<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/NCT04405102</url>
  </required_header>
  <id_info>
    <org_study_id>2021-3474</org_study_id>
    <nct_id>NCT04405102</nct_id>
  </id_info>
  <brief_title>COVID-19 Ozanimod Intervention Study</brief_title>
  <acronym>COZI</acronym>
  <official_title>A Randomized Trial on Efficacy and Safety of Ozanimod for the Treatment of COVID-19 Patients Requiring Oxygen Support - A Pilot Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Celgene</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut universitaire de cardiologie et de pneumologie de Québec, University Laval</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 virus SARS-CoV-2 causes severe pneumonia which, in a proportion of patients progresses&#xD;
      towards an Acute Respiratory Distress Syndrome (ARDS) mainly related to the antiviral immune&#xD;
      response. To date, there is no available treatment that significantly improves outcome of&#xD;
      patients with COVID-19 pneumonia. Sphingosine-1-phosphate receptor 1 (S1P1) ligands control&#xD;
      vascular leakage in the airways and sphingosine-1-phosphate (S1P) receptor ligands devoid of&#xD;
      activity on sphingosine-1-phosphate receptor 3 (S1P3) show an excellent safety profile,&#xD;
      including ozanimod. Critically, S1P1 ligands mildly impact, but do not compromise viral&#xD;
      clearance and they reduced lung injury in preclinical models, even without concomitant use of&#xD;
      antivirals and with a synergistic effect when associated to antiviral agents. Ozanimod was&#xD;
      approved by the FDA for the treatment of relapsing multiple sclerosis at the end of March&#xD;
      2020, and was recently (October 2020) approved by Health Canada for the same indication. The&#xD;
      investigators believe that this immune modulator is at the top of the list of agents that&#xD;
      should be trialed in order to mitigate the morbidity and mortality of COVID-19.&#xD;
&#xD;
      The primary objective is to substantiate the impact of ozanimod on key outcomes of COVID-19&#xD;
      patient progression, which will guide decision making around sample size and the choice of&#xD;
      endpoints for future clinical trial.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Screening was stopped by the Sponsor (43/48 participants enrolled), given the very low number&#xD;
    of eligible patients (high vaccination rate and occurrence of the Omicron variant). The last&#xD;
    patient randomized performed his follow-up visit.&#xD;
  </why_stopped>
  <start_date type="Actual">September 16, 2020</start_date>
  <completion_date type="Actual">May 12, 2022</completion_date>
  <primary_completion_date type="Actual">March 14, 2022</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>Daily Patient progression assessed with the World Health Organization-adapted 6-points ordinal scale</measure>
    <time_frame>through whole duration of the hospitalization, an average of 14 days</time_frame>
    <description>Clinical improvement until hospital discharge</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The mean oxygen flow required to maintain the oxygen saturation (SpO2) target at 92%</measure>
    <time_frame>First 7 days of the trial</time_frame>
    <description>Titrated every second with automated oxygen titration device (FreeO2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of non invasive ventilation (NIV) / high flow nasal therapy (HFNT) use</measure>
    <time_frame>through whole duration of the hospitalization, an average of 14 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of intubation</measure>
    <time_frame>through whole duration of the hospitalization, an average of 14 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator-free and oxygen-free days at day 28</measure>
    <time_frame>through whole duration of the hospitalization, an average of 14 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of ICU admission/length of stay/mortality</measure>
    <time_frame>through whole duration of the hospitalization, an average of 14 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity index measurement</measure>
    <time_frame>through whole duration of the hospitalization, an average of 14 days</time_frame>
    <description>Sepsis-related organ failure assessment (SOFA), national early warning score (NEWS2), early warning score for oxygen therapy (EWS.O2), decrease of at least 2 points on the 6-point ordinal scale</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Ozanimod + standard of care</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>During hospitalization, the experiment treatment of Ozanimod will be given with the standard of care (Recommendations for standard of care management of COVID-19 will be provided for anticoagulation, fluid resuscitation, corticoids and other immunomodulators, antipyretics agents, antiviral agents and other treatments. These recommendations are subject to modifications based on the new literature data.).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>During hospitalization, patient will be given standard of care (Recommendations for standard of care management of COVID-19 will be provided for anticoagulation, fluid resuscitation, corticoids and other immunomodulators, antipyretics agents, antiviral agents and other treatments. These recommendations are subject to modifications based on the new literature data).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ozanimod</intervention_name>
    <description>The investigational medical product (IMP) for this study is ozanimod. Ozanimod 0.23 mg be administered once daily for 4 days and then ozanimod 0.46 mg will be administered once daily for ten days.</description>
    <arm_group_label>Ozanimod + standard of care</arm_group_label>
    <other_name>Zeposia (USA)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of care</intervention_name>
    <description>During hospitalization, patient will be given standard of care (Recommendations for standard of care management of COVID-19 will be provided for anticoagulation, fluid resuscitation, corticoids and other immunomodulators, antipyretics agents, antiviral agents and other treatments. These recommendations are subject to modifications based on the new literature data).</description>
    <arm_group_label>Ozanimod + standard of care</arm_group_label>
    <arm_group_label>Standard of care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria&#xD;
&#xD;
          -  Confirmed COVID-19 (positive polymerase chain reaction (PCR) for COVID-19 from any&#xD;
             specimen)&#xD;
&#xD;
          -  Patients older than 18 years old and younger than 85 years old.&#xD;
&#xD;
          -  BMI higher than 20 but lower than 40&#xD;
&#xD;
          -  Patients with hypoxemia related to viral pneumonia (COVID-19) requiring oxygen or&#xD;
             nasal high flow therapy (to maintain SpO2 above 92%) without criteria for immediate&#xD;
             intubation or need for other respiratory supports (CPAP, non-invasive ventilation).&#xD;
&#xD;
          -  Initiation of oxygen supplementation &lt; 72 hours&#xD;
&#xD;
          -  eGFR (CKD EPI) &gt; 30 ml/min/1.73m2&#xD;
&#xD;
          -  Serum troponin i &lt; 80 ng/L&#xD;
&#xD;
          -  Heart rate ≥ 55 bpm if beta blockers or calcium channel blocker nondihydropyridine are&#xD;
             used, and ≥ 60 bpm in the other patients&#xD;
&#xD;
        Exclusion criteria Medical conditions&#xD;
&#xD;
          -  Level of care B (unless patient agrees to intubation at study enrollment), C or D&#xD;
             (patient admitted for palliative care; or physician is not committed to&#xD;
             life-sustaining therapies)&#xD;
&#xD;
          -  No SpO2 signal available (only if FreeO2 apparatus is used)&#xD;
&#xD;
          -  Patient agitation (only if FreeO2 apparatus is used)&#xD;
&#xD;
          -  Severe untreated sleep apnea&#xD;
&#xD;
          -  History of or currently active primary or secondary immunodeficiency&#xD;
&#xD;
          -  Recent (within the last 6 months) occurrence of myocardial infarction, unstable&#xD;
             angina, stroke, transient ischemic attack, decompensated heart failure requiring&#xD;
             hospitalization, class III/IV heart failure&#xD;
&#xD;
          -  Known presence of Mobitz type II second-degree or third-degree atrioventricular block,&#xD;
             sick sinus syndrome, or sinoatrial block, unless patient has a functioning pacemaker&#xD;
&#xD;
          -  Child-Pugh score class C&#xD;
&#xD;
          -  Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin measured&#xD;
             during screening&#xD;
&#xD;
          -  Persistent hypotension.&#xD;
&#xD;
        Prior/concomitant therapy&#xD;
&#xD;
          -  Receipt of a live vaccine within 4 weeks prior to randomization&#xD;
&#xD;
          -  Receiving MAO inhibitor (tranylcypromine, selegiline or phenelzine)&#xD;
&#xD;
          -  Receiving pharmacological treatment for a form of multiple sclerosis&#xD;
&#xD;
          -  Use of long-term immunosuppressors (Ex. tacrolimus, cyclosporin, azathioprine,&#xD;
             mycophenolate, sirolimus, methotrexate or chronic use of corticosteroid (&gt; 7.5 mg per&#xD;
             day more than 3 months)&#xD;
&#xD;
          -  Receiving Class Ia and class III anti-arrythmic drugs amiodarone, sotalol, flecainide,&#xD;
             propafenone&#xD;
&#xD;
          -  Patients receiving or anticipated to receive hydroxychloroquine or azithromycin.&#xD;
&#xD;
        Prior/concurrent clinical study experience -Current enrolment in an interventional arm of a&#xD;
        clinical trial with similar endpoints to the COZI trial&#xD;
&#xD;
        Other exclusions&#xD;
&#xD;
        -Patients or legal/authorized representatives who refuse to participate to the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>François Lellouche, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IUCPQ-UL</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David Marsolais, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>CRIUCPQ-UL</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nathalie Châteauvert, B. pharm</last_name>
    <role>Study Chair</role>
    <affiliation>CRIUCPQ-UL</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pascale Blais-Lecours, PhD</last_name>
    <role>Study Director</role>
    <affiliation>CRIUCPQ-UL</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hôpital de la Cité-de-la-Santé (CISSS de Laval)</name>
      <address>
        <city>Laval</city>
        <state>Quebec</state>
        <zip>H7M 3L9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Santa Cabrini Ospedale (CIUSSS EMTL)</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H1T 1P7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval</name>
      <address>
        <city>Québec</city>
        <zip>G1V 4G5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>May 26, 2020</study_first_submitted>
  <study_first_submitted_qc>May 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 28, 2020</study_first_posted>
  <last_update_submitted>May 13, 2022</last_update_submitted>
  <last_update_submitted_qc>May 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec</investigator_affiliation>
    <investigator_full_name>François Lellouche</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>S1P1 ligand</keyword>
  <keyword>SARS-CoV-2</keyword>
  <keyword>Oxygen requirement</keyword>
  <keyword>WHO-adapted 6-points ordinal scale</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>Ozanimod</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04405102
org study id: 2021-3474
nct id: NCT04405102
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The virus SARS-CoV-2 causes severe pneumonia which, in a proportion of patients progresses
      towards an Acute Respiratory Distress Syndrome (ARDS) mainly related to the antiviral immune
      response. To date, there is no available treatment that significantly improves outcome of
      patients with COVID-19 pneumonia. Sphingosine-1-phosphate receptor 1 (S1P1) ligands control
      vascular leakage in the airways and sphingosine-1-phosphate (S1P) receptor ligands devoid of
      activity on sphingosine-1-phosphate receptor 3 (S1P3) show an excellent safety profile,
      including ozanimod. Critically, S1P1 ligands mildly impact, but do not compromise viral
      clearance and they reduced lung injury in preclinical models, even without concomitant use of
      antivirals and with a synergistic effect when associated to antiviral agents. Ozanimod was
      approved by the FDA for the treatment of relapsing multiple sclerosis at the end of March
      2020, and was recently (October 2020) approved by Health Canada for the same indication. The
      investigators believe that this immune modulator is at the top of the list of agents that
      should be trialed in order to mitigate the morbidity and mortality of COVID-19.

      The primary objective is to substantiate the impact of ozanimod on key outcomes of COVID-19
      patient progression, which will guide decision making around sample size and the choice of
      endpoints for future clinical trial.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Daily Patient progression assessed with the World Health Organization-adapted 6-points ordinal scale
time frame: through whole duration of the hospitalization, an average of 14 days
description: Clinical improvement until hospital discharge
measure: The mean oxygen flow required to maintain the oxygen saturation (SpO2) target at 92%
time frame: First 7 days of the trial
description: Titrated every second with automated oxygen titration device (FreeO2)
measure: Rate of non invasive ventilation (NIV) / high flow nasal therapy (HFNT) use
time frame: through whole duration of the hospitalization, an average of 14 days
measure: Rate of intubation
time frame: through whole duration of the hospitalization, an average of 14 days
measure: Ventilator-free and oxygen-free days at day 28
time frame: through whole duration of the hospitalization, an average of 14 days
measure: Rate of ICU admission/length of stay/mortality
time frame: through whole duration of the hospitalization, an average of 14 days
measure: Severity index measurement
time frame: through whole duration of the hospitalization, an average of 14 days
description: Sepsis-related organ failure assessment (SOFA), national early warning score (NEWS2), early warning score for oxygen therapy (EWS.O2), decrease of at least 2 points on the 6-point ordinal scale
arm group label: Ozanimod + standard of care
arm group type: Experimental
description: During hospitalization, the experiment treatment of Ozanimod will be given with the standard of care (Recommendations for standard of care management of COVID-19 will be provided for anticoagulation, fluid resuscitation, corticoids and other immunomodulators, antipyretics agents, antiviral agents and other treatments. These recommendations are subject to modifications based on the new literature data.).
arm group label: Standard of care
arm group type: Active Comparator
description: During hospitalization, patient will be given standard of care (Recommendations for standard of care management of COVID-19 will be provided for anticoagulation, fluid resuscitation, corticoids and other immunomodulators, antipyretics agents, antiviral agents and other treatments. These recommendations are subject to modifications based on the new literature data).
intervention type: Drug
intervention name: Ozanimod
description: The investigational medical product (IMP) for this study is ozanimod. Ozanimod 0.23 mg be administered once daily for 4 days and then ozanimod 0.46 mg will be administered once daily for ten days.
arm group label: Ozanimod + standard of care
other name: Zeposia (USA)
intervention type: Other
intervention name: Standard of care
description: During hospitalization, patient will be given standard of care (Recommendations for standard of care management of COVID-19 will be provided for anticoagulation, fluid resuscitation, corticoids and other immunomodulators, antipyretics agents, antiviral agents and other treatments. These recommendations are subject to modifications based on the new literature data).
arm group label: Ozanimod + standard of care
arm group label: Standard of care
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: François Lellouche, MD
role: Principal Investigator
affiliation: IUCPQ-UL
last name: David Marsolais, PhD
role: Study Chair
affiliation: CRIUCPQ-UL
last name: Nathalie Châteauvert, B. pharm
role: Study Chair
affiliation: CRIUCPQ-UL
last name: Pascale Blais-Lecours, PhD
role: Study Director
affiliation: CRIUCPQ-UL
facility: 
facility: 
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec
investigator full name: François Lellouche
investigator title: MD
mesh term: COVID-19
mesh term: Ozanimod
sharing ipd: No