<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/NCT04488081</url>
  </required_header>
  <id_info>
    <org_study_id>I-SPY-COVID</org_study_id>
    <nct_id>NCT04488081</nct_id>
  </id_info>
  <brief_title>I-SPY COVID-19 TRIAL: An Adaptive Platform Trial for Critically Ill Patients</brief_title>
  <acronym>I-SPY_COVID</acronym>
  <official_title>I-SPY COVID TRIAL: An Adaptive Platform Trial to Reduce Mortality and Ventilator Requirements for Critically Ill Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>QuantumLeap Healthcare Collaborative</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Emory University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Alabama at Birmingham</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Southern California</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sanford Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Long Beach Memorial Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Georgetown University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, Davis</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hoag Memorial Hospital Presbyterian</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Iowa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Main Line Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>DHR Health Institute for Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mercy Hospital Springfield</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, Irvine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Spectrum Health Hospitals</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kaiser Permanente</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Rochester</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>West Virginia University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stamford Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Miami</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospitals Cleveland Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Logan Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Virtua Memorial Hospital Mount Holly</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sanford USD Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>UC Irvine Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Florida Health Shands Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>QuantumLeap Healthcare Collaborative</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The goal of this project is to rapidly screen promising agents, in the setting of an adaptive&#xD;
      platform trial, for treatment of critically ill COVID-19 patients. In this phase 2 platform&#xD;
      design, agents will be identified with a signal suggesting a big impact on reducing mortality&#xD;
      and the need for, as well as duration, of mechanical ventilation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This platform trial will provide access to repurposed and investigational agents for&#xD;
      critically ill patients infected with SARS-CoV-2 who have severe or life-threatening&#xD;
      COVID-19. The main focus of this trial is a platform study for identifying effective agents&#xD;
      for the treatment of COVID-19. Any critically ill patient with known or presumed COVID-19&#xD;
      will be automatically entered into the screening phase of the trial until SARS-CoV-2&#xD;
      infection is confirmed. Basic data will be assembled for each patient (such as ventilatory&#xD;
      status and survival). If interested in the therapeutic portion of the trial, potential&#xD;
      participants will be asked to sign a consent form describing the backbone treatment and the&#xD;
      two specific investigational agent arms to which they may be randomized. The primary&#xD;
      endpoints will be time to recover to a durable level 4 (or less) on the WHO COVID-19 ordinal&#xD;
      scale for clinical improvement and time to mortality (death). For this trial, a durable level&#xD;
      4 is defined as at least 48 hours at COVID level 4 or less (nasal prongs oxygen) without&#xD;
      returning to high flow oxygen or intubation. Acute care facility resource utilization will be&#xD;
      automatically calculated (total length of stay in a critical care setting, days intubated,&#xD;
      and survival). Any change in status, including intubation, extubation, death or discharge,&#xD;
      will be recorded and verified by the attending physician.&#xD;
&#xD;
      Patients will be evaluated based on their initial status (ventilation at entry vs. high flow&#xD;
      oxygen). Exploratory biomarkers will be evaluated over time (ARDS phenotypes and other&#xD;
      proposed markers) to facilitate clinical learning. A maximum of two investigational arms may&#xD;
      be open at a time. The anticipated accrual will be 50 patients per week. The maximum number&#xD;
      of participants assigned to an arm without graduation will be 125 patients. Agents can be&#xD;
      dropped for futility after enrollment of 40 patients. As the trial proceeds and a better&#xD;
      understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded&#xD;
      biomarker and data collection can be added as needed to further elucidate how agents are or&#xD;
      are not working. The study design features comparison of investigational agent efficacy using&#xD;
      a Bayesian design, which will allow the detection of strong efficacy signals with the fewest&#xD;
      possible patients. Initially the control will be patients given current standard of care&#xD;
      (supportive care for ARDS, including lung protective ventilation and remdesivir and&#xD;
      dexamethasone as backbone therapy). As other treatments (for example, anticoagulation) become&#xD;
      part of standard supportive care across sites, these will be added to the backbone therapy.&#xD;
      If an agent meets the threshold for graduation the company leadership will be informed as&#xD;
      will the FDA. The arm with the graduated agent will cease to enroll, allowing a new arm with&#xD;
      a different investigational agent to be added. Information about agents disposition will be&#xD;
      as follows:&#xD;
&#xD;
      Every trial participant will have blood collected at trial enrollment, day 3, and day 7 for&#xD;
      pre-specified biomarker and DNA and RNA analysis. Additional biomarkers can be added as the&#xD;
      trial proceeds. Patient outcomes will also be evaluated on the basis of whether patients are&#xD;
      ventilated initially or not. All COVID-19 confirmed patients who start high-flow oxygen (WHO&#xD;
      COVID-19 level 5; ≥6L oxygen by nasal prongs or mask) will be entered in an Observational&#xD;
      Component which will collect data via extraction of medical records.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 31, 2020</start_date>
  <completion_date type="Anticipated">November 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">July 24, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Platform Trial, Bayesian Design, from 2 arms up to 8 arms</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Identify agents that will result in substantial improvements to the clinical condition of participants with severe COVID-19</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Time to achieve durable change in COVID-19 to ordinal level 4 or less for at least 48 hours</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Time to death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement in disease severity</measure>
    <time_frame>Up to 60 days</time_frame>
    <description>% of COVID-19 level 5 who never progress to COVID-19 level 6/7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health care utilization</measure>
    <time_frame>Up to 60 days</time_frame>
    <description>Ventilator-free Days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of serious AEs</measure>
    <time_frame>Up to 60 days</time_frame>
    <description>Total grade 3 or higher AEs by arm and total number of patients with grade 3 or higher AEs by arm.&#xD;
● Total grade 3 or higher AEs of special interest by arm and total number of patients with grade 3 or higher AEs of special interest by arms (based upon lab assessments)</description>
  </secondary_outcome>
  <number_of_arms>12</number_of_arms>
  <enrollment type="Anticipated">1500</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Control/Backbone (Remdesivir and Dexamethasone)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants randomized to the backbone control will be given standard of care (supportive care for ARDS, including remdesivir and, if needed, lung protective ventilation). Because dexamethasone was shown to have benefit in at least one large randomized clinical trial, patients in the backbone control arm should receive dexamethasone for a total of 10 days during the hospitalization or until or hospital discharge.&#xD;
Remdesivir (intravenous): 200-mg loading dose on day 1, followed by a daily maintenance dose of 100-mg on days 2 through 10.&#xD;
Dexamethasone (intravenous): 6 mg intravenous or oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Imatinib + Standard of Care</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be administered standard of care + 800 mg imatinib on Day 1 orally, in divided doses of 400 mg administered twice per day. 400 mg daily will be administered orally for the following 9 days or until discharge, whichever is sooner.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cenicriviroc + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + cenicriviroc orally , loading 300 mg qAM followed by 150 mg qPM, 12 hours apart on day 1, then 150 mg BID for total of 14 to 28 days depending on date of hospital discharge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Icatibant + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + icatibant subcutaneously, a safety run-in for the first 10 subjects was conducted using a regimen of 30 mg q8h × 3 days. All subsequent subjects received drug at 30 mg q8h x 6 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Apremilast + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + apremilast orally , 30 mg bid × 14 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dornase + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>For Non-intubated subjects: Subjects administered standard of care + dornase, 2.5 mg BID until hospital discharge, improvement to room air (or baseline oxygen use prior to illness) for 24 hours, or total of 14 days of study drug, whichever comes first.&#xD;
For intubated subjects: Subjects administered standard of care + dornase, 5.0 mg BID in 10 mL normal saline until extubation or 14 days, whichever comes first. If intubated for less than 14 days, extubated subjects received 2.5 mg BID for a total Dornase treatment of 14 days, or until hospital discharge, whichever comes first.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Celecoxib/famotidine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + celecoxib/famotidine orally .&#xD;
Celecoxib, oral: 400 mg BID for 7 days.&#xD;
Famotidine, oral: High dose 80 mg QID for 7 days followed by 40 mg BID for a course of 14 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IC14 + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + IC14 intravenously , 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Narsoplimab + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + narsoplimab dosed at 4 mg/kg, given as a 30-minute intravenous infusion (up to a maximum of 370 mg per infusion) twice weekly for a total of four weeks (i.e. 9 doses) or until hospital discharge whichever comes first.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Aviptadil + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + aviptadil (inhalation via nebulizer), 100 µg three times (TID) daily for a maximum of 14 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyproheptadine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + cyproheptadine via 4 mg tablet, with dosing regimen of 8 mg every 8 hours daily for ten (10) days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyclosporine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects administered standard of care + modified cyclosporine at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Remdesivir</intervention_name>
    <description>Participants who receive remdesivir as part of their standard of care will be administered remdesivir by IV for up to ten days. Remdesivir 200mg loading dose on day 1, followed by 100mg IV once daily maintenance doses for 4 or 9 days.</description>
    <arm_group_label>Apremilast + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Aviptadil + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Celecoxib/famotidine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Cenicriviroc + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Control/Backbone (Remdesivir and Dexamethasone)</arm_group_label>
    <arm_group_label>Cyclosporine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Cyproheptadine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Dornase + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>IC14 + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Icatibant + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Imatinib + Standard of Care</arm_group_label>
    <arm_group_label>Narsoplimab + Standard of Care (CLOSED)</arm_group_label>
    <other_name>GS-5734</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Imatinib Mesylate</intervention_name>
    <description>Subjects will be administered 800 mg on Day 1 orally, in divided doses of 400 mg administered twice per day. 400 mg daily will be administered orally for the following 9 days or until discharge, whichever is sooner.</description>
    <arm_group_label>Imatinib + Standard of Care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.</description>
    <arm_group_label>Apremilast + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Aviptadil + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Celecoxib/famotidine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Cenicriviroc + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Control/Backbone (Remdesivir and Dexamethasone)</arm_group_label>
    <arm_group_label>Cyclosporine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Cyproheptadine + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Dornase + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>IC14 + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Icatibant + Standard of Care (CLOSED)</arm_group_label>
    <arm_group_label>Imatinib + Standard of Care</arm_group_label>
    <arm_group_label>Narsoplimab + Standard of Care (CLOSED)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cenicriviroc</intervention_name>
    <description>Oral, loading 300 mg qAM followed by 150 mg qPM, 12 hours apart on day 1, then 150 mg BID for total of 14 to 28 days depending on date of hospital discharge.</description>
    <arm_group_label>Cenicriviroc + Standard of Care (CLOSED)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Icatibant</intervention_name>
    <description>Subcutaneous, a safety run-in for the first 10 subjects was conducted using a regimen of 30 mg q8h × 3 days. All subsequent subjects received drug at 30 mg q8h x 6 days.</description>
    <arm_group_label>Icatibant + Standard of Care (CLOSED)</arm_group_label>
    <other_name>Firazyr</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apremilast</intervention_name>
    <description>oral, 30 mg bid × 14 days.</description>
    <arm_group_label>Apremilast + Standard of Care (CLOSED)</arm_group_label>
    <other_name>Otezla</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>dornase alfa</intervention_name>
    <description>For Non-intubated subjects: 2.5 mg BID until hospital discharge, improvement to room air (or baseline oxygen use prior to illness) for 24 hours, or total of 14 days of study drug, whichever comes first.&#xD;
For intubated subjects: 5.0 mg BID in 10 mL normal saline until extubation or 14 days, whichever comes first. If intubated for less than 14 days, extubated subjects received 2.5 mg BID for a total Dornase treatment of 14 days, or until hospital discharge, whichever comes first.</description>
    <arm_group_label>Dornase + Standard of Care (CLOSED)</arm_group_label>
    <other_name>Pulmozyme</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Celecoxib</intervention_name>
    <description>Oral: 400 mg BID for 7 days.</description>
    <arm_group_label>Celecoxib/famotidine + Standard of Care (CLOSED)</arm_group_label>
    <other_name>celebrex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Famotidine</intervention_name>
    <description>Oral: High dose 80 mg QID for 7 days followed by 40 mg BID for a course of 14 days.</description>
    <arm_group_label>Celecoxib/famotidine + Standard of Care (CLOSED)</arm_group_label>
    <other_name>Pepcid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>IC14</intervention_name>
    <description>intravenous, 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4</description>
    <arm_group_label>IC14 + Standard of Care (CLOSED)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aviptadil</intervention_name>
    <description>Inhalation via nebulizer, 100 µg three times (TID) daily for a maximum of 14 days</description>
    <arm_group_label>Aviptadil + Standard of Care (CLOSED)</arm_group_label>
    <other_name>Zyesami</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>narsoplimab</intervention_name>
    <description>Dosed at 4 mg/kg, given as a 30-minute intravenous infusion (up to a maximum of 370 mg per infusion) twice weekly for a total of four weeks (i.e. 9 doses) or until hospital discharge whichever comes first.</description>
    <arm_group_label>Narsoplimab + Standard of Care (CLOSED)</arm_group_label>
    <other_name>OMS721</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyproheptadine</intervention_name>
    <description>4 mg tablet, with dosing regimen of 8 mg every 8 hours daily for ten (10) days. If the patient weighs less than 48 kg, the regimen is 6 mg every 8 hours daily for ten (10) days. If the participant was discharged before completion of this dosing regimen the drug was not continued.</description>
    <arm_group_label>Cyproheptadine + Standard of Care (CLOSED)</arm_group_label>
    <other_name>periactin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclosporine</intervention_name>
    <description>Modified CsA at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.</description>
    <arm_group_label>Cyclosporine + Standard of Care (CLOSED)</arm_group_label>
    <other_name>CsA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        A. Male or Female, at least 18 years old.&#xD;
&#xD;
        B. Admitted to the hospital and placed on high flow oxygen (greater than 6L by nasal&#xD;
        cannula or mask delivery system) or intubated for the treatment of (established or&#xD;
        presumed) COVID-19.&#xD;
&#xD;
        C. Informed consent provided by the patient or health care proxy.&#xD;
&#xD;
        D. Confirmation of SARS-CoV-2 infection by PCR or Rapid antigen testing for SARS-CoV-2&#xD;
        infection prior to randomization.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        A. Pregnant or breastfeeding women (must be documented by a pregnancy test during&#xD;
        hospitalization)&#xD;
&#xD;
        B. History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
        composition to study agent based on review of the medical record and patient history.&#xD;
&#xD;
        C. Comfort measures only.&#xD;
&#xD;
        D. Acute liver disease, or chronic liver disease with a Child-Pugh score greater than 11.&#xD;
&#xD;
        E. Resident for more than six months at a skilled nursing facility.&#xD;
&#xD;
        F. Estimated mortality greater than 50% over the next six months from underlying chronic&#xD;
        conditions.&#xD;
&#xD;
        G. Time since requirement for high flow oxygen or ventilation greater than 5 days.&#xD;
&#xD;
        H. Anticipated transfer to another hospital which is not a study site within 72 hours.&#xD;
&#xD;
        I. Patients with either end-stage kidney disease or acute kidney injury who are on&#xD;
        dialysis.&#xD;
&#xD;
        J. Co-enrollment in clinical trials of pharmacologic agents requiring an IND&#xD;
&#xD;
        K. On 3 or more vasopressors&#xD;
&#xD;
        L. Pre-existing heart failure with a known left ventricular ejection fraction &lt;25% or&#xD;
        unstable angina pectoris&#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>Carolyn Carolyn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kathleen D Liu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Laura Esserman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Paul Henderson, PhD</last_name>
    <phone>1-925-570-1615</phone>
    <email>p.henderson@quantumleaphealth.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Karyn DiGiorgio, MS</last_name>
    <phone>1-415-307-1539</phone>
    <email>karyn.digiorgio@quantumleaphealth.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Valerie Caterinicchia, RN, BSN</last_name>
      <phone>205-934-5367</phone>
      <email>val7@uab.edu</email>
    </contact>
    <investigator>
      <last_name>Derek Russell, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sheetal Gandotra, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UC Davis Medical Center</name>
      <address>
        <city>Davis</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Skyler Pearson</last_name>
      <phone>916-734-3867</phone>
      <email>sjpearson@ucdavis.edu</email>
    </contact>
    <investigator>
      <last_name>Timothy Albertson, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UC Irvine Medical Center</name>
      <address>
        <city>Irvine</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Richard Lee, MD</last_name>
      <phone>714-456-7890</phone>
      <email>richaral@hs.uci.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Long Beach Memorial Medical Center</name>
      <address>
        <city>Long Beach</city>
        <state>California</state>
        <zip>90806</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Daniel Blevins</last_name>
      <phone>562-760-6817</phone>
      <email>DBlevins@memorialcare.org</email>
    </contact>
    <investigator>
      <last_name>Fady Youseff, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Kaiser LAMC</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kenneth Wei, MD</last_name>
      <phone>323-783-8191</phone>
      <email>Kenneth.K.Wei@kp.org</email>
    </contact>
    <contact_backup>
      <last_name>David Silberstein, MD</last_name>
      <phone>3237831009</phone>
      <email>david.j.silberstein@kp.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>University of Southern California</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melissa Ramos, BSN, RN</last_name>
      <phone>818-309-5542</phone>
      <email>Melissa.Ramos@med.usc.edu</email>
    </contact>
    <investigator>
      <last_name>Santhi Kumar, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hoag Memorial Hospital Presbyterian</name>
      <address>
        <city>Newport Beach</city>
        <state>California</state>
        <zip>92663</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Esmeralda Martinez</last_name>
      <phone>949-764-5827</phone>
      <email>Esmeralda.Martinez@hoag.org</email>
    </contact>
    <investigator>
      <last_name>Philip Robinson, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of California San Francisco (UCSF)</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <phone>877-827-3222</phone>
    </contact>
    <investigator>
      <last_name>Kathleen Liu, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Carolyn Calfee, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Laura Esserman, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tessa Mcspadden</last_name>
      <phone>720-848-0609</phone>
      <email>tessa.mcspadden@ucdenver.edu</email>
    </contact>
    <investigator>
      <last_name>Ellen Burnham, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Yale Cancer Center</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Trisha Burello, MS</last_name>
      <phone>203-737-2848</phone>
      <email>trisha.burrello@yale.edu</email>
    </contact>
    <investigator>
      <last_name>Jonathan Koff, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Georgetown University</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20007</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amen Hamed</last_name>
      <phone>202-444-0895</phone>
      <email>amen.hamed@gunet.georgetown.edu</email>
    </contact>
    <investigator>
      <last_name>Nathan Cobb, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32608</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ali Zarrinpar</last_name>
      <phone>310-691-4108</phone>
      <email>ali.zarrinpar@surgery.ufl.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Emory University</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christine Spainhour, CCRC</last_name>
      <phone>404-778-7850</phone>
      <email>christine.spainhour@emory.edu</email>
    </contact>
    <investigator>
      <last_name>Sara Auld, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Helen Donnelly</last_name>
      <phone>312-503-1097</phone>
      <email>h-donnelly@northwestern.edu</email>
    </contact>
    <investigator>
      <last_name>Richard Wunderink, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Iowa</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kimberly Sprenger</last_name>
      <phone>319-353-8862</phone>
      <email>kimberly-sprenger@uiowa.edu</email>
    </contact>
    <investigator>
      <last_name>Kevin Doerschug, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Spectrum Health</name>
      <address>
        <city>Grand Rapids</city>
        <state>Michigan</state>
        <zip>49503</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Malik Khan, MD</last_name>
      <phone>866-989-7999</phone>
      <email>malik.khan@spectrumhealth.org</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Mercy Hospital Springfield</name>
      <address>
        <city>Springfield</city>
        <state>Missouri</state>
        <zip>65804</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Karthik Vadamalai, MD</last_name>
      <phone>417-820-2000</phone>
      <email>Karthik.Vadamalai@Mercy.Net</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kalispell Regional Medical Center</name>
      <address>
        <city>Kalispell</city>
        <state>Montana</state>
        <zip>59901</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amanda Bartlett, RN, CCRC</last_name>
      <phone>406-607-8021</phone>
      <email>abartlett@krmc.org</email>
    </contact>
    <investigator>
      <last_name>Timothy Obermiller, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Logan Health Medical Center</name>
      <address>
        <city>Kalispell</city>
        <state>Montana</state>
        <zip>59901</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Timothy Obermiller, MD</last_name>
      <phone>406-752-5111</phone>
      <email>tobermiller@logan.org</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Montefiore Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10461</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jeremy Beitler, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Rochester Medical Center</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Caroline Quill, MD</last_name>
      <phone>585-275-2100</phone>
      <email>Caroline_Quill@URMC.Rochester.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Wake Forest Baptist Comprehensive Cancer Center</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Angela Howell, MD</last_name>
      <phone>336-716-5440</phone>
      <email>anhowell@wakehealth.edu</email>
    </contact>
    <investigator>
      <last_name>D. Clark Files, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Karl Thomas, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania (U Penn)</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lauren Bayne</last_name>
      <phone>215-349-5398</phone>
      <email>Lauren.Bayne@uphs.upenn.edu</email>
    </contact>
    <investigator>
      <last_name>Nuala Meyer, MD, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Lankenau Medical Center (Mainline Health)</name>
      <address>
        <city>Wynnewood</city>
        <state>Pennsylvania</state>
        <zip>19096</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elliot Friedman, MD</last_name>
      <phone>484-476-2000</phone>
      <email>FriedmanE@mlhs.org</email>
    </contact>
    <contact_backup>
      <last_name>Ebuwa Erebor</last_name>
      <email>EreborE@mlhs.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Main Line Health - Lankenau Medical Center</name>
      <address>
        <city>Wynnewood</city>
        <state>Pennsylvania</state>
        <zip>19096</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christina Angelucci</last_name>
      <email>AngelucciC@mlhs.org</email>
    </contact>
    <investigator>
      <last_name>Eliot Friedman, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sanford Health</name>
      <address>
        <city>Sioux Falls</city>
        <state>South Dakota</state>
        <zip>57109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Allison Lutz</last_name>
      <phone>605-312-6971</phone>
      <email>Allison.Lutz@SanfordHealth.org</email>
    </contact>
    <investigator>
      <last_name>Paul Berger, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>DHR Health</name>
      <address>
        <city>Edinburg</city>
        <state>Texas</state>
        <zip>78539</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Praveen Vijhani, MD</last_name>
      <phone>956-342-5413</phone>
      <email>p.vijhani@dhr-rgv.com</email>
    </contact>
    <contact_backup>
      <last_name>Lu Cantu</last_name>
      <phone>956-362-2396</phone>
      <email>l-cantu@dhr-rgv.com</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>University of Texas MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joseph Nates, MD</last_name>
      <phone>832-876-9382</phone>
      <email>jlnates@mdanderson.org</email>
    </contact>
    <contact_backup>
      <last_name>Jessica Suarez</last_name>
      <phone>713-320-1516</phone>
      <email>jsuarez2@mdanderson.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>WVU Medicine</name>
      <address>
        <city>Morgantown</city>
        <state>West Virginia</state>
        <zip>26506</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jeremiah Hayanga, MD</last_name>
      <phone>336-716-4587</phone>
      <email>jeremiah.hayanga@wvumedicine.org</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.nature.com/articles/s41591-021-01617-x</url>
    <description>Clinical trial design during and beyond the pandemic: the I-SPY COVID trial, 20Jan2022</description>
  </link>
  <reference>
    <citation>Files DC, Matthay MA, Calfee CS, Aggarwal NR, Asare AL, Beitler JR, Berger PA, Burnham EL, Cimino G, Coleman MH, Crippa A, Discacciati A, Gandotra S, Gibbs KW, Henderson PT, Ittner CAG, Jauregui A, Khan KT, Koff JL, Lang J, LaRose M, Levitt J, Lu R, McKeehan JD, Meyer NJ, Russell DW, Thomas KW, Eklund M, Esserman LJ, Liu KD; ISPY COVID Adaptive Platform Trial Network; undefined. I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations. BMJ Open. 2022 Jun 6;12(6):e060664. doi: 10.1136/bmjopen-2021-060664.</citation>
    <PMID>35667714</PMID>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>October 6, 2022</last_update_submitted>
  <last_update_submitted_qc>October 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 10, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>severe disease</keyword>
  <keyword>Platform Trial</keyword>
  <keyword>Acute Respiratory Distress Syndrome</keyword>
  <keyword>ARDS</keyword>
  <keyword>SARS-COV-2</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>Cyproheptadine</mesh_term>
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Remdesivir</mesh_term>
    <mesh_term>Cenicriviroc</mesh_term>
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Celecoxib</mesh_term>
    <mesh_term>Apremilast</mesh_term>
    <mesh_term>Icatibant</mesh_term>
    <mesh_term>Imatinib Mesylate</mesh_term>
    <mesh_term>Famotidine</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>We will share data on a case by case basis with appropriate IRB review and review by our Data Safety Monitoring Comittee.</ipd_description>
    <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_time_frame>Post publication or earlier if warranted.</ipd_time_frame>
    <ipd_access_criteria>Sharing criteria are based on the circumstances of the request and whether the data have been published.</ipd_access_criteria>
  </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/NCT04488081
org study id: I-SPY-COVID
nct id: NCT04488081
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has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The goal of this project is to rapidly screen promising agents, in the setting of an adaptive
      platform trial, for treatment of critically ill COVID-19 patients. In this phase 2 platform
      design, agents will be identified with a signal suggesting a big impact on reducing mortality
      and the need for, as well as duration, of mechanical ventilation.
This platform trial will provide access to repurposed and investigational agents for
      critically ill patients infected with SARS-CoV-2 who have severe or life-threatening
      COVID-19. The main focus of this trial is a platform study for identifying effective agents
      for the treatment of COVID-19. Any critically ill patient with known or presumed COVID-19
      will be automatically entered into the screening phase of the trial until SARS-CoV-2
      infection is confirmed. Basic data will be assembled for each patient (such as ventilatory
      status and survival). If interested in the therapeutic portion of the trial, potential
      participants will be asked to sign a consent form describing the backbone treatment and the
      two specific investigational agent arms to which they may be randomized. The primary
      endpoints will be time to recover to a durable level 4 (or less) on the WHO COVID-19 ordinal
      scale for clinical improvement and time to mortality (death). For this trial, a durable level
      4 is defined as at least 48 hours at COVID level 4 or less (nasal prongs oxygen) without
      returning to high flow oxygen or intubation. Acute care facility resource utilization will be
      automatically calculated (total length of stay in a critical care setting, days intubated,
      and survival). Any change in status, including intubation, extubation, death or discharge,
      will be recorded and verified by the attending physician.

      Patients will be evaluated based on their initial status (ventilation at entry vs. high flow
      oxygen). Exploratory biomarkers will be evaluated over time (ARDS phenotypes and other
      proposed markers) to facilitate clinical learning. A maximum of two investigational arms may
      be open at a time. The anticipated accrual will be 50 patients per week. The maximum number
      of participants assigned to an arm without graduation will be 125 patients. Agents can be
      dropped for futility after enrollment of 40 patients. As the trial proceeds and a better
      understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded
      biomarker and data collection can be added as needed to further elucidate how agents are or
      are not working. The study design features comparison of investigational agent efficacy using
      a Bayesian design, which will allow the detection of strong efficacy signals with the fewest
      possible patients. Initially the control will be patients given current standard of care
      (supportive care for ARDS, including lung protective ventilation and remdesivir and
      dexamethasone as backbone therapy). As other treatments (for example, anticoagulation) become
      part of standard supportive care across sites, these will be added to the backbone therapy.
      If an agent meets the threshold for graduation the company leadership will be informed as
      will the FDA. The arm with the graduated agent will cease to enroll, allowing a new arm with
      a different investigational agent to be added. Information about agents disposition will be
      as follows:

      Every trial participant will have blood collected at trial enrollment, day 3, and day 7 for
      pre-specified biomarker and DNA and RNA analysis. Additional biomarkers can be added as the
      trial proceeds. Patient outcomes will also be evaluated on the basis of whether patients are
      ventilated initially or not. All COVID-19 confirmed patients who start high-flow oxygen (WHO
      COVID-19 level 5; ≥6L oxygen by nasal prongs or mask) will be entered in an Observational
      Component which will collect data via extraction of medical records.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Platform Trial, Bayesian Design, from 2 arms up to 8 arms
primary purpose: Treatment
masking: None (Open Label)
measure: Identify agents that will result in substantial improvements to the clinical condition of participants with severe COVID-19
time frame: Up to 28 days
description: Time to achieve durable change in COVID-19 to ordinal level 4 or less for at least 48 hours
measure: Mortality
time frame: Up to 28 days
description: Time to death
measure: Improvement in disease severity
time frame: Up to 60 days
description: % of COVID-19 level 5 who never progress to COVID-19 level 6/7
measure: Health care utilization
time frame: Up to 60 days
description: Ventilator-free Days
measure: Frequency of serious AEs
time frame: Up to 60 days
description: Total grade 3 or higher AEs by arm and total number of patients with grade 3 or higher AEs by arm.
● Total grade 3 or higher AEs of special interest by arm and total number of patients with grade 3 or higher AEs of special interest by arms (based upon lab assessments)
arm group label: Control/Backbone (Remdesivir and Dexamethasone)
arm group type: Active Comparator
description: Participants randomized to the backbone control will be given standard of care (supportive care for ARDS, including remdesivir and, if needed, lung protective ventilation). Because dexamethasone was shown to have benefit in at least one large randomized clinical trial, patients in the backbone control arm should receive dexamethasone for a total of 10 days during the hospitalization or until or hospital discharge.
Remdesivir (intravenous): 200-mg loading dose on day 1, followed by a daily maintenance dose of 100-mg on days 2 through 10.
Dexamethasone (intravenous): 6 mg intravenous or oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
arm group label: Imatinib + Standard of Care
arm group type: Experimental
description: Subjects will be administered standard of care + 800 mg imatinib on Day 1 orally, in divided doses of 400 mg administered twice per day. 400 mg daily will be administered orally for the following 9 days or until discharge, whichever is sooner.
arm group label: Cenicriviroc + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + cenicriviroc orally , loading 300 mg qAM followed by 150 mg qPM, 12 hours apart on day 1, then 150 mg BID for total of 14 to 28 days depending on date of hospital discharge.
arm group label: Icatibant + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + icatibant subcutaneously, a safety run-in for the first 10 subjects was conducted using a regimen of 30 mg q8h × 3 days. All subsequent subjects received drug at 30 mg q8h x 6 days.
arm group label: Apremilast + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + apremilast orally , 30 mg bid × 14 days.
arm group label: Dornase + Standard of Care (CLOSED)
arm group type: Experimental
description: For Non-intubated subjects: Subjects administered standard of care + dornase, 2.5 mg BID until hospital discharge, improvement to room air (or baseline oxygen use prior to illness) for 24 hours, or total of 14 days of study drug, whichever comes first.
For intubated subjects: Subjects administered standard of care + dornase, 5.0 mg BID in 10 mL normal saline until extubation or 14 days, whichever comes first. If intubated for less than 14 days, extubated subjects received 2.5 mg BID for a total Dornase treatment of 14 days, or until hospital discharge, whichever comes first.
arm group label: Celecoxib/famotidine + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + celecoxib/famotidine orally .
Celecoxib, oral: 400 mg BID for 7 days.
Famotidine, oral: High dose 80 mg QID for 7 days followed by 40 mg BID for a course of 14 days.
arm group label: IC14 + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + IC14 intravenously , 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4
arm group label: Narsoplimab + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + narsoplimab dosed at 4 mg/kg, given as a 30-minute intravenous infusion (up to a maximum of 370 mg per infusion) twice weekly for a total of four weeks (i.e. 9 doses) or until hospital discharge whichever comes first.
arm group label: Aviptadil + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + aviptadil (inhalation via nebulizer), 100 µg three times (TID) daily for a maximum of 14 days
arm group label: Cyproheptadine + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + cyproheptadine via 4 mg tablet, with dosing regimen of 8 mg every 8 hours daily for ten (10) days.
arm group label: Cyclosporine + Standard of Care (CLOSED)
arm group type: Experimental
description: Subjects administered standard of care + modified cyclosporine at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.
intervention type: Drug
intervention name: Remdesivir
description: Participants who receive remdesivir as part of their standard of care will be administered remdesivir by IV for up to ten days. Remdesivir 200mg loading dose on day 1, followed by 100mg IV once daily maintenance doses for 4 or 9 days.
arm group label: Apremilast + Standard of Care (CLOSED)
arm group label: Aviptadil + Standard of Care (CLOSED)
arm group label: Celecoxib/famotidine + Standard of Care (CLOSED)
arm group label: Cenicriviroc + Standard of Care (CLOSED)
arm group label: Control/Backbone (Remdesivir and Dexamethasone)
arm group label: Cyclosporine + Standard of Care (CLOSED)
arm group label: Cyproheptadine + Standard of Care (CLOSED)
arm group label: Dornase + Standard of Care (CLOSED)
arm group label: IC14 + Standard of Care (CLOSED)
arm group label: Icatibant + Standard of Care (CLOSED)
arm group label: Imatinib + Standard of Care
arm group label: Narsoplimab + Standard of Care (CLOSED)
other name: GS-5734
intervention type: Drug
intervention name: Imatinib Mesylate
description: Subjects will be administered 800 mg on Day 1 orally, in divided doses of 400 mg administered twice per day. 400 mg daily will be administered orally for the following 9 days or until discharge, whichever is sooner.
arm group label: Imatinib + Standard of Care
intervention type: Drug
intervention name: Dexamethasone
description: 6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
arm group label: Apremilast + Standard of Care (CLOSED)
arm group label: Aviptadil + Standard of Care (CLOSED)
arm group label: Celecoxib/famotidine + Standard of Care (CLOSED)
arm group label: Cenicriviroc + Standard of Care (CLOSED)
arm group label: Control/Backbone (Remdesivir and Dexamethasone)
arm group label: Cyclosporine + Standard of Care (CLOSED)
arm group label: Cyproheptadine + Standard of Care (CLOSED)
arm group label: Dornase + Standard of Care (CLOSED)
arm group label: IC14 + Standard of Care (CLOSED)
arm group label: Icatibant + Standard of Care (CLOSED)
arm group label: Imatinib + Standard of Care
arm group label: Narsoplimab + Standard of Care (CLOSED)
intervention type: Drug
intervention name: Cenicriviroc
description: Oral, loading 300 mg qAM followed by 150 mg qPM, 12 hours apart on day 1, then 150 mg BID for total of 14 to 28 days depending on date of hospital discharge.
arm group label: Cenicriviroc + Standard of Care (CLOSED)
intervention type: Drug
intervention name: Icatibant
description: Subcutaneous, a safety run-in for the first 10 subjects was conducted using a regimen of 30 mg q8h × 3 days. All subsequent subjects received drug at 30 mg q8h x 6 days.
arm group label: Icatibant + Standard of Care (CLOSED)
other name: Firazyr
intervention type: Drug
intervention name: Apremilast
description: oral, 30 mg bid × 14 days.
arm group label: Apremilast + Standard of Care (CLOSED)
other name: Otezla
intervention type: Biological
intervention name: dornase alfa
description: For Non-intubated subjects: 2.5 mg BID until hospital discharge, improvement to room air (or baseline oxygen use prior to illness) for 24 hours, or total of 14 days of study drug, whichever comes first.
For intubated subjects: 5.0 mg BID in 10 mL normal saline until extubation or 14 days, whichever comes first. If intubated for less than 14 days, extubated subjects received 2.5 mg BID for a total Dornase treatment of 14 days, or until hospital discharge, whichever comes first.
arm group label: Dornase + Standard of Care (CLOSED)
other name: Pulmozyme
intervention type: Drug
intervention name: Celecoxib
description: Oral: 400 mg BID for 7 days.
arm group label: Celecoxib/famotidine + Standard of Care (CLOSED)
other name: celebrex
intervention type: Drug
intervention name: Famotidine
description: Oral: High dose 80 mg QID for 7 days followed by 40 mg BID for a course of 14 days.
arm group label: Celecoxib/famotidine + Standard of Care (CLOSED)
other name: Pepcid
intervention type: Biological
intervention name: IC14
description: intravenous, 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4
arm group label: IC14 + Standard of Care (CLOSED)
intervention type: Drug
intervention name: Aviptadil
description: Inhalation via nebulizer, 100 µg three times (TID) daily for a maximum of 14 days
arm group label: Aviptadil + Standard of Care (CLOSED)
other name: Zyesami
intervention type: Biological
intervention name: narsoplimab
description: Dosed at 4 mg/kg, given as a 30-minute intravenous infusion (up to a maximum of 370 mg per infusion) twice weekly for a total of four weeks (i.e. 9 doses) or until hospital discharge whichever comes first.
arm group label: Narsoplimab + Standard of Care (CLOSED)
other name: OMS721
intervention type: Drug
intervention name: Cyproheptadine
description: 4 mg tablet, with dosing regimen of 8 mg every 8 hours daily for ten (10) days. If the patient weighs less than 48 kg, the regimen is 6 mg every 8 hours daily for ten (10) days. If the participant was discharged before completion of this dosing regimen the drug was not continued.
arm group label: Cyproheptadine + Standard of Care (CLOSED)
other name: periactin
intervention type: Drug
intervention name: Cyclosporine
description: Modified CsA at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.
arm group label: Cyclosporine + Standard of Care (CLOSED)
other name: CsA
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Carolyn Carolyn, MD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Kathleen D Liu, MD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Laura Esserman, MD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Paul Henderson, PhD
phone: 1-925-570-1615
email: p.henderson@quantumleaphealth.org
last name: Karyn DiGiorgio, MS
phone: 1-415-307-1539
email: karyn.digiorgio@quantumleaphealth.org
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country: United States
url: https://www.nature.com/articles/s41591-021-01617-x
description: Clinical trial design during and beyond the pandemic: the I-SPY COVID trial, 20Jan2022
citation: Files DC, Matthay MA, Calfee CS, Aggarwal NR, Asare AL, Beitler JR, Berger PA, Burnham EL, Cimino G, Coleman MH, Crippa A, Discacciati A, Gandotra S, Gibbs KW, Henderson PT, Ittner CAG, Jauregui A, Khan KT, Koff JL, Lang J, LaRose M, Levitt J, Lu R, McKeehan JD, Meyer NJ, Russell DW, Thomas KW, Eklund M, Esserman LJ, Liu KD; ISPY COVID Adaptive Platform Trial Network; undefined. I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations. BMJ Open. 2022 Jun 6;12(6):e060664. doi: 10.1136/bmjopen-2021-060664.
PMID: 35667714
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Cyproheptadine
mesh term: Cyclosporine
mesh term: Remdesivir
mesh term: Cenicriviroc
mesh term: Dexamethasone
mesh term: Celecoxib
mesh term: Apremilast
mesh term: Icatibant
mesh term: Imatinib Mesylate
mesh term: Famotidine
mesh term: Cyclosporins
sharing ipd: Yes
ipd description: We will share data on a case by case basis with appropriate IRB review and review by our Data Safety Monitoring Comittee.
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 time frame: Post publication or earlier if warranted.
ipd access criteria: Sharing criteria are based on the circumstances of the request and whether the data have been published.