control group, an equivalent amount of Ringer's solution is administered. After 24 hours, the heparin infusion gets started, similar the described for study group.&#xD;
In both groups patient's transfer from the heparin infusion to the introduction of low-molecular-weight heparins is performed after normalization of the D-dimer level.</description>
    <arm_group_label>Control group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Severe pulmonary coronavirus disease 19 (COVID 19) with suspect for MicroCLOTS&#xD;
             (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome)&#xD;
&#xD;
          2. P/F ratio &lt;200 mmHg&gt; 70 mmHg&#xD;
&#xD;
          3. a.) Contrast CT scan positive for pulmonary thrombosis, OR b.) Contrast CT scan&#xD;
             negative for pulmonary thrombosis:&#xD;
&#xD;
               -  D-Dimer &gt; 10 mcg/mL, OR&#xD;
&#xD;
               -  5 &lt; D-dimer &lt; 10 mcg/mL and C Reactive Protein (CRP) &gt; 100 mg/dL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Known allergy to iodinated contrast dye&#xD;
&#xD;
          -  Severe vasoplegic shock: norepinephrine &gt; 300 ng/kg*min&#xD;
&#xD;
          -  Glomerular Filtration rate &lt; 30 ml/min&#xD;
&#xD;
          -  Active bleeding or absolute contraindication to anticoagulant therapy (Stroke&#xD;
             (intracranial hemorrhage, hemorrhagic stroke), including a history of the last 6&#xD;
             months.; cancer of the Central nervous system and other localities with an increased&#xD;
             risk of bleeding, vascular aneurysm, traumatic open heart massage, obstetric delivery,&#xD;
             General operations, severe uncontrolled hypertension, gastric ulcer and 12-duodenal&#xD;
             ulcer (for 3 months. from the moment of exacerbation), arterial or venous&#xD;
             malformations, liver failure, liver cirrhosis, portal hypertension, esophageal&#xD;
             varicose veins, active hepatitis).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>June 26, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>March 10, 2021</last_update_submitted>
  <last_update_submitted_qc>March 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>MicroCLOTS</keyword>
  <keyword>Atypical Acute Respiratory Distress Syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
    <mesh_term>Respiratory Distress Syndrome, Newborn</mesh_term>
    <mesh_term>Acute Lung Injury</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tissue Plasminogen Activator</mesh_term>
    <mesh_term>Plasminogen</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04453371
org study id: tPA-2020
nct id: NCT04453371
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
At the beginning COVID-associated lung injury was considered as typical ARDS, hence
      respiratory and nonrespiratory treatments were delivered according to general principles for
      this kind of illness. There is hypothesis that in predisposed individuals, alveolar viral
      damage is followed by an inflammatory reaction and by microvascular pulmonary thrombosis. The
      investigators suggest that thrombolytic therapy may be beneficial when compared to standard
      care in patients with SARS-CoV-2 and severe respiratory failure.
COVID 19 pandemic is a serious challenge for International medical community. There is lack
      of knowledge about the nature and character of the lung injury caused by this kind of
      infection. At the beginning COVID-associated lung injury was considered as typical ARDS,
      hence respiratory and nonrespiratory treatments were delivered according to general
      principles for this kind of illness. There is hypothesis that in predisposed individuals,
      alveolar viral damage is followed by an inflammatory reaction and by microvascular pulmonary
      thrombosis. This progressive endothelial thromboinflammatory syndrome may also involve the
      microvascular bed of the brain and other vital organs, leading to multiple organ failure and
      death. Understanding the crucial role of microthrombosis in the genesis of SARS-2-CoV led to
      a widespread anticoagulant use. Moreover, there is evidence about a possible benefit of
      thrombolysis in patients with severe COVID-19 pulmonary disease. For Instance, some
      investigators reported about three patients with COVID 19 lung injury treated with alteplase
      (tPA). Authors oversaw positive changes in P/F ratio in 3/3 patients, even if in two of these
      patients changes lasted for a short period. Another investigators reported about the
      improvements in alveolar ventilation, arterial oxygenation and diminishing in vasopressor's
      support in 4 patients with SARS-2CoV after thrombolysis. Encouraging results were obtained
      also by another team in case series of 5 patients who received alteplase. Thus, there is
      evidence suggesting that thrombolytic therapy may be beneficial when compared to standard
      care in patients with SARS-CoV-2 and severe respiratory failure. This hypothesis is based on
      a well-established pathophysiological concept of the occurrence of pulmonary damage as a
      result of microthrombosis of the lung vessels. Hence, it seems crucial to conduct a
      randomized clinical trial to test the effectiveness of this treatment.

      Objective: To establish whether plasminogen activator (tPA) treatment improves alveolar
      ventilation P/F (PaO2/FiO2) ratio will be calculated each 6 hours during first 3 days after
      the end of thrombolysis procedure in patients with an Atypical Acute Respiratory Distress
      Syndrome (Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome
      (MicroCLOTS).

      Methods: Research assistants and/or clinician screen all mechanically ventilated patients for
      eligibility. Patients satisfying all of the Inclusion and Exclusion Criteria are classified
      as 'Eligible'. With informed consent from a substitute decision maker or under the decision
      of Concilium of three independent physicians, Eligible patients are 'Enrolled' into the
      study. Eligible patients Qualify for Randomization to one of the 2 groups: with or without
      thrombolytic therapy. In summary, patients are consented and Enrolled prior to Randomization.
      To enroll or randomize Eligible patients, research coordinators obtain informed consent and
      access the automated web-based system through Internet based program (available 24
      hours/day). Each participating center has a separate computer-generated randomization
      schedule, with 1:1 (control to intervention) assignment, stratified by center, and using
      random variable block sizes.

      The thrombolysis procedure: In the study group, tPA (Alteplase) 25 mg i/v over 2 hours,
      followed by a 25 mg tPA infusion over the subsequent 22 hours. After the end of thrombolytic
      therapy, unfractionated heparin is administered i/v at a starting dose of 10 units / kg per
      hour. The target value of PTT is 40C-50C. In the control group, an equivalent amount of
      Ringer's solution is administered. After 24 hours, the heparin infusion gets started, similar
      the described for study group.

      In both groups patient's transfer from the heparin infusion to the introduction of
      low-molecular-weight heparins is performed after normalization of the D-dimer level.

      Statistical analysis: Primary data analysis will be based on intention to treat (ITT)
      analysis.

      Data will be analyzed also on a modified ITT approach (mITT). Will be included in this
      analysis only patients with evidence of an Atypical Acute Respiratory Distress Syndrome
      (Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome (MicroCLOTS).

      Subgroups analysis: Some pre-defined subgroups analysis will be performed:

        1. Patients with with P/F <200 mmHg>100 mmHg;

        2. Patients with with P/F <100 mmHg;

        3. Patient 65+ group;

        4. Patients under 65 years old. Interim analyses: Interim analyses will not be performed
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
measure: P/F (PaO2/FiO2) change during the first 72hrs after the end of the procedure in adult patients with severe atypical ARDS caused by SARS-2-CoV.
time frame: Each 6 hours during first 3 days after the end of thrombolysis procedure.
measure: Ventilator-free time (days free from MV) for 28 days of observation.
time frame: 28 days
description: Calculated as 28 days - number of days when patient receive any kind of ventilatory support (MV + SV + NIV).
measure: Mortality in 28 days and 1 year after randomization despite of the reason.
time frame: 28 days, 1 year after randomization
measure: Length of stay in the ICU
time frame: 28 days
description: Number of days when patient was in ICU
measure: Length of stay in hospital
time frame: 28 days
description: Number of days when patient was in hospital
measure: The time needed for "improvement of 2 points" according to WHO "Ordinal Scale for Clinical Improvement"
time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 month
measure: Chest radiographs on a daily basis and define barotrauma as the presence of new pneumothorax, pneumomediastinum, pneumoperitoneum, or subcutaneous emphysema.
time frame: Daily up to extubation than once a week/or on attending intensivist's discretion up to 1 month
measure: Blood Pressure in millimetres of mercury
time frame: Each 4 hours during first 2 weeks after the end of thrombolysis procedure.
measure: Heart Rate in beats per minute
time frame: Each 4 hours during first 2 weeks after the end of thrombolysis procedure.
measure: Blood Oxygen Saturation
time frame: Each 4 hours during first 2 weeks after the end of thrombolysis procedure.
measure: ECG Q-wave
time frame: Each 24 hours during first 2 weeks after the end of thrombolysis procedure.
measure: ECG ST-segment
time frame: Each 24 hours during first 2 weeks after the end of thrombolysis procedure.
arm group label: Study group
arm group type: Experimental
description: Thrombolysis
arm group label: Control group
arm group type: Placebo Comparator
description: Ringer's solution infusion
intervention type: Drug
intervention name: Tissue plasminogen activator
description: In the study group, tPA (Alteplase) 25 mg i/v over 2 hours, followed by a 25 mg tPA infusion over the subsequent 22 hours. After the end of thrombolytic therapy, unfractionated heparin is administered i/v at a starting dose of 10 units / kg per hour. The target value of PTT is 40C-50C.
In both groups patient's transfer from the heparin infusion to the introduction of low-molecular-weight heparins is performed after normalization of the D-dimer level.
arm group label: Study group
other name: Alteplase
intervention type: Drug
intervention name: Ringer solution
description: In the control group, an equivalent amount of Ringer's solution is administered. After 24 hours, the heparin infusion gets started, similar the described for study group.
In both groups patient's transfer from the heparin infusion to the introduction of low-molecular-weight heparins is performed after normalization of the D-dimer level.
arm group label: Control group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Acute Lung Injury
mesh term: Syndrome
mesh term: Tissue Plasminogen Activator
mesh term: Plasminogen