<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/NCT04482621</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00247544</org_study_id>
    <nct_id>NCT04482621</nct_id>
  </id_info>
  <brief_title>Decitabine for Coronavirus (COVID-19) Pneumonia- Acute Respiratory Distress Syndrome (ARDS) Treatment: DART Trial</brief_title>
  <acronym>DART</acronym>
  <official_title>Decitabine for COVID-19 Pneumonia-ARDS Treatment: DART Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Johns Hopkins University</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>
      This is a a randomized double blind placebo controlled Phase 2 trial with a 12 patient&#xD;
      lead-in to evaluate safety, prior to full enrollment to an additional 28 patients (for a&#xD;
      total of 40 patients) to assess efficacy of decitabine in the treatment of critically ill&#xD;
      patients with COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard&#xD;
      of care plus Decitabine or standard of care plus saline based placebo. The primary objective&#xD;
      is to determine safety and efficacy of decitabine for COVID-19 ARDS based on clinical&#xD;
      improvement on a 6-point clinical scale.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomized double blind placebo controlled Phase 2 trial with a 12 patient lead-in&#xD;
      to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40&#xD;
      patients) to assess efficacy of decitabine in the treatment of critically ill patients with&#xD;
      COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard of care plus&#xD;
      Decitabine or standard of care plus saline based placebo.&#xD;
&#xD;
      Eligible patients will receive decitabine 10 mg/m2 daily for 5 days, 1 cycle only. This is a&#xD;
      dose that is half the FDA approved dose for myelodysplastic syndrome (MDS), and using a&#xD;
      single cycle.&#xD;
&#xD;
      If less than 2 of the first 6 (treatment arm) patients experience an unacceptable toxicity,&#xD;
      defined as any treatment related grade III or higher adverse events, as per section 5.7,&#xD;
      within 15 days of initiation of treatment, the drug is safe to continue. If the investigators&#xD;
      observe more than 33% patients with unacceptable toxicity, the investigators will pause the&#xD;
      accrual pending safety evaluation. After validating safety, the investigators will enroll&#xD;
      additional 28 patients towards the primary efficacy endpoint. The investigators will monitor&#xD;
      safety throughout the trial by monitoring clinical hematologic, chemistry, vital signs,&#xD;
      respiratory parameters, medications, and clinical changes daily as per the schedule of&#xD;
      procedures.&#xD;
&#xD;
      Bio samples from peripheral blood mononuclear cell (PBMC) and Mini Bronchoalveolar lavage&#xD;
      (BAL) will be collected and stored for secondary analysis and mini BAL will only be collected&#xD;
      as an optional sub-study for patient consented to a separate study protocol either at&#xD;
      time-point of for-cause clinically indicated bronchoscopy, or for subjects consented to a&#xD;
      separate Bronchoalveolar lavage (BAL) interventional study, under the auspices of that&#xD;
      protocol. For research bio specimens required after study drug initiation, a window period of&#xD;
      +/-24 hours while inpatient, and +/- 4 days for outpatient monitoring will be permitted.&#xD;
&#xD;
      These objectives will allow for the planning of subsequent phase 3 studies, and strengthen&#xD;
      implementation of a multi-center randomized trial should this study confirm safety, and&#xD;
      suggest efficacy of therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 14, 2020</start_date>
  <completion_date type="Anticipated">June 2024</completion_date>
  <primary_completion_date type="Anticipated">September 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>This is a randomized double blind placebo controlled Phase 2 trial with a 12 patient lead-in to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40 patients) to assess efficacy of decitabine in the treatment of critically ill patients with COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard of care plus Decitabine or standard of care plus saline based placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients who are alive and free of respiratory failure at day 28</measure>
    <time_frame>From the day of randomization to day 28</time_frame>
    <description>The proportion of patients who are alive and free of respiratory failure at day 28 since start of randomization.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety as assessed by adverse events</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>Safety assessments using adverse events will be monitored daily while inpatient and weekly through end of study at week 6 once discharged from hospital. They will be monitored and graded using Common Terminology Criteria Adverse Events version 5.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in oxygenation index</measure>
    <time_frame>Daily, up to 6 weeks</time_frame>
    <description>Oxygenation index is used to assess severity of hypoxic respiratory failure. (OI = mean airway pressure (MAP) × Fraction of inspired oxygen (FiO2) × 100÷ partial pressure of oxygen (PaO2). This will be measured daily while subject is on mechanical ventilation up to 6 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fraction of inspired oxygen</measure>
    <time_frame>Up to day 29</time_frame>
    <description>Fraction of inspired oxygen in the oxygen delivery system during hospital stay. Measured at 8 am daily during hospital stay and then weekly until day 29.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>Patients status of alive versus death at completion of study follow up period, i.e. 6 weeks from start.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay in hospital</measure>
    <time_frame>Till hospital discharge, up to 6 weeks</time_frame>
    <description>Duration of days from baseline to hospital discharge.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator free days</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>For subjects who received mechanical ventilation, total number of days from baseline to end of study at 6 weeks that subject was not on mechanical or non invasive mechanical ventilation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Polymerase chain reaction (PCR) negativity</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>If viremic at starting date of decitabine - time from baseline to 1st recorded negative COVID nucleic acid amplification (NAT) based assay, measured in days.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of patients with National Early Warning Score 2 of 3 or more</measure>
    <time_frame>Weekly while patient is in hospital, up to 6 weeks</time_frame>
    <description>Determines the degree of illness of a patient and prompts critical care intervention. This composite score includes Respiratory Rate, Temperature, oxygen Saturation, Blood Pressure, Oxygen inspired and cognitive status. This will be measured at baseline and weekly while patient is in hospital.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality at 28 days since randomization</measure>
    <time_frame>Daily upto day 28</time_frame>
    <description>Total number of death at 28 days since day of randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of change of clinical score based on World Health Organization 9-point scale at day 10 from randomization</measure>
    <time_frame>Daily from randomization to day 10</time_frame>
    <description>Determine clinical score from randomization date to day 10</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of change of clinical score based on WHO 9-point scale</measure>
    <time_frame>Weekly while patient is in hospital, up to 6 weeks</time_frame>
    <description>11. Time from randomization to an at least 2-point decrease in clinical score based on WHO 9-point scale</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Decitabine + Standard of Care (SOC)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Study drug Decitabine will be administered via Intravenous injection. Dosage Regimen: 10mg/m^2/day IV day x 5 days (1 cycle only)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care (SOC) + Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Saline based placebo will be administered via Intravenous injection. Dosage Regimen: 10mg/m^2/day IV day x 5 days (1 cycle only)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Decitabine</intervention_name>
    <description>Study duration is 6 weeks after the last dose of study drug. Number of study visits is dependent on Length of hospitalization of study participant. Study visits are scheduled on days 0-7, 11, 15, 29, and may occur via telemedicine or inpatient assessment or outpatient assessment in COVID recovered participants.&#xD;
Decitabine will be administered via Intravenous Administration 10/mg/m^2/day Dosage: 10mg/m^2/day IV day x 5 days (1 cycle only)</description>
    <arm_group_label>Decitabine + Standard of Care (SOC)</arm_group_label>
    <other_name>5-aza-2'- deoxycytidine</other_name>
    <other_name>DACOGEN</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo Saline</intervention_name>
    <description>Saline based placebo will be administered via Intravenous injection. Dosage Regimen: 10mg/m^2/day IV day x 5 days (1 cycle only)</description>
    <arm_group_label>Standard of Care (SOC) + Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. ≥18 years&#xD;
&#xD;
          2. Use of Intermittent Mechanical Ventilation, non-invasive mechanical ventilation (NIMV)&#xD;
             or High Flow Nasal Cannula.&#xD;
&#xD;
          3. Have ARDS or Acute Lung Injury physiology confirmed by Pao2/Fio2 ratio of &lt; 300&#xD;
&#xD;
          4. Severe Acute Respiratory Distress Syndrome (SARS) - Coronavirus (CoV-2) determined by&#xD;
             lab polymerase chain reaction assay in either upper or lower respiratory tract&#xD;
             sampling (e.g. bronchoalveolar lavage or nasopharyngeal swab)&#xD;
&#xD;
          5. If childbearing age: agree to practice effective birth control from screening until at&#xD;
             least 180 days after last dose&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Hematologic cytopenias: Absolute Neutrophil Count (ANC) &lt;1500/mm3, Hgb&lt;7.0 and/or&#xD;
             platelets &lt;100,000/mm3&#xD;
&#xD;
          2. Subjects receiving or enrolled in clinical trial for other investigational treatment&#xD;
             for SARS- 2-CoV.&#xD;
&#xD;
          3. Active malignancy, solid tumors, and current or recent chemotherapy&#xD;
&#xD;
          4. Concomitant use of nonbiologic immunosuppressants (e.g. Janus Kinase (JAK) inhibitors,&#xD;
             Bruton's Tyrosine Kinase (BTK) inhibitors)&#xD;
&#xD;
          5. Active HIV viremia, or any other uncontrolled secondary infection.&#xD;
&#xD;
          6. Concurrent immunomodulating biologics or use of Palifermin, Dipyrone, Deferiprone&#xD;
&#xD;
          7. Subjects with severe sepsis with vasopressors or extrapulmonary organ failure:&#xD;
&#xD;
          8. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) /alkaline&#xD;
             phosphatase (ALK) Phos ≥3x upper limit of normal (ULN) and Total Bilirubin (TBILI) ≥2x&#xD;
             ULN; or Creatinine clearance &lt;30 mL/min&#xD;
&#xD;
          9. Pregnant women or women who are breastfeeding&#xD;
&#xD;
         10. Any Condition, per opinion of PI that would affect subject safety and/or compliance&#xD;
&#xD;
         11. Prior hypersensitivity to decitabine&#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>Franco D'Alessio, M.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins UIniversity</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins University</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>July 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 22, 2020</study_first_posted>
  <last_update_submitted>June 8, 2023</last_update_submitted>
  <last_update_submitted_qc>June 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Pneumonia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Decitabine</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/NCT04482621
org study id: IRB00247544
nct id: NCT04482621
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a a randomized double blind placebo controlled Phase 2 trial with a 12 patient
      lead-in to evaluate safety, prior to full enrollment to an additional 28 patients (for a
      total of 40 patients) to assess efficacy of decitabine in the treatment of critically ill
      patients with COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard
      of care plus Decitabine or standard of care plus saline based placebo. The primary objective
      is to determine safety and efficacy of decitabine for COVID-19 ARDS based on clinical
      improvement on a 6-point clinical scale.
This is a randomized double blind placebo controlled Phase 2 trial with a 12 patient lead-in
      to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40
      patients) to assess efficacy of decitabine in the treatment of critically ill patients with
      COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard of care plus
      Decitabine or standard of care plus saline based placebo.

      Eligible patients will receive decitabine 10 mg/m2 daily for 5 days, 1 cycle only. This is a
      dose that is half the FDA approved dose for myelodysplastic syndrome (MDS), and using a
      single cycle.

      If less than 2 of the first 6 (treatment arm) patients experience an unacceptable toxicity,
      defined as any treatment related grade III or higher adverse events, as per section 5.7,
      within 15 days of initiation of treatment, the drug is safe to continue. If the investigators
      observe more than 33% patients with unacceptable toxicity, the investigators will pause the
      accrual pending safety evaluation. After validating safety, the investigators will enroll
      additional 28 patients towards the primary efficacy endpoint. The investigators will monitor
      safety throughout the trial by monitoring clinical hematologic, chemistry, vital signs,
      respiratory parameters, medications, and clinical changes daily as per the schedule of
      procedures.

      Bio samples from peripheral blood mononuclear cell (PBMC) and Mini Bronchoalveolar lavage
      (BAL) will be collected and stored for secondary analysis and mini BAL will only be collected
      as an optional sub-study for patient consented to a separate study protocol either at
      time-point of for-cause clinically indicated bronchoscopy, or for subjects consented to a
      separate Bronchoalveolar lavage (BAL) interventional study, under the auspices of that
      protocol. For research bio specimens required after study drug initiation, a window period of
      +/-24 hours while inpatient, and +/- 4 days for outpatient monitoring will be permitted.

      These objectives will allow for the planning of subsequent phase 3 studies, and strengthen
      implementation of a multi-center randomized trial should this study confirm safety, and
      suggest efficacy of therapy.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a randomized double blind placebo controlled Phase 2 trial with a 12 patient lead-in to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40 patients) to assess efficacy of decitabine in the treatment of critically ill patients with COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard of care plus Decitabine or standard of care plus saline based placebo.
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Proportion of patients who are alive and free of respiratory failure at day 28
time frame: From the day of randomization to day 28
description: The proportion of patients who are alive and free of respiratory failure at day 28 since start of randomization.
measure: Safety as assessed by adverse events
time frame: Up to 6 weeks
description: Safety assessments using adverse events will be monitored daily while inpatient and weekly through end of study at week 6 once discharged from hospital. They will be monitored and graded using Common Terminology Criteria Adverse Events version 5.0.
measure: Change in oxygenation index
time frame: Daily, up to 6 weeks
description: Oxygenation index is used to assess severity of hypoxic respiratory failure. (OI = mean airway pressure (MAP) × Fraction of inspired oxygen (FiO2) × 100÷ partial pressure of oxygen (PaO2). This will be measured daily while subject is on mechanical ventilation up to 6 weeks.
measure: Change in fraction of inspired oxygen
time frame: Up to day 29
description: Fraction of inspired oxygen in the oxygen delivery system during hospital stay. Measured at 8 am daily during hospital stay and then weekly until day 29.
measure: Overall survival
time frame: Up to 6 weeks
description: Patients status of alive versus death at completion of study follow up period, i.e. 6 weeks from start.
measure: Length of stay in hospital
time frame: Till hospital discharge, up to 6 weeks
description: Duration of days from baseline to hospital discharge.
measure: Ventilator free days
time frame: Up to 6 weeks
description: For subjects who received mechanical ventilation, total number of days from baseline to end of study at 6 weeks that subject was not on mechanical or non invasive mechanical ventilation.
measure: Time to Polymerase chain reaction (PCR) negativity
time frame: Up to 6 weeks
description: If viremic at starting date of decitabine - time from baseline to 1st recorded negative COVID nucleic acid amplification (NAT) based assay, measured in days.
measure: Percentage of patients with National Early Warning Score 2 of 3 or more
time frame: Weekly while patient is in hospital, up to 6 weeks
description: Determines the degree of illness of a patient and prompts critical care intervention. This composite score includes Respiratory Rate, Temperature, oxygen Saturation, Blood Pressure, Oxygen inspired and cognitive status. This will be measured at baseline and weekly while patient is in hospital.
measure: All-cause mortality at 28 days since randomization
time frame: Daily upto day 28
description: Total number of death at 28 days since day of randomization
measure: Percentage of change of clinical score based on World Health Organization 9-point scale at day 10 from randomization
time frame: Daily from randomization to day 10
description: Determine clinical score from randomization date to day 10
measure: Percentage of change of clinical score based on WHO 9-point scale
time frame: Weekly while patient is in hospital, up to 6 weeks
description: 11. Time from randomization to an at least 2-point decrease in clinical score based on WHO 9-point scale
arm group label: Decitabine + Standard of Care (SOC)
arm group type: Active Comparator
description: Study drug Decitabine will be administered via Intravenous injection. Dosage Regimen: 10mg/m^2/day IV day x 5 days (1 cycle only)
arm group label: Standard of Care (SOC) + Placebo
arm group type: Placebo Comparator
description: Saline based placebo will be administered via Intravenous injection. Dosage Regimen: 10mg/m^2/day IV day x 5 days (1 cycle only)
intervention type: Drug
intervention name: Decitabine
description: Study duration is 6 weeks after the last dose of study drug. Number of study visits is dependent on Length of hospitalization of study participant. Study visits are scheduled on days 0-7, 11, 15, 29, and may occur via telemedicine or inpatient assessment or outpatient assessment in COVID recovered participants.
Decitabine will be administered via Intravenous Administration 10/mg/m^2/day Dosage: 10mg/m^2/day IV day x 5 days (1 cycle only)
arm group label: Decitabine + Standard of Care (SOC)
other name: 5-aza-2'- deoxycytidine
other name: DACOGEN
intervention type: Other
intervention name: Placebo Saline
description: Saline based placebo will be administered via Intravenous injection. Dosage Regimen: 10mg/m^2/day IV day x 5 days (1 cycle only)
arm group label: Standard of Care (SOC) + Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Franco D'Alessio, M.D
role: Principal Investigator
affiliation: Johns Hopkins UIniversity
facility: 
country: United States
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responsible party type: Sponsor
mesh term: COVID-19
mesh term: Pneumonia
mesh term: Decitabine
sharing ipd: No