<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/NCT04412291</url>
  </required_header>
  <id_info>
    <org_study_id>2020-001748-24</org_study_id>
    <nct_id>NCT04412291</nct_id>
  </id_info>
  <brief_title>A Study in Patients With COVID-19 and Respiratory Distress Not Requiring Mechanical Ventilation, to Compare Standard-of-care With Anakinra and Tocilizumab Treatment The Immunomodulation-CoV Assessment (ImmCoVA) Study</brief_title>
  <official_title>A Multi-center, Randomized, Open-label Study in Patients With COVID-19 and Respiratory Distress Not Requiring Mechanical Ventilation, to Compare Standard-of-care With Anakinra and Tocilizumab Treatment The Immunomodulation-CoV Assessment (ImmCoVA) Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Karolinska University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Karolinska University 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 study is designed as a randomized, controlled, multi-center open-label trial to compare&#xD;
      standard-of-care (SOC) treatment with SOC + anakinra or SOC + tocilizumab treatment in&#xD;
      hospitalized adult subjects who are diagnosed with severe COVID 19.&#xD;
&#xD;
      Arm A: Standard-of-care Treatment (SOC) Arm B: Anakinra + SOC Arm C: Tocilizumab + SOC.&#xD;
&#xD;
      All subjects will be treated with standard-of-care treatment. Arms B and C will also receive&#xD;
      broad spectrum antibiotics initiated before or latest 24 hours after initiation of treatment&#xD;
      with study drug.&#xD;
&#xD;
      The primary follow-up period of the study is 29 days.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">June 11, 2020</start_date>
  <completion_date type="Anticipated">June 2021</completion_date>
  <primary_completion_date type="Anticipated">March 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to recovery</measure>
    <time_frame>Day 1 through Day 29</time_frame>
    <description>Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale:1) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 1; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Not hospitalized, no limitations on activities.&#xD;
1 LMWH-injections (Fragmin, Innohep) do not count as medical care</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Days on mechanical ventilation</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days of supplemental oxygen use</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients requiring initiation of mechanical ventilation</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to improvement in oxygenation for at least 48 hours</measure>
    <time_frame>Up to day 29</time_frame>
    <description>Definition of improvement in oxygenation: Increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean change in the 8-point ordinal scale</measure>
    <time_frame>Up to day 15</time_frame>
    <description>8-point Ordinal Scale:&#xD;
Death&#xD;
Hospitalized, on invasive mechanical ventilation or ECMO;&#xD;
Hospitalized, on non-invasive ventilation or high flow nasal cannula;&#xD;
Hospitalized, requiring supplemental oxygen&#xD;
Hospitalized, not requiring supplemental oxygen&#xD;
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care&#xD;
Not hospitalized, limitation on activities and/or requiring home oxygen;&#xD;
Not hospitalized</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients on level e-h on the 8-point ordinal scale at day 15</measure>
    <time_frame>Day 15</time_frame>
    <description>8-point Ordinal Scale:&#xD;
Death&#xD;
Hospitalized, on invasive mechanical ventilation or ECMO;&#xD;
Hospitalized, on non-invasive ventilation or high flow nasal cannula;&#xD;
Hospitalized, requiring supplemental oxygen&#xD;
Hospitalized, not requiring supplemental oxygen&#xD;
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care&#xD;
Not hospitalized, limitation on activities and/or requiring home oxygen;&#xD;
Not hospitalized</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to improvement in one category from baseline using the 8-point ordinal scale</measure>
    <time_frame>Up to day 29</time_frame>
    <description>8-point Ordinal Scale:&#xD;
Death&#xD;
Hospitalized, on invasive mechanical ventilation or ECMO;&#xD;
Hospitalized, on non-invasive ventilation or high flow nasal cannula;&#xD;
Hospitalized, requiring supplemental oxygen&#xD;
Hospitalized, not requiring supplemental oxygen&#xD;
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care&#xD;
Not hospitalized, limitation on activities and/or requiring home oxygen;&#xD;
Not hospitalized</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean change in Sequential organ failure assessment score (SOFA)</measure>
    <time_frame>Up to day 15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to resolution of fever for at least 48 hours by clinical severity</measure>
    <time_frame>Up to day 29</time_frame>
    <description>Defined as ≤36.6°C (axilla), ≤37.2°C (oral) or ≤37.8°C (rectal or tympanic)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to improvement of three points from baseline in National Early Warning Score 2 (NEWS2) scoring system</measure>
    <time_frame>Up to day 29</time_frame>
    <description>NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to score of &lt;2 maintained for 24 hours in NEWS2 scoring system (National Early Warning Score)</measure>
    <time_frame>Up to day 29</time_frame>
    <description>NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of Air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean change in NEWS2 scoring system (National Early Warning Score)</measure>
    <time_frame>Up to day 15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days with fever.</measure>
    <time_frame>Up to day 29</time_frame>
    <description>Based on highest measured daily body temperature. Defined as &gt;36.6°C (axilla), &gt;37.2°C (oral) or &gt;37.8°C (rectal or tympanic</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days of resting respiratory rate &gt;24 breaths/min</measure>
    <time_frame>Up to day 29</time_frame>
    <description>Based on highest respiratory rate measured between 06.00 and 09.00 each day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to saturation ≥94% on room air</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative dose of steroids; equivalent to betamethasone dosage (mg)</measure>
    <time_frame>From start of steroid treatment for Covid-19 up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative dose of steroids during the study; equivalent to betamethasone dosage (mg)</measure>
    <time_frame>From day 1 up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of serious adverse events</measure>
    <time_frame>Up to day 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with grade 4 neutropenia</measure>
    <time_frame>Up to day 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of hypersensitivity reactions</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of infusion reactions</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of ventilator free days in the first 28 days</measure>
    <time_frame>Baseline to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients requiring non-invasive ventilation</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients requiring the use of high flow nasal cannula</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients requiring Extracorporeal membrane oxygenation (ECMO)</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients that have been admitted into an intensive care unit (ICU)</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients that have been admitted into a High Dependency Unit (&quot;Intermediärvårdsavdelning&quot;)</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days admitted into a High Dependency Unit (&quot;Intermediärvårdsavdelning&quot;) or intensive care unit (ICU) [</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days of hospitalization in survivors</measure>
    <time_frame>Up to day 29</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients discharged to institution other than normal domicile.</measure>
    <time_frame>Up to day 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of deaths due to any cause</measure>
    <time_frame>Up to day 60</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Covid-19</condition>
  <arm_group>
    <arm_group_label>Standard-of-care Treatment (SOC)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>SOC according to local recommendations at the Karolinska University Hospital:&#xD;
Oxygen supplementation so to achieve SpO2&gt;93%. Thrombosis prophylaxis (Fragmin or Innohep or Klexane or new oral anticoagulants incl. dabigatran, apixaban or rivaroxaban).&#xD;
Steroids (Betapred)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Anakinra + SOC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Anakinra: A total dose of 400mg per day (divided in 4 doses of 100 mg iv every 6 hours) for 7 days.&#xD;
SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2&gt;93%. Thrombosis prophylaxis (Fragmin or Innohep) Steroids (Betapred) Prophylactic broad spectrum antibiotics for seven days..</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tocilizumab + SOC.</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Tocilizumab: 8mg/kg for a single infusion iv up to max 800 mg. If no clinical response is obtained, another dose of 8mg/kg may be administered after earliest 2 days SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2&gt;93%. Thrombosis prophylaxis (Fragmin or Innohep) Steroids (Betapred) Prophylactic broad spectrum antibiotics for seven days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra Prefilled Syringe</intervention_name>
    <description>A total dose of 400mg per day (divided in 4 doses of 100 mg iv every 6 hours) for 7 days.</description>
    <arm_group_label>Anakinra + SOC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab Prefilled Syringe</intervention_name>
    <description>8mg/kg for a single infusion iv up to max 800 mg. If no clinical response is obtained, another dose of 8mg/kg may be administered after earliest 2 days after inclusion with the following condition: The clinical symptoms are worsened (as assessed by decreasing PaO2/FiO2 and/or need of increased ventilatory support such as NIV, HFNC or mechanical ventilation).</description>
    <arm_group_label>Tocilizumab + SOC.</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard-of-care treatment</intervention_name>
    <description>SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2&gt;93%. Thrombosis prophylaxis (Fragmin or Innohep and Klexane® or new oral anticoagulants including dabigatran, apixaban or rivaroxaban).&#xD;
Steroids (Betapred 6 mg po) Broad spectrum antibiotics (only in arm B and C)</description>
    <arm_group_label>Anakinra + SOC</arm_group_label>
    <arm_group_label>Standard-of-care Treatment (SOC)</arm_group_label>
    <arm_group_label>Tocilizumab + SOC.</arm_group_label>
    <other_name>Oxygen supplementation</other_name>
    <other_name>Thrombosis prophylaxis</other_name>
    <other_name>Steroids</other_name>
    <other_name>Antibiotics</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥18 years&#xD;
&#xD;
          2. Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction&#xD;
             (PCR) or other commercial or public health assay &lt; 7 days prior to screening&#xD;
&#xD;
          3. SARS-CoV-2 infection with duration at least 7 days (i e may be included on day 7) as&#xD;
             determined by onset of symptoms (defined as day 1)&#xD;
&#xD;
          4. 5 liters/minute of Oxygen for at least 8 hours to maintain SpO2 at ≥93%. A shorter&#xD;
             duration is also accepted if presentation is acute, and the patient needs more than 10&#xD;
             liters/minute of Oxygen, or high flow nasal cannula or non-invasive ventilation, to&#xD;
             maintain SpO2 at ≥93%..&#xD;
&#xD;
          5. CRP &gt; 70 mg/L with no non-SARS-Cov2 infections. Values measured up to 48 hours before&#xD;
             inclusion are accepted.&#xD;
&#xD;
          6. Ferritin &gt; 500 µg/L Values measured up to 48 hours before inclusion are accepted.&#xD;
&#xD;
          7. At least two points on a scale of 0-3 where 1 point is awarded for each value of;&#xD;
             lymphocytes &lt; 1x 10(9)/L; D-dimer ≥ 0.5 mg/L and; Lactate Dehydrogenase ≥ 8&#xD;
             microkatal/L. The values do not have to be concurrently positive and may be up to 3&#xD;
             days old at inclusion.&#xD;
&#xD;
          8. Ability to provide informed consent signed by study patient&#xD;
&#xD;
          9. Willingness and ability to comply with study-related procedures/assessments&#xD;
&#xD;
         10. In fertile females, willing to comply with effective contraceptive methods for up to 3&#xD;
             months after last dose of study drug. These may include surgical sterilization of&#xD;
             patient or partner, intrauterine device or condoms. Gestagen-only birth control pills&#xD;
             (mini-pills), which do not increase the risk of deep venous thrombosis, may also be&#xD;
             used. Non-fertile woman is defined as more than 12 months of amenorrhea without an&#xD;
             alternative medical cause or, in case of ambiguities, an FSH level in the&#xD;
             postmenopausal range.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or breast feeding.&#xD;
&#xD;
          2. Ongoing or completed mechanical ventilation.&#xD;
&#xD;
          3. In the opinion of the investigator, unlikely to survive for &gt;48 hours from screening.&#xD;
&#xD;
          4. In the opinion of the investigator, expected overall survival due to other&#xD;
             comorbidities less than 3 months.&#xD;
&#xD;
          5. Severe renal dysfunction eGFR &lt; 30 ml/min.&#xD;
&#xD;
          6. Medical history including chronic liver disease with inflammation, fibrosis or&#xD;
             cirrhosis including underlying diseases such as alcoholic liver disease, non-alcoholic&#xD;
             fatty liver disease, chronic viral hepatitis, alcoholic liver disease, autoimmune&#xD;
             liver disease, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency,&#xD;
             cholangitis, or carcinoma.&#xD;
&#xD;
          7. Uncontrolled hypertension Systolic BP &gt;180 mm Hg, Diastolic BP &gt; 110 mm Hg.&#xD;
&#xD;
          8. History of hypersensitivity to the study drugs&#xD;
&#xD;
          9. Presence of any of the following abnormal laboratory values at screening: absolute&#xD;
             neutrophil count (ANC) less than 2 x 109/L, aspartate aminotransferase (AST) or&#xD;
             alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN), platelets&#xD;
             &lt;100 x 109/L&#xD;
&#xD;
         10. Treatment with anakinra, anti-IL 6, anti-IL-6R antagonists, Janus kinase inhibitors&#xD;
             (JAKi) in the past 30 days or plans to receive during the study period&#xD;
&#xD;
         11. Current treatment with conventional synthetic disease-modifying antirheumatic drugs&#xD;
             (DMARDs)/immunosuppressive agents&#xD;
&#xD;
         12. Use of chronic oral corticosteroids for a non-COVID-19-related condition in a dose&#xD;
             higher than prednisone 10 mg or equivalent per day. Ongoing acute treatment for&#xD;
             COVID-19 with any peroral or iv steroid is permitted for up to five days before&#xD;
             inclusion. Chronic or acute treatment with inhaled steroids is also permitted&#xD;
&#xD;
         13. History of, or current autoimmune or inflammatory systemic or localized disease(s)&#xD;
             other than rheumatoid arthritis&#xD;
&#xD;
         14. Acute systemic infection; verified by blood cultures systemic bacterial infection,&#xD;
             systemic fungi-infection or prosthesis-related infection&#xD;
&#xD;
         15. History of stem-cell or solid organ transplantation&#xD;
&#xD;
         16. Known active tuberculosis (TB), history of incompletely treated TB, suspected or known&#xD;
             extrapulmonary TB, suspected or known systemic bacterial or fungal infections&#xD;
&#xD;
         17. Diagnosis of, or suspicion of HIV infection, acute hepatitis A and/or chronic&#xD;
             hepatitis B and/or C&#xD;
&#xD;
         18. Previous history of gastrointestinal ulceration or diverticulitis.&#xD;
&#xD;
         19. Patients who have received immunosuppressive antibody therapy within the past 3&#xD;
             months, including intravenous immunoglobulin or plans to receive during the study&#xD;
             period&#xD;
&#xD;
         20. Participation in any clinical research study evaluating an investigational product&#xD;
             (IP) or therapy within 3 months and less than 5 half-lives of IP prior to the&#xD;
             screening visit. The use of remdesivir is permitted.&#xD;
&#xD;
         21. Any physical examination findings and/or history of any illness that, in the opinion&#xD;
             of the study investigator, might confound the results of the study or pose an&#xD;
             additional risk to the patient by their participation in the study&#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>jonas Sundén-Cullberg, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Karolinska Universitetssjukhuset</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Investigator Jonas Sundén-Cullberg, MD PhD</last_name>
    <phone>+46-8-58580000</phone>
    <email>Jonas.sunden-cullberg@sll.se</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jon Lampa, MD PhD</last_name>
    <phone>+46-8-58580000</phone>
    <email>jon.lampa@sll.se</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Huddinge</city>
        <state>Stockholm</state>
        <zip>141 86</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jonas Sundén-Cullberg, MD, PHD</last_name>
      <email>jonas.sunden-cullberg@sll.se</email>
    </contact>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>June 1, 2020</study_first_submitted>
  <study_first_submitted_qc>June 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 2, 2020</study_first_posted>
  <last_update_submitted>February 17, 2021</last_update_submitted>
  <last_update_submitted_qc>February 17, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Karolinska University Hospital</investigator_affiliation>
    <investigator_full_name>Jonas Sundén-Cullberg</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Coronavirus 2</keyword>
  <keyword>SARS-CoV-2</keyword>
  <keyword>Anakinra</keyword>
  <keyword>Tocilizumab</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>Anti-Bacterial Agents</mesh_term>
    <mesh_term>Interleukin 1 Receptor Antagonist Protein</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
  </patient_data>
  <pending_results>
    <submitted>April 26, 2023</submitted>
  </pending_results>
  <!-- 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/NCT04412291
org study id: 2020-001748-24
nct id: NCT04412291
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The study is designed as a randomized, controlled, multi-center open-label trial to compare
      standard-of-care (SOC) treatment with SOC + anakinra or SOC + tocilizumab treatment in
      hospitalized adult subjects who are diagnosed with severe COVID 19.

      Arm A: Standard-of-care Treatment (SOC) Arm B: Anakinra + SOC Arm C: Tocilizumab + SOC.

      All subjects will be treated with standard-of-care treatment. Arms B and C will also receive
      broad spectrum antibiotics initiated before or latest 24 hours after initiation of treatment
      with study drug.

      The primary follow-up period of the study is 29 days.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Time to recovery
time frame: Day 1 through Day 29
description: Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale:1) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 1; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Not hospitalized, no limitations on activities.
1 LMWH-injections (Fragmin, Innohep) do not count as medical care
measure: Mortality
time frame: Up to day 29
measure: Number of Days on mechanical ventilation
time frame: Up to day 29
measure: Number of days of supplemental oxygen use
time frame: Up to day 29
measure: Number of patients requiring initiation of mechanical ventilation
time frame: Up to day 29
measure: Time to improvement in oxygenation for at least 48 hours
time frame: Up to day 29
description: Definition of improvement in oxygenation: Increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2
measure: Mean change in the 8-point ordinal scale
time frame: Up to day 15
description: 8-point Ordinal Scale:
Death
Hospitalized, on invasive mechanical ventilation or ECMO;
Hospitalized, on non-invasive ventilation or high flow nasal cannula;
Hospitalized, requiring supplemental oxygen
Hospitalized, not requiring supplemental oxygen
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
Not hospitalized, limitation on activities and/or requiring home oxygen;
Not hospitalized
measure: Proportion of patients on level e-h on the 8-point ordinal scale at day 15
time frame: Day 15
description: 8-point Ordinal Scale:
Death
Hospitalized, on invasive mechanical ventilation or ECMO;
Hospitalized, on non-invasive ventilation or high flow nasal cannula;
Hospitalized, requiring supplemental oxygen
Hospitalized, not requiring supplemental oxygen
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
Not hospitalized, limitation on activities and/or requiring home oxygen;
Not hospitalized
measure: Time to improvement in one category from baseline using the 8-point ordinal scale
time frame: Up to day 29
description: 8-point Ordinal Scale:
Death
Hospitalized, on invasive mechanical ventilation or ECMO;
Hospitalized, on non-invasive ventilation or high flow nasal cannula;
Hospitalized, requiring supplemental oxygen
Hospitalized, not requiring supplemental oxygen
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
Not hospitalized, limitation on activities and/or requiring home oxygen;
Not hospitalized
measure: Mean change in Sequential organ failure assessment score (SOFA)
time frame: Up to day 15
measure: Time to resolution of fever for at least 48 hours by clinical severity
time frame: Up to day 29
description: Defined as ≤36.6°C (axilla), ≤37.2°C (oral) or ≤37.8°C (rectal or tympanic)
measure: Time to improvement of three points from baseline in National Early Warning Score 2 (NEWS2) scoring system
time frame: Up to day 29
description: NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C)
measure: Time to score of <2 maintained for 24 hours in NEWS2 scoring system (National Early Warning Score)
time frame: Up to day 29
description: NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of Air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C)
measure: Mean change in NEWS2 scoring system (National Early Warning Score)
time frame: Up to day 15
measure: Number of days with fever.
time frame: Up to day 29
description: Based on highest measured daily body temperature. Defined as >36.6°C (axilla), >37.2°C (oral) or >37.8°C (rectal or tympanic
measure: Number of days of resting respiratory rate >24 breaths/min
time frame: Up to day 29
description: Based on highest respiratory rate measured between 06.00 and 09.00 each day
measure: Time to saturation ≥94% on room air
time frame: Up to day 29
measure: Cumulative dose of steroids; equivalent to betamethasone dosage (mg)
time frame: From start of steroid treatment for Covid-19 up to day 29
measure: Cumulative dose of steroids during the study; equivalent to betamethasone dosage (mg)
time frame: From day 1 up to day 29
measure: Incidence of serious adverse events
time frame: Up to day 60
measure: Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection
time frame: Up to day 29
measure: Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with grade 4 neutropenia
time frame: Up to day 60
measure: Incidence of hypersensitivity reactions
time frame: Up to day 29
measure: Incidence of infusion reactions
time frame: Up to day 29
measure: Number of ventilator free days in the first 28 days
time frame: Baseline to day 29
measure: Number of patients requiring non-invasive ventilation
time frame: Up to day 29
measure: Number of patients requiring the use of high flow nasal cannula
time frame: Up to day 29
measure: Number of patients requiring Extracorporeal membrane oxygenation (ECMO)
time frame: Up to day 29
measure: Number of patients that have been admitted into an intensive care unit (ICU)
time frame: Up to day 29
measure: Number of patients that have been admitted into a High Dependency Unit ("Intermediärvårdsavdelning")
time frame: Up to day 29
measure: Number of days admitted into a High Dependency Unit ("Intermediärvårdsavdelning") or intensive care unit (ICU) [
time frame: Up to day 29
measure: Number of days of hospitalization in survivors
time frame: Up to day 29
measure: Number of patients discharged to institution other than normal domicile.
time frame: Up to day 60
measure: Number of deaths due to any cause
time frame: Up to day 60
arm group label: Standard-of-care Treatment (SOC)
arm group type: Active Comparator
description: SOC according to local recommendations at the Karolinska University Hospital:
Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep or Klexane or new oral anticoagulants incl. dabigatran, apixaban or rivaroxaban).
Steroids (Betapred)
arm group label: Anakinra + SOC
arm group type: Active Comparator
description: Anakinra: A total dose of 400mg per day (divided in 4 doses of 100 mg iv every 6 hours) for 7 days.
SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep) Steroids (Betapred) Prophylactic broad spectrum antibiotics for seven days..
arm group label: Tocilizumab + SOC.
arm group type: Active Comparator
description: Tocilizumab: 8mg/kg for a single infusion iv up to max 800 mg. If no clinical response is obtained, another dose of 8mg/kg may be administered after earliest 2 days SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep) Steroids (Betapred) Prophylactic broad spectrum antibiotics for seven days.
intervention type: Drug
intervention name: Anakinra Prefilled Syringe
description: A total dose of 400mg per day (divided in 4 doses of 100 mg iv every 6 hours) for 7 days.
arm group label: Anakinra + SOC
intervention type: Drug
intervention name: Tocilizumab Prefilled Syringe
description: 8mg/kg for a single infusion iv up to max 800 mg. If no clinical response is obtained, another dose of 8mg/kg may be administered after earliest 2 days after inclusion with the following condition: The clinical symptoms are worsened (as assessed by decreasing PaO2/FiO2 and/or need of increased ventilatory support such as NIV, HFNC or mechanical ventilation).
arm group label: Tocilizumab + SOC.
intervention type: Drug
intervention name: Standard-of-care treatment
description: SOC according to local recommendations at the Karolinska University Hospital. Oxygen supplementation so to achieve SpO2>93%. Thrombosis prophylaxis (Fragmin or Innohep and Klexane® or new oral anticoagulants including dabigatran, apixaban or rivaroxaban).
Steroids (Betapred 6 mg po) Broad spectrum antibiotics (only in arm B and C)
arm group label: Anakinra + SOC
arm group label: Standard-of-care Treatment (SOC)
arm group label: Tocilizumab + SOC.
other name: Oxygen supplementation
other name: Thrombosis prophylaxis
other name: Steroids
other name: Antibiotics
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: jonas Sundén-Cullberg, MD PhD
role: Principal Investigator
affiliation: Karolinska Universitetssjukhuset
last name: Investigator Jonas Sundén-Cullberg, MD PhD
phone: +46-8-58580000
email: Jonas.sunden-cullberg@sll.se
last name: Jon Lampa, MD PhD
phone: +46-8-58580000
email: jon.lampa@sll.se
facility: 
status: Recruiting
contact: 
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Karolinska University Hospital
investigator full name: Jonas Sundén-Cullberg
investigator title: MD, PhD
mesh term: COVID-19
mesh term: Anti-Bacterial Agents
mesh term: Interleukin 1 Receptor Antagonist Protein
sharing ipd: Yes
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
submitted: April 26, 2023