<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/NCT04476992</url>
  </required_header>
  <id_info>
    <org_study_id>NICOR</org_study_id>
    <nct_id>NCT04476992</nct_id>
  </id_info>
  <brief_title>Nitric Oxide Therapy for COVID-19 Patients With Oxygen Requirement</brief_title>
  <acronym>NICOR</acronym>
  <official_title>A Safety Study on the Use of Intermittent Versus Continuous Inhalation of NO in Spontaneous Breathing COVID-19 Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tomsk National Research Medical Center of the Russian Academy of Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Siberian State Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Tomsk National Research Medical Center of the Russian Academy of Sciences</source>
  <oversight_info>
    <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>
      Preliminary data support the effect of Nitric Oxide (NO) on improving the oxygenation in&#xD;
      mechanically ventilated patients and spontaneously breathing patients with COVID-19. In vitro&#xD;
      studies showed an antiviral effect of NO against SARS-coronavirus. The optimal therapeutic&#xD;
      regimen of NO gas in spontaneously breathing hypoxemic patients with COVID-19 is not known.&#xD;
      We hypothesize that high concentration inhaled NO with an adjunct of continuous low dose&#xD;
      administration between the high concentration treatments can be safely administered in&#xD;
      hypoxemic COVID-19 patients compared to the high dose treatment alone. Prolonged&#xD;
      administration of NO gas may benefit the patients in terms of the severity of the clinical&#xD;
      course and time to recovery. Together with a clinical effect on ventilation-perfusion&#xD;
      matching, a prolonged regimen would allow also an increase in antiviral activity (dose and&#xD;
      time-dependent).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Coronavirus disease 2019 (COVID-19) consists mainly of a respiratory infection that spans&#xD;
      from a mild involvement of the upper respiratory tract to severe pneumonia leading to&#xD;
      respiratory distress, shock, and death. Fever, cough, and dyspnea/tachypnea, together with&#xD;
      myalgia and fatigue, have been identified as the most common presenting symptoms. Most of the&#xD;
      patients remain in a state of mild upper respiratory tract disease for a relatively long&#xD;
      period (a median of 8-10 days), after which a proportion of up to 25% may develop severe&#xD;
      hypoxemia and ARDS with the necessity of mechanical ventilation. Deterioration with ICU&#xD;
      admission (most likely in older patients with comorbidities) raises the incidence of&#xD;
      mortality in a range that goes from 3.4 up to 61%. Moreover, ICU admission poses a&#xD;
      significant strain in terms of healthcare resources. Thus, a treatment able to avoid the&#xD;
      progression of the disease from the mild to the severe phases would have a substantial&#xD;
      benefit both in terms of lives saved and hospital resources spared. However, at the time,&#xD;
      only Remdesivir and Dexamethasone have shown some benefits in robust clinical trials.&#xD;
&#xD;
      Nitric Oxide gas is a therapy currently approved for the treatment of pulmonary hypertension&#xD;
      in newborns and is also used as rescue therapy in patients with acute respiratory distress&#xD;
      syndrome (ARDS). The clinical role of NO gas in COVID-19 patients could be of particular&#xD;
      relevance since there is in-vitro evidence of NO antiviral activity specifically against SARS&#xD;
      coronavirus. At the time of the SARS pandemic, a small rescue trial on intubated patients&#xD;
      with SARS showed that NO was effective in improving the oxygenation, fasten the resolution of&#xD;
      chest X-ray abnormalities, and improve the clinical outcomes. Moreover, in vitro studies&#xD;
      demonstrated that the NO-donor compound S-nitroso-N-acetylpenicillamine was able to increase&#xD;
      the survival rate of in vitro mammalian cells infected with SARS-CoV. SARS-CoV and SARS-CoV-2&#xD;
      share the same subgenus inside the family Coronaviridae. The literature seems to point&#xD;
      towards an a-specific rather than pathogen-specific antimicrobial effect of NO. Thus, the&#xD;
      role of exogenous inhaled NO as a viricidal agent during COVID-19 infection could be&#xD;
      hypothesized.&#xD;
&#xD;
      Nitric Oxide at high concentration has been found to be microbicidal but still safe in&#xD;
      spontaneously breathing subjects in a phase I trial. There are several trials testing the&#xD;
      efficacy of NO therapy in improving the outcome of COVID-19 patients. So far, only a&#xD;
      retrospective observational study showed that NO gas is useful in improving the oxygenation&#xD;
      in spontaneously breathing patients. However, the optimal therapeutic regimens and the&#xD;
      efficacy of NO gas in improving the oxygenation in hypoxemic COVID-19 patients haven't been&#xD;
      tested.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 24, 2020</start_date>
  <completion_date type="Actual">September 17, 2021</completion_date>
  <primary_completion_date type="Actual">July 17, 2021</primary_completion_date>
  <phase>Phase 1/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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Methemoglobin level at 48 hours</measure>
    <time_frame>48 hours</time_frame>
    <description>The primary outcome will be evaluated with the difference in Methemoglobin levels between the groups at 48 hours after randomization.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Methemoglobin level at 96 hours</measure>
    <time_frame>96 hours</time_frame>
    <description>The primary outcome will be evaluated with the difference in Methemoglobineamia between the groups at 96 hours after randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement in oxygenation between the groups at 48 hours or at discharge if before 48 hours</measure>
    <time_frame>48 hours</time_frame>
    <description>The secondary outcome, &quot;Improve the oxygenation at 48 hours,&quot; will be evaluated with the measure of the difference in oxygenation among the groups at 48 hours. Oxygenation will be measured in terms of the SpO2/FiO2 ratio.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement in oxygenation between the groups at 96 hours or at discharge if before 96 hours</measure>
    <time_frame>96 hours</time_frame>
    <description>The secondary outcome, &quot;Improve the oxygenation at 96 hours,&quot; will be evaluated with the measure of the difference in oxygenation between the groups at 96 hours. Oxygenation will be measured in terms of the SpO2/FiO2 ratio.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of positive RT-PCR for SARS-CoV-2 between groups in 5 days, discharge, and 28 days</measure>
    <time_frame>28 days</time_frame>
    <description>The secondary outcome &quot;difference in the rate of negative RT-PCR for SARS CoV-2&quot; will be evaluated as the rate of negativization of the RT-PCR for SARS-CoV-2 at 5 days after randomization, at discharge and at 28 days after randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to clinical recovery among groups, defined as time to interruption of oxygen administration for 24 hours or discharge</measure>
    <time_frame>28 days</time_frame>
    <description>The secondary outcome &quot;different time to clinical recovery&quot; will be evaluated as the time between the randomization and the clinical indication to interrupt the administration of oxygen for 24 hours.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in the inflammatory markers among groups</measure>
    <time_frame>7 days</time_frame>
    <description>The secondary outcome &quot;Different reduction in inflammatory markers&quot; will be evaluated as improvement in the inflammatory markers (IL-6; Ferritin; White Blood Cells; Leucocyte count; CRP; D-Dimer) observed in blood samples collected at day 1, 2, 3, 4, and 7 compared to the Baseline value.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Acute Kidney Disease (AKI) between groups during hospitalization</measure>
    <time_frame>28 days</time_frame>
    <description>The secondary outcome &quot;rate of AKI between groups&quot; will be evaluated as the presence of a comparable rate of AKI during the hospital stay. The AKI will be defined according to the KDIGO classification.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in Katz score between groups</measure>
    <time_frame>28 days</time_frame>
    <description>The secondary outcome &quot;Difference in Katz score between groups&quot; will be evaluated as the difference in Katz Activities of Daily Living between Baseline and day 28. This questionnaire will coincide with the 28-day phone call to assess health status and survival.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Effect of NO gas treatment on cardiovascular hemodynamics assessed using cardiac ultrasound in COVID-19 hypoxemic patients</measure>
    <time_frame>96 hours</time_frame>
    <description>1. The exploratory outcome &quot;Effect of nitric oxide on heart function in COVID-19 hypoxemic patients&quot; will be evaluated as:&#xD;
the changes observed in heart ultrasound at 48 and 96 hours (or at discharge) compared to the Baseline in all groups.&#xD;
the changes observed in heart ultrasound during the administration of NO comparing pre-treatment, during treatment, and post-treatment.</description>
  </other_outcome>
  <other_outcome>
    <measure>Effect of NO gas treatment on lung function evaluated with serial spirometry in COVID-19 hypoxemic patients</measure>
    <time_frame>96 hours</time_frame>
    <description>2. The secondary outcome &quot;Effect of NO gas on lung function in COVID-19 hypoxemic patients&quot; will be evaluated as:&#xD;
the changes observed in spirometry at 48 and 96 hours (or at discharge) compared to the Baseline in all groups.&#xD;
the changes observed in spirometry during the administration of NO comparing pre-treatment, during treatment, and post-treatment.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Hypoxemia</condition>
  <condition>Pneumonia, Viral</condition>
  <condition>Coronavirus Infection</condition>
  <arm_group>
    <arm_group_label>NO High Concentration</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Nitric oxide will be delivered twice a day with a non-rebreathing system that allows a safe administration of Nitric Oxide gas at high concentrations limiting the amount of NO2 delivered to the patient.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NO High Concentration + Continuous Low Concentration</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nitric oxide will be delivered twice a day with a non-rebreathing system that allows a safe administration of Nitric Oxide gas at high concentrations limiting the amount of NO2 delivered to the patient.&#xD;
This arm will receive in addition a continuous low flow of Nitric Oxide at 20 ppm among the high concentration treatments.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitric Oxide-Sessions</intervention_name>
    <description>Nitric Oxide will be delivered at 200 ppm in 2 daily sessions (morning, evening; 9-12 hours apart) for 14 days. Each session will last 30 minutes, for a total of 60 minutes/day for each patient. A tank of NO gas will be connected to the inspiratory limb of the circuit, and the flow will be adjusted to deliver a target concentration of 200 ppm NO. Commercially available tanks will be used to provide the gas. The desired mixture of air, oxygen (O2), and NO will be titrated with the respective flowmeter to reach a concentration of 200 ppm at the inspiratory limb with the desired Fraction of inspired oxygen (FiO2).</description>
    <arm_group_label>NO High Concentration</arm_group_label>
    <other_name>Nitric Oxide inhalation at high concentration</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitric Oxide-Continuous and Sessions</intervention_name>
    <description>Nitric Oxide will be delivered at 200 ppm in 2 daily sessions (morning, evening; 9-12 hours apart) for 14 days. Each session will last 30 minutes, for a total of 60 minutes/day for each patient. A tank of NO gas will be connected to the inspiratory limb of the circuit, and the flow will be adjusted to deliver a target concentration of 200 ppm NO. Commercially available tanks will be used to provide the gas. The desired mixture of air, oxygen (O2), and NO will be titrated with the respective flowmeter to reach a concentration of 200 ppm at the inspiratory limb with the desired Fraction of inspired oxygen (FiO2).&#xD;
The subjects assigned to the group &quot;NO High Concentration + Continuous Low Concentration&quot; will receive in adjunction a continuous dose of NO at 20 ppm.</description>
    <arm_group_label>NO High Concentration + Continuous Low Concentration</arm_group_label>
    <other_name>Nitric Oxide inhalation at high concentration + low concentration</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  COVID-19 confirmed by a positive RT-PCR test&#xD;
&#xD;
          -  Hospital admission within 11 days from the onset of symptoms&#xD;
&#xD;
          -  Spontaneous breathing with oxygen requirement ≥1 L/min&#xD;
&#xD;
          -  Expected discharge &gt; 96 hours at randomization&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Presence of a tracheostomy&#xD;
&#xD;
          -  Assistance by any non-invasive CPAP or NIV at the screening&#xD;
&#xD;
          -  Treatment with high flow nasal cannula at the screening&#xD;
&#xD;
          -  Clinical contraindication to the use of NO&#xD;
&#xD;
          -  Patients enrolled in another interventional trial&#xD;
&#xD;
          -  Hospitalized and confirmed diagnosis of COVID-19 for more than 7 days&#xD;
&#xD;
          -  Previous intubation for COVID-19&#xD;
&#xD;
          -  Subject not committed to full support (DNR, DNI or CMO)&#xD;
&#xD;
          -  Subject requiring oxygen at home for lung comorbidities&#xD;
&#xD;
          -  The primary cause of hospitalization not due to COVID-19&#xD;
&#xD;
          -  Subject receiving vasopressor at the time of screening&#xD;
&#xD;
          -  History of malignancy or other irreversible disease/conditions with 6-month mortality&#xD;
             &gt;50%&#xD;
&#xD;
          -  Oxygen saturation of 100% at screening, despite oxygen requirement&#xD;
&#xD;
          -  Patients on dialysis at the time of enrollment&#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>Nikolay O Kamenshchikov, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences</name>
      <address>
        <city>Tomsk</city>
        <zip>634012</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>July 16, 2020</study_first_submitted>
  <study_first_submitted_qc>July 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>January 24, 2023</last_update_submitted>
  <last_update_submitted_qc>January 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tomsk National Research Medical Center of the Russian Academy of Sciences</investigator_affiliation>
    <investigator_full_name>Nikolay Kamenshchikov</investigator_full_name>
    <investigator_title>Medical Doctor</investigator_title>
  </responsible_party>
  <keyword>Nitric Oxide gas</keyword>
  <keyword>COVID-19</keyword>
  <keyword>Hypoxemia</keyword>
  <keyword>Viral Pneumonia</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>
    <mesh_term>Coronavirus Infections</mesh_term>
    <mesh_term>Pneumonia, Viral</mesh_term>
    <mesh_term>Hypoxia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitric Oxide</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04476992
org study id: NICOR
nct id: NCT04476992
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Preliminary data support the effect of Nitric Oxide (NO) on improving the oxygenation in
      mechanically ventilated patients and spontaneously breathing patients with COVID-19. In vitro
      studies showed an antiviral effect of NO against SARS-coronavirus. The optimal therapeutic
      regimen of NO gas in spontaneously breathing hypoxemic patients with COVID-19 is not known.
      We hypothesize that high concentration inhaled NO with an adjunct of continuous low dose
      administration between the high concentration treatments can be safely administered in
      hypoxemic COVID-19 patients compared to the high dose treatment alone. Prolonged
      administration of NO gas may benefit the patients in terms of the severity of the clinical
      course and time to recovery. Together with a clinical effect on ventilation-perfusion
      matching, a prolonged regimen would allow also an increase in antiviral activity (dose and
      time-dependent).
Coronavirus disease 2019 (COVID-19) consists mainly of a respiratory infection that spans
      from a mild involvement of the upper respiratory tract to severe pneumonia leading to
      respiratory distress, shock, and death. Fever, cough, and dyspnea/tachypnea, together with
      myalgia and fatigue, have been identified as the most common presenting symptoms. Most of the
      patients remain in a state of mild upper respiratory tract disease for a relatively long
      period (a median of 8-10 days), after which a proportion of up to 25% may develop severe
      hypoxemia and ARDS with the necessity of mechanical ventilation. Deterioration with ICU
      admission (most likely in older patients with comorbidities) raises the incidence of
      mortality in a range that goes from 3.4 up to 61%. Moreover, ICU admission poses a
      significant strain in terms of healthcare resources. Thus, a treatment able to avoid the
      progression of the disease from the mild to the severe phases would have a substantial
      benefit both in terms of lives saved and hospital resources spared. However, at the time,
      only Remdesivir and Dexamethasone have shown some benefits in robust clinical trials.

      Nitric Oxide gas is a therapy currently approved for the treatment of pulmonary hypertension
      in newborns and is also used as rescue therapy in patients with acute respiratory distress
      syndrome (ARDS). The clinical role of NO gas in COVID-19 patients could be of particular
      relevance since there is in-vitro evidence of NO antiviral activity specifically against SARS
      coronavirus. At the time of the SARS pandemic, a small rescue trial on intubated patients
      with SARS showed that NO was effective in improving the oxygenation, fasten the resolution of
      chest X-ray abnormalities, and improve the clinical outcomes. Moreover, in vitro studies
      demonstrated that the NO-donor compound S-nitroso-N-acetylpenicillamine was able to increase
      the survival rate of in vitro mammalian cells infected with SARS-CoV. SARS-CoV and SARS-CoV-2
      share the same subgenus inside the family Coronaviridae. The literature seems to point
      towards an a-specific rather than pathogen-specific antimicrobial effect of NO. Thus, the
      role of exogenous inhaled NO as a viricidal agent during COVID-19 infection could be
      hypothesized.

      Nitric Oxide at high concentration has been found to be microbicidal but still safe in
      spontaneously breathing subjects in a phase I trial. There are several trials testing the
      efficacy of NO therapy in improving the outcome of COVID-19 patients. So far, only a
      retrospective observational study showed that NO gas is useful in improving the oxygenation
      in spontaneously breathing patients. However, the optimal therapeutic regimens and the
      efficacy of NO gas in improving the oxygenation in hypoxemic COVID-19 patients haven't been
      tested.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Change in Methemoglobin level at 48 hours
time frame: 48 hours
description: The primary outcome will be evaluated with the difference in Methemoglobin levels between the groups at 48 hours after randomization.
measure: Change in Methemoglobin level at 96 hours
time frame: 96 hours
description: The primary outcome will be evaluated with the difference in Methemoglobineamia between the groups at 96 hours after randomization.
measure: Improvement in oxygenation between the groups at 48 hours or at discharge if before 48 hours
time frame: 48 hours
description: The secondary outcome, "Improve the oxygenation at 48 hours," will be evaluated with the measure of the difference in oxygenation among the groups at 48 hours. Oxygenation will be measured in terms of the SpO2/FiO2 ratio.
measure: Improvement in oxygenation between the groups at 96 hours or at discharge if before 96 hours
time frame: 96 hours
description: The secondary outcome, "Improve the oxygenation at 96 hours," will be evaluated with the measure of the difference in oxygenation between the groups at 96 hours. Oxygenation will be measured in terms of the SpO2/FiO2 ratio.
measure: Rate of positive RT-PCR for SARS-CoV-2 between groups in 5 days, discharge, and 28 days
time frame: 28 days
description: The secondary outcome "difference in the rate of negative RT-PCR for SARS CoV-2" will be evaluated as the rate of negativization of the RT-PCR for SARS-CoV-2 at 5 days after randomization, at discharge and at 28 days after randomization.
measure: Time to clinical recovery among groups, defined as time to interruption of oxygen administration for 24 hours or discharge
time frame: 28 days
description: The secondary outcome "different time to clinical recovery" will be evaluated as the time between the randomization and the clinical indication to interrupt the administration of oxygen for 24 hours.
measure: Reduction in the inflammatory markers among groups
time frame: 7 days
description: The secondary outcome "Different reduction in inflammatory markers" will be evaluated as improvement in the inflammatory markers (IL-6; Ferritin; White Blood Cells; Leucocyte count; CRP; D-Dimer) observed in blood samples collected at day 1, 2, 3, 4, and 7 compared to the Baseline value.
measure: Rate of Acute Kidney Disease (AKI) between groups during hospitalization
time frame: 28 days
description: The secondary outcome "rate of AKI between groups" will be evaluated as the presence of a comparable rate of AKI during the hospital stay. The AKI will be defined according to the KDIGO classification.
measure: Difference in Katz score between groups
time frame: 28 days
description: The secondary outcome "Difference in Katz score between groups" will be evaluated as the difference in Katz Activities of Daily Living between Baseline and day 28. This questionnaire will coincide with the 28-day phone call to assess health status and survival.
measure: Effect of NO gas treatment on cardiovascular hemodynamics assessed using cardiac ultrasound in COVID-19 hypoxemic patients
time frame: 96 hours
description: 1. The exploratory outcome "Effect of nitric oxide on heart function in COVID-19 hypoxemic patients" will be evaluated as:
the changes observed in heart ultrasound at 48 and 96 hours (or at discharge) compared to the Baseline in all groups.
the changes observed in heart ultrasound during the administration of NO comparing pre-treatment, during treatment, and post-treatment.
measure: Effect of NO gas treatment on lung function evaluated with serial spirometry in COVID-19 hypoxemic patients
time frame: 96 hours
description: 2. The secondary outcome "Effect of NO gas on lung function in COVID-19 hypoxemic patients" will be evaluated as:
the changes observed in spirometry at 48 and 96 hours (or at discharge) compared to the Baseline in all groups.
the changes observed in spirometry during the administration of NO comparing pre-treatment, during treatment, and post-treatment.
arm group label: NO High Concentration
arm group type: Active Comparator
description: Nitric oxide will be delivered twice a day with a non-rebreathing system that allows a safe administration of Nitric Oxide gas at high concentrations limiting the amount of NO2 delivered to the patient.
arm group label: NO High Concentration + Continuous Low Concentration
arm group type: Experimental
description: Nitric oxide will be delivered twice a day with a non-rebreathing system that allows a safe administration of Nitric Oxide gas at high concentrations limiting the amount of NO2 delivered to the patient.
This arm will receive in addition a continuous low flow of Nitric Oxide at 20 ppm among the high concentration treatments.
intervention type: Drug
intervention name: Nitric Oxide-Sessions
description: Nitric Oxide will be delivered at 200 ppm in 2 daily sessions (morning, evening; 9-12 hours apart) for 14 days. Each session will last 30 minutes, for a total of 60 minutes/day for each patient. A tank of NO gas will be connected to the inspiratory limb of the circuit, and the flow will be adjusted to deliver a target concentration of 200 ppm NO. Commercially available tanks will be used to provide the gas. The desired mixture of air, oxygen (O2), and NO will be titrated with the respective flowmeter to reach a concentration of 200 ppm at the inspiratory limb with the desired Fraction of inspired oxygen (FiO2).
arm group label: NO High Concentration
other name: Nitric Oxide inhalation at high concentration
intervention type: Drug
intervention name: Nitric Oxide-Continuous and Sessions
description: Nitric Oxide will be delivered at 200 ppm in 2 daily sessions (morning, evening; 9-12 hours apart) for 14 days. Each session will last 30 minutes, for a total of 60 minutes/day for each patient. A tank of NO gas will be connected to the inspiratory limb of the circuit, and the flow will be adjusted to deliver a target concentration of 200 ppm NO. Commercially available tanks will be used to provide the gas. The desired mixture of air, oxygen (O2), and NO will be titrated with the respective flowmeter to reach a concentration of 200 ppm at the inspiratory limb with the desired Fraction of inspired oxygen (FiO2).
The subjects assigned to the group "NO High Concentration + Continuous Low Concentration" will receive in adjunction a continuous dose of NO at 20 ppm.
arm group label: NO High Concentration + Continuous Low Concentration
other name: Nitric Oxide inhalation at high concentration + low concentration
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nikolay O Kamenshchikov, M.D.
role: Principal Investigator
affiliation: Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences
facility: 
country: Russian Federation
responsible party type: Principal Investigator
investigator affiliation: Tomsk National Research Medical Center of the Russian Academy of Sciences
investigator full name: Nikolay Kamenshchikov
investigator title: Medical Doctor
mesh term: COVID-19
mesh term: Pneumonia
mesh term: Coronavirus Infections
mesh term: Pneumonia, Viral
mesh term: Hypoxia
mesh term: Nitric Oxide