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Nitric Oxide Therapy for COVID-19 Patients With Oxygen Requirement (NICOR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04476992
Recruitment Status : Active, not recruiting
First Posted : July 20, 2020
Last Update Posted : April 6, 2021
Sponsor:
Collaborator:
Siberian State Medical University
Information provided by (Responsible Party):
Nikolay O. Kamenshchikov, Tomsk National Research Medical Center of the Russian Academy of Sciences

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Hypoxemia Pneumonia, Viral Coronavirus Infection Drug: Nitric Oxide-Sessions Drug: Nitric Oxide-Continuous and Sessions Phase 1 Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Safety Study on the Use of Intermittent Versus Continuous Inhalation of NO in Spontaneous Breathing COVID-19 Patients
Actual Study Start Date : July 24, 2020
Estimated Primary Completion Date : July 17, 2021
Estimated Study Completion Date : September 17, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: NO High Concentration
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.
Drug: Nitric Oxide-Sessions
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).
Other Name: Nitric Oxide inhalation at high concentration

Experimental: NO High Concentration + Continuous Low Concentration

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.

Drug: Nitric Oxide-Continuous and Sessions

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.

Other Name: Nitric Oxide inhalation at high concentration + low concentration




Primary Outcome Measures :
  1. Change in Methemoglobin level at 48 hours [ Time Frame: 48 hours ]
    The primary outcome will be evaluated with the difference in Methemoglobin levels between the groups at 48 hours after randomization.


Secondary Outcome Measures :
  1. Change in Methemoglobin level at 96 hours [ Time Frame: 96 hours ]
    The primary outcome will be evaluated with the difference in Methemoglobineamia between the groups at 96 hours after randomization.

  2. Improvement in oxygenation between the groups at 48 hours or at discharge if before 48 hours [ Time Frame: 48 hours ]
    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.

  3. Improvement in oxygenation between the groups at 96 hours or at discharge if before 96 hours [ Time Frame: 96 hours ]
    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.

  4. Rate of positive RT-PCR for SARS-CoV-2 between groups in 5 days, discharge, and 28 days [ Time Frame: 28 days ]
    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.

  5. Time to clinical recovery among groups, defined as time to interruption of oxygen administration for 24 hours or discharge [ Time Frame: 28 days ]
    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.

  6. Reduction in the inflammatory markers among groups [ Time Frame: 7 days ]
    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.

  7. Rate of Acute Kidney Disease (AKI) between groups during hospitalization [ Time Frame: 28 days ]
    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.

  8. Difference in Katz score between groups [ Time Frame: 28 days ]
    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.


Other Outcome Measures:
  1. Effect of NO gas treatment on cardiovascular hemodynamics assessed using cardiac ultrasound in COVID-19 hypoxemic patients [ Time Frame: 96 hours ]

    1. The exploratory outcome "Effect of nitric oxide on heart function in COVID-19 hypoxemic patients" will be evaluated as:

    1. the changes observed in heart ultrasound at 48 and 96 hours (or at discharge) compared to the Baseline in all groups.
    2. the changes observed in heart ultrasound during the administration of NO comparing pre-treatment, during treatment, and post-treatment.

  2. Effect of NO gas treatment on lung function evaluated with serial spirometry in COVID-19 hypoxemic patients [ Time Frame: 96 hours ]

    2. The secondary outcome "Effect of NO gas on lung function in COVID-19 hypoxemic patients" will be evaluated as:

    1. the changes observed in spirometry at 48 and 96 hours (or at discharge) compared to the Baseline in all groups.
    2. the changes observed in spirometry during the administration of NO comparing pre-treatment, during treatment, and post-treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. COVID-19 confirmed by a positive RT-PCR test
  2. Hospital admission within 11 days from the onset of symptoms
  3. Spontaneous breathing with oxygen requirement ≥1 L/min
  4. Expected discharge > 96 hours at randomization

Exclusion Criteria:

  1. Pregnancy
  2. Presence of a tracheostomy
  3. Assistance by any non-invasive CPAP or NIV at the screening
  4. Treatment with high flow nasal cannula at the screening
  5. Clinical contraindication to the use of NO
  6. Patients enrolled in another interventional trial
  7. Hospitalized and confirmed diagnosis of COVID-19 for more than 7 days
  8. Previous intubation for COVID-19
  9. Subject not committed to full support (DNR, DNI or CMO)
  10. Subject requiring oxygen at home for lung comorbidities
  11. The primary cause of hospitalization not due to COVID-19
  12. Subject receiving vasopressor at the time of screening
  13. History of malignancy or other irreversible disease/conditions with 6-month mortality >50%
  14. Oxygen saturation of 100% at screening, despite oxygen requirement
  15. Patients on dialysis at the time of enrollment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04476992


Locations
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Russian Federation
Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences
Tomsk, Russian Federation, 634012
Sponsors and Collaborators
Tomsk National Research Medical Center of the Russian Academy of Sciences
Siberian State Medical University
Investigators
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Principal Investigator: Nikolay O Kamenshchikov, M.D. Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences
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Responsible Party: Nikolay O. Kamenshchikov, Medical Doctor, Tomsk National Research Medical Center of the Russian Academy of Sciences
ClinicalTrials.gov Identifier: NCT04476992    
Other Study ID Numbers: 8322/1
First Posted: July 20, 2020    Key Record Dates
Last Update Posted: April 6, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Nikolay O. Kamenshchikov, Tomsk National Research Medical Center of the Russian Academy of Sciences:
Nitric Oxide gas
COVID-19
Hypoxemia
Viral Pneumonia
Additional relevant MeSH terms:
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Coronavirus Infections
Pneumonia, Viral
Pneumonia
Hypoxia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Signs and Symptoms, Respiratory
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents