<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/NCT04486508</url>
  </required_header>
  <id_info>
    <org_study_id>99060</org_study_id>
    <nct_id>NCT04486508</nct_id>
  </id_info>
  <brief_title>Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19</brief_title>
  <acronym>INSPIRATION</acronym>
  <official_title>Intermediate-dose Versus Standard Prophylactic Anticoagulation In cRitically-ill pATIents With COVID-19: An opeN Label Randomized Controlled Trial---A Randomized Trial of Atorvastatin vs. Placebo In Critically-ill Patients With COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rajaie Cardiovascular Medical and Research Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Tehran Heart Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Masih Daneshvari Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hazrat Rasool Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Modarres Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Firuzgar hospital affiliated to Iran University of Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Imam Khomeini Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sina Hospital, Iran</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Tabriz University of Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Shariati Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Imam Ali Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Labbafinejhad Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rajaie Cardiovascular Medical and Research Center</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>
      In a 2x2 factorial design randomized controlled trial, the investigators aim to elaborate the&#xD;
      safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients&#xD;
      with COVID-19. The first randomization entails open-label assignment to intermediate versus&#xD;
      standard dose prophylactic anticoagulation. The investigators hypothesize that intermediate&#xD;
      dose compared with standard prophylactic dose anticoagulation will have a superior efficacy&#xD;
      with respect to a composite of venous thromboembolism (VTE), requirement for extracorporeal&#xD;
      membrane oxygenation (ECMO), or all-cause mortality. The second randomization will be&#xD;
      double-blind assignment of the included patients to atorvastatin 20mg daily versus matching&#xD;
      placebo. The hypothesis is that statin therapy, compared with placebo, will reduce the&#xD;
      composite of VTE, need for ECMO, or all-cause mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Coronavirus disease-2019 (COVID-19) -- a viral illness caused by the severe acute respiratory&#xD;
      syndrome coronavirus 2 (SARS-CoV-2) -- has important manifestations outside the pulmonary&#xD;
      parenchyma, including microthrombosis and macrothrombosis, with venous thrombosis being the&#xD;
      most common form of thrombotic involvement. Existing studies, depending on the type of&#xD;
      outcome assessment and type and dose of prophylaxis, have reported thrombotic events in 7-85%&#xD;
      of patients with COVID-19.&#xD;
&#xD;
      However, the optimal antithrombotic regimen in these patients remains uncertain. Although&#xD;
      many clinicians continue to consider standard-dose prophylactic anticoagulation, other&#xD;
      believe that more intense anticoagulation may reduce the thrombotic events, and improve&#xD;
      outcomes. However, limited high-quality data exist to inform clinical practice and the&#xD;
      existing guidelines recommendations are mostly based on expert opinion and consensus.&#xD;
&#xD;
      In addition, exuberant inflammatory response is known to play a role in the pathophysiology&#xD;
      of acute respiratory distress syndrome (ARDS) and COVID-19. It is possible that the&#xD;
      pleiotropic effects of statins, which include anti-inflammatory and antithrombotic effects,&#xD;
      prove beneficial in patients with severe COVID-19.&#xD;
&#xD;
      This study plans to investigate the safety and efficacy of two pharmacological regimens on&#xD;
      outcomes of critically-ill patients with COVID-19 using a 2x2 factorial design.&#xD;
&#xD;
      First, patients will be assessed for the eligibility criteria for the anticoagulation&#xD;
      hypothesis. Those meeting the criteria, will be assigned to intermediate versus standard dose&#xD;
      prophylactic anticoagulation. These patients will subsequently be assessed for eligibility&#xD;
      for the second randomization, and if meeting the criteria, will be assigned to atorvastatin&#xD;
      20mg/d or matching placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 30, 2020</start_date>
  <completion_date type="Actual">July 5, 2021</completion_date>
  <primary_completion_date type="Actual">April 4, 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>Factorial Assignment</intervention_model>
    <intervention_model_description>1:1 multicenter open-label 2x2 factorial design randomized controlled trial with allocation sequence concealment and blinded endpoint adjudication.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>For the first hypothesis, allocation sequence concealment and blinded endpoint adjudication.&#xD;
For the second hypothesis, allocation sequence concealment, double-blind medication administration, and blinded endpoint adjudication.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of all-cause mortality</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Patient status regarding to being alive or dead at the end of 30-day follow up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of objectively-confirmed VTE</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator free days</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Difference between days of ICU stay and days on invasive mechanical ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of major bleeding</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of clinically-relevant non-major bleeding</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Clinically-significant bleeding, not fulfilling criteria for major bleeding)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of severe thrombocytopenia</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Platelet count &lt;20.000</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of rise in liver enzymes</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Increase liver function tests 3 times greater than upper limit of normal</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinically-diagnosed myopathy</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Assessed by clinical and biomarker tests according to the treating physicians.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objectively-confirmed arterial thrombosis</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Rate of objectively clinically-diagnosed type I acute myocardial infarction</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>According to the fourth universal definition of myocardial infraction and confirmed by coronary angiography, intravascular imaging or autopsy</description>
  </other_outcome>
  <other_outcome>
    <measure>Rate of objectively clinically -diagnosed stroke</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Any stroke episode which has been confirmed with appropriate diagnostic imaging (brain CT and/or brain MRI)</description>
  </other_outcome>
  <other_outcome>
    <measure>Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Imaging confirmed acute peripheral arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)</description>
  </other_outcome>
  <other_outcome>
    <measure>Median ICU length of stay</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Number of days that a patient has stayed in the ICU</description>
  </other_outcome>
  <other_outcome>
    <measure>ICU discharge status</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Status of patients regarding to mortality (alive/dead) at the time of discharge from ICU</description>
  </other_outcome>
  <other_outcome>
    <measure>Incident atrial fibrillation</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Any AF episode which has been confirmed by at least one ECG or telemetry monitoring, in patients without prior history of AF</description>
  </other_outcome>
  <other_outcome>
    <measure>Rate of need for renal replacement therapy</measure>
    <time_frame>30 days from enrollment</time_frame>
    <description>Use hemodialysis or veno-venous hemofiltration or peritoneal dialysis for a patient during the hospitalization period, due to acute kidney injury</description>
  </other_outcome>
  <other_outcome>
    <measure>Post-COVID-19 Functional Status</measure>
    <time_frame>60 and 90 -day</time_frame>
    <description>Based on Post-COVID-19 Functional Status questionnaire, which varies fro score 0 to 4, and higher scores mean worse outcome.</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">600</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>Intermediate dose anticoagulation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intermediate dose anticoagulation will be the the tested regimen. The anticoagulation regimen will be modified according to weight/ body mass index, and creatinine clearance level (Cl Cr). Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according to Cockcroft-Gault Formula.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Prophylaxis</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard prophylaxis dose anticoagulation will be the anticoagulation of choice in the control arm. Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according Cockcroft-Gault Formula.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atorvastatin 20</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atorvastatin 20 mg Matched placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matching placebo will be used for the control arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>intermediate dose Enoxaparin/ unfractionated heparin</intervention_name>
    <description>Intermediate dose anticoagulation according to creatinine clearance and weight</description>
    <arm_group_label>Intermediate dose anticoagulation</arm_group_label>
    <other_name>Intermediate dose anticoagulation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>standard prophylactic dose Enoxaparin/ unfractionated heparin</intervention_name>
    <description>Standard prophylaxis anticoagulation according to creatinine clearance and weight</description>
    <arm_group_label>Standard Prophylaxis</arm_group_label>
    <other_name>Standard dose prophylaxis anticoagulation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin 20mg</intervention_name>
    <description>Statin</description>
    <arm_group_label>Atorvastatin 20</arm_group_label>
    <other_name>Statin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Matched placebo</intervention_name>
    <description>Matched placebo to atorvastatin 20 mg</description>
    <arm_group_label>Atorvastatin 20 mg Matched placebo</arm_group_label>
    <other_name>Statin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for Anticoagulation Hypothesis&#xD;
&#xD;
          1. Adult patients (≥18 years), with polymerase chain reaction (PCR)-confirmed COVID-19&#xD;
             admitted to ICU within 7 days of initial hospitalization , who do not have another&#xD;
             firm indication for anticoagulation (such as mechanical valve, high-risk atrial&#xD;
             fibrillation (AF), VTE, or left ventricle (LV) thrombus),who are not enrolled in&#xD;
             another blinded randomized trial, and are willing to participate in the study and&#xD;
             provide informed consent .&#xD;
&#xD;
          2. Estimated survival of at least 24 hours at the discretion of enrolling physician&#xD;
&#xD;
        Exclusion Criteria for Anticoagulation Hypothesis&#xD;
&#xD;
          1. Weight &lt;40 Kilogram (kg)&#xD;
&#xD;
          2. Overt bleeding at the day of enrollment&#xD;
&#xD;
          3. Known major bleeding within 30 days (according to the Bleeding Academic Research&#xD;
             Consortium (BARC) definition, Appendix A)&#xD;
&#xD;
          4. Platelet count &lt;50,000/Fl&#xD;
&#xD;
          5. Pregnancy (as confirmed by Beta human chorionic gonadotropin (HCG) testing among&#xD;
             female patients &lt;50 years)&#xD;
&#xD;
          6. Patients on Extracorporeal Membrane Oxygenation (ECMO)&#xD;
&#xD;
          7. History of heparin induced thrombocytopenia or immune thrombocytopenia&#xD;
&#xD;
          8. Ischemic stroke within the past 2 weeks&#xD;
&#xD;
          9. Craniotomy/major neurosurgery within the past 3 months&#xD;
&#xD;
         10. Major head or spinal trauma in the past 30 days&#xD;
&#xD;
         11. Known brain metastases or vascular malformations (aneurysm)&#xD;
&#xD;
         12. Presence of an epidural, spinal or pericardial catheter&#xD;
&#xD;
         13. Major surgery other than neurosurgery within 14 days prior to enrollment&#xD;
&#xD;
         14. Coexistence of severe obesity (weight &gt;120 kg or BMI&gt;35 kg/m2 along with severe renal&#xD;
             insufficiency defined as creatinine clearance (CrCl) &lt;30 mL/sec)&#xD;
&#xD;
         15. Allergic reaction to study medications&#xD;
&#xD;
         16. Lack or withdrawal of informed consent&#xD;
&#xD;
        Inclusion Criteria for the Statin Randomization&#xD;
&#xD;
          1. Patients enrolled for the anticoagulation randomization&#xD;
&#xD;
          2. Willingness to participation in the study and providing informed consent&#xD;
&#xD;
        Exclusions Criteria for the Statin Randomization&#xD;
&#xD;
          1. Baseline liver function tests&gt; 3 times upper normal limits (ULN) or creatine kinase&#xD;
             (CK) &gt;500 U/L&#xD;
&#xD;
          2. Active liver disease (LFT&gt;3 ULN plus histologic finding including cirrhosis or&#xD;
             inflammation or necrosis)&#xD;
&#xD;
          3. Routine use of statins prior to the index hospitalization&#xD;
&#xD;
          4. Previous documented statin intolerance&#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>Parham Sadeghipour, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rajaie Cardiovascular Medical and Research Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Behnood Bikdeli, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brigham and Women's Hospital, Harvard Medical School</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Masih Daneshvari Hospital</name>
      <address>
        <city>Tehran</city>
        <zip>199691110</zip>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Iran, Islamic Republic of</country>
  </location_countries>
  <link>
    <url>https://pubmed.ncbi.nlm.nih.gov/32311448/</url>
    <description>COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review</description>
  </link>
  <link>
    <url>https://pubmed.ncbi.nlm.nih.gov/32473596/</url>
    <description>Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research</description>
  </link>
  <results_reference>
    <citation>Bikdeli B, Talasaz AH, Rashidi F, Sharif-Kashani B, Farrokhpour M, Bakhshandeh H, Sezavar H, Dabbagh A, Beigmohammadi MT, Payandemehr P, Yadollahzadeh M, Riahi T, Khalili H, Jamalkhani S, Rezaeifar P, Abedini A, Lookzadeh S, Shahmirzaei S, Tahamtan O, Matin S, Amin A, Parhizgar SE, Jimenez D, Gupta A, Madhavan MV, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Mohebbi B, Piazza G, Kirtane AJ, Lip GYH, Krumholz HM, Goldhaber SZ, Sadeghipour P. Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies. Thromb Res. 2020 Dec;196:382-394. doi: 10.1016/j.thromres.2020.09.027. Epub 2020 Sep 24.</citation>
    <PMID>32992075</PMID>
  </results_reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2020</study_first_posted>
  <last_update_submitted>August 14, 2021</last_update_submitted>
  <last_update_submitted_qc>August 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 17, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rajaie Cardiovascular Medical and Research Center</investigator_affiliation>
    <investigator_full_name>Parham Sadeghipour</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>anticoagulation</keyword>
  <keyword>statin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heparin</mesh_term>
    <mesh_term>Calcium heparin</mesh_term>
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Enoxaparin sodium</mesh_term>
    <mesh_term>Atorvastatin</mesh_term>
    <mesh_term>Hydroxymethylglutaryl-CoA Reductase Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04486508
org study id: 99060
nct id: NCT04486508
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
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collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
In a 2x2 factorial design randomized controlled trial, the investigators aim to elaborate the
      safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients
      with COVID-19. The first randomization entails open-label assignment to intermediate versus
      standard dose prophylactic anticoagulation. The investigators hypothesize that intermediate
      dose compared with standard prophylactic dose anticoagulation will have a superior efficacy
      with respect to a composite of venous thromboembolism (VTE), requirement for extracorporeal
      membrane oxygenation (ECMO), or all-cause mortality. The second randomization will be
      double-blind assignment of the included patients to atorvastatin 20mg daily versus matching
      placebo. The hypothesis is that statin therapy, compared with placebo, will reduce the
      composite of VTE, need for ECMO, or all-cause mortality.
Coronavirus disease-2019 (COVID-19) -- a viral illness caused by the severe acute respiratory
      syndrome coronavirus 2 (SARS-CoV-2) -- has important manifestations outside the pulmonary
      parenchyma, including microthrombosis and macrothrombosis, with venous thrombosis being the
      most common form of thrombotic involvement. Existing studies, depending on the type of
      outcome assessment and type and dose of prophylaxis, have reported thrombotic events in 7-85%
      of patients with COVID-19.

      However, the optimal antithrombotic regimen in these patients remains uncertain. Although
      many clinicians continue to consider standard-dose prophylactic anticoagulation, other
      believe that more intense anticoagulation may reduce the thrombotic events, and improve
      outcomes. However, limited high-quality data exist to inform clinical practice and the
      existing guidelines recommendations are mostly based on expert opinion and consensus.

      In addition, exuberant inflammatory response is known to play a role in the pathophysiology
      of acute respiratory distress syndrome (ARDS) and COVID-19. It is possible that the
      pleiotropic effects of statins, which include anti-inflammatory and antithrombotic effects,
      prove beneficial in patients with severe COVID-19.

      This study plans to investigate the safety and efficacy of two pharmacological regimens on
      outcomes of critically-ill patients with COVID-19 using a 2x2 factorial design.

      First, patients will be assessed for the eligibility criteria for the anticoagulation
      hypothesis. Those meeting the criteria, will be assigned to intermediate versus standard dose
      prophylactic anticoagulation. These patients will subsequently be assessed for eligibility
      for the second randomization, and if meeting the criteria, will be assigned to atorvastatin
      20mg/d or matching placebo.
allocation: Randomized
intervention model: Factorial Assignment
intervention model description: 1:1 multicenter open-label 2x2 factorial design randomized controlled trial with allocation sequence concealment and blinded endpoint adjudication.
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: For the first hypothesis, allocation sequence concealment and blinded endpoint adjudication.
For the second hypothesis, allocation sequence concealment, double-blind medication administration, and blinded endpoint adjudication.
measure: a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality
time frame: 30 days from enrollment
description: composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality.
measure: Rate of all-cause mortality
time frame: 30 days from enrollment
description: Patient status regarding to being alive or dead at the end of 30-day follow up
measure: Rate of objectively-confirmed VTE
time frame: 30 days from enrollment
description: Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan
measure: Ventilator free days
time frame: 30 days from enrollment
description: Difference between days of ICU stay and days on invasive mechanical ventilation
measure: Rate of major bleeding
time frame: 30 days from enrollment
description: According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)
measure: Rate of clinically-relevant non-major bleeding
time frame: 30 days from enrollment
description: Clinically-significant bleeding, not fulfilling criteria for major bleeding)
measure: Rate of severe thrombocytopenia
time frame: 30 days from enrollment
description: Platelet count <20.000
measure: Rate of rise in liver enzymes
time frame: 30 days from enrollment
description: Increase liver function tests 3 times greater than upper limit of normal
measure: Clinically-diagnosed myopathy
time frame: 30 days from enrollment
description: Assessed by clinical and biomarker tests according to the treating physicians.
measure: Objectively-confirmed arterial thrombosis
time frame: 30 days from enrollment
description: Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)
measure: Rate of objectively clinically-diagnosed type I acute myocardial infarction
time frame: 30 days from enrollment
description: According to the fourth universal definition of myocardial infraction and confirmed by coronary angiography, intravascular imaging or autopsy
measure: Rate of objectively clinically -diagnosed stroke
time frame: 30 days from enrollment
description: Any stroke episode which has been confirmed with appropriate diagnostic imaging (brain CT and/or brain MRI)
measure: Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis
time frame: 30 days from enrollment
description: Imaging confirmed acute peripheral arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)
measure: Median ICU length of stay
time frame: 30 days from enrollment
description: Number of days that a patient has stayed in the ICU
measure: ICU discharge status
time frame: 30 days from enrollment
description: Status of patients regarding to mortality (alive/dead) at the time of discharge from ICU
measure: Incident atrial fibrillation
time frame: 30 days from enrollment
description: Any AF episode which has been confirmed by at least one ECG or telemetry monitoring, in patients without prior history of AF
measure: Rate of need for renal replacement therapy
time frame: 30 days from enrollment
description: Use hemodialysis or veno-venous hemofiltration or peritoneal dialysis for a patient during the hospitalization period, due to acute kidney injury
measure: Post-COVID-19 Functional Status
time frame: 60 and 90 -day
description: Based on Post-COVID-19 Functional Status questionnaire, which varies fro score 0 to 4, and higher scores mean worse outcome.
arm group label: Intermediate dose anticoagulation
arm group type: Experimental
description: Intermediate dose anticoagulation will be the the tested regimen. The anticoagulation regimen will be modified according to weight/ body mass index, and creatinine clearance level (Cl Cr). Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according to Cockcroft-Gault Formula.
arm group label: Standard Prophylaxis
arm group type: Active Comparator
description: Standard prophylaxis dose anticoagulation will be the anticoagulation of choice in the control arm. Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according Cockcroft-Gault Formula.
arm group label: Atorvastatin 20
arm group type: Experimental
description: Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm
arm group label: Atorvastatin 20 mg Matched placebo
arm group type: Placebo Comparator
description: Matching placebo will be used for the control arm
intervention type: Drug
intervention name: intermediate dose Enoxaparin/ unfractionated heparin
description: Intermediate dose anticoagulation according to creatinine clearance and weight
arm group label: Intermediate dose anticoagulation
other name: Intermediate dose anticoagulation
intervention type: Drug
intervention name: standard prophylactic dose Enoxaparin/ unfractionated heparin
description: Standard prophylaxis anticoagulation according to creatinine clearance and weight
arm group label: Standard Prophylaxis
other name: Standard dose prophylaxis anticoagulation
intervention type: Drug
intervention name: Atorvastatin 20mg
description: Statin
arm group label: Atorvastatin 20
other name: Statin
intervention type: Drug
intervention name: Matched placebo
description: Matched placebo to atorvastatin 20 mg
arm group label: Atorvastatin 20 mg Matched placebo
other name: Statin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Parham Sadeghipour, MD
role: Principal Investigator
affiliation: Rajaie Cardiovascular Medical and Research Center
last name: Behnood Bikdeli, MD, MS
role: Principal Investigator
affiliation: Brigham and Women's Hospital, Harvard Medical School
facility: 
country: Iran, Islamic Republic of
url: https://pubmed.ncbi.nlm.nih.gov/32311448/
description: COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review
url: https://pubmed.ncbi.nlm.nih.gov/32473596/
description: Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research
citation: Bikdeli B, Talasaz AH, Rashidi F, Sharif-Kashani B, Farrokhpour M, Bakhshandeh H, Sezavar H, Dabbagh A, Beigmohammadi MT, Payandemehr P, Yadollahzadeh M, Riahi T, Khalili H, Jamalkhani S, Rezaeifar P, Abedini A, Lookzadeh S, Shahmirzaei S, Tahamtan O, Matin S, Amin A, Parhizgar SE, Jimenez D, Gupta A, Madhavan MV, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Mohebbi B, Piazza G, Kirtane AJ, Lip GYH, Krumholz HM, Goldhaber SZ, Sadeghipour P. Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies. Thromb Res. 2020 Dec;196:382-394. doi: 10.1016/j.thromres.2020.09.027. Epub 2020 Sep 24.
PMID: 32992075
responsible party type: Principal Investigator
investigator affiliation: Rajaie Cardiovascular Medical and Research Center
investigator full name: Parham Sadeghipour
investigator title: Associate Professor
mesh term: COVID-19
mesh term: Heparin
mesh term: Calcium heparin
mesh term: Enoxaparin
mesh term: Enoxaparin sodium
mesh term: Atorvastatin
mesh term: Hydroxymethylglutaryl-CoA Reductase Inhibitors
sharing ipd: No