Nitric Oxide Therapy for COVID-19 Patients With Oxygen Requirement

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-07-24

Study Completion Date

2021-09-17

Brief Summary

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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).

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Detailed Description

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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.

Conditions

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Hypoxemia Pneumonia, Viral Coronavirus Infection

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

Nitric Oxide-Sessions

Intervention Type DRUG

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).

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.

Group Type EXPERIMENTAL

Nitric Oxide-Continuous and Sessions

Intervention Type DRUG

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.

Interventions

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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).

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Nitric Oxide inhalation at high concentration Nitric Oxide inhalation at high concentration + low concentration

Eligibility Criteria

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Inclusion Criteria

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

Exclusion Criteria

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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No