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.

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