Nitric Oxide Gas Inhalation for Severe Acute Respiratory Syndrome in COVID-19.

Study Overview
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Brief Summary
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The investigators will enroll 104 patients with severe COVID-19 infection that mechanical ventilation is needed for respiratory support. Patients will be randomized to receive either inhaled nitric oxide (per protocol) or a placebo. ICU Standards of care will be the institution's own protocols (such as ventilation strategies and use and dose of antivirals and antimicrobials, steroids, inotropic and vasopressor agents).

Detailed Description
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The outbreak of COVID-19 and its global pandemic have posed a threat to public health. The deadly virus, SARS-CoV-2, has been evolving to new, more infectious variant and other lineages with additional immune escape mutations. The highly transmissible Omicron variant has been present for around one year and has supplanted Delta as the leading strain in the global pandemic. Although the severity of symptoms caused by the Omicron variant is significantly reduced when compared to its earlier variants, people who are infected with Omicron have the full spectrum of disease, everything from asymptomatic infection all the way through severe disease and death. People with underlying conditions, advanced age, and unvaccinated can have a severe form of COVID-19 following infection from Omicron. On December 7, 2022, the State Council of China issued an announcement on further optimization of measures for preventing and controlling the COVID-19 epidemic ( easing of rigorous zero COVID policies). Since then, the rapid spread of COVID-19 has caused surge of COVID-19 infections in majority of China, which caused a dramatic increase of severe cases. In severe cases with COVID-19 infection significantly affects the respiratory functions by massively disrupting the pulmonary oxygenation and activating the synthesis of proinflammatory cytokines, inducing severe oxidative stress, enhanced vascular permeability, and endothelial dysfunction which have rendered researchers and clinicians to depend on prophylactic treatment due to the unavailability of proper disease management approaches. Inhaled nitric oxide gas (NO) has shown antiviral activity against Coronavirus during the 2003 SARS outbreak. Previous studies have indicated that nitric oxide (NO) application appears to be significant concerning the antiviral activities, antioxidant, and anti-inflammatory properties in relieving disease-related symptoms. Inhaled nitric oxide had been widely used during the Covid-19 pandemic. In the scoping and systemic reviews, it was demonstrated that nitric oxide inhalation was effective in improve oxygenation, cardiopulmonary function, and fasten virus clearance. The investigators designed this study to assess whether inhaled NO improves respiratory recovery in patients affected with severe COVID-19 infection. Here, the investigators propose a randomized clinical trial aimed to improve recovery of the disease in patients with severe acute respiratory syndrome. Control group: the institutional standard of care will be delivered. Treatment group: In addition to standard therapy, the subjects will receive inhalation of NO. Inspired NO/N2 will be delivered at 80 parts per million (ppm) in the first 48 hours of enrollment (within 48 hours after initiation of mechanical ventilation). Weaning from NO will start after 48-h consecutive NO inhalation. Physician will follow their own institutional weaning protocols. In the absence of institutional protocols, NO will be reduced every 4 hours in step-wise fashion starting from 40 ppm to 20, 10, 5, 3, 2 and 1 ppm. If hypoxemia (SpO2 < 93%) or acute hypotension (systolic blood pressure < 90 mmHg) occurs during weaning, NO should be increased to a prior higher concentration. Safety: prolonged treatment with inhaled NO can lead to increased methemoglobin levels. Blood levels of methemoglobin will be monitored via a non-invasive CO-oximeter or MetHb levels in blood. If methemoglobin levels rise above 5% at any point of the study, inhaled NO concentration will be halved.

Official Title
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Nitric Oxide Gas Inhalation Therapy for Severe Acute Respiratory Syndrome Due to COVID-19.

Conditions
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Coronavirus Covid-19 Infection Variant Omicron, SARS (Severe Acute Respiratory Syndrome)

Intervention / Treatment
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* Drug: Nitric Oxide Gas
* Other: The delivery system will be set up anyway without study gas administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Diagnosed Covid-19 infection Severe cases of Covid-19 infection needs mechanical ventilation Exclusion Criteria: Physician makes a decision that trial involvement is not in the patient's best interest or any condition that does not allow the protocol to be followed safely Pregnant or positive pregnancy test in a pre-dose examination mechanical ventilation initiated for more than 48 hrs Rescue Use ECMO With severe organ dysfunction or failure (Child Pugh≥12, eGFRC30 ml/min/1.73m2, on RRT or dialysis)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group<br>Nitric Oxide gas will be administered in the ventilatory circuit. | Drug: Nitric Oxide Gas<br>* Inspired NO/N2 will be delivered at 80 parts per million (ppm) in the first 48 hours of enrollment (within 48 hours after initiation of mechanical ventilation). Weaning from NO will start after 48-h consecutive NO inhalation. The physicians will follow their own institutional weaning protocols.<br>* Other names: Nitric Oxide inhalation;|
| Sham Comparator: Control Group<br>The delivery system will be set up anyway without study gas administration | Other: The delivery system will be set up anyway without study gas administration<br>* The delivery system will be set up anyway without study gas administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilation free days (VFDs) | count the days that patients do not need mechanical ventilation | 28 days since beginning of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at 28 days | count the number of patients that survive to 28 days after randomization | 28 days | 
| Survival at 90 days | count the number of patients that survive to 90 days after randomization | 90 days | 
| WHO COVID Ordinal Outcomes Scale | 8 score scale, where no limitation of activity =1, death = 8 | 28 days | 
| time to improvement of oxygenation | time from randomization to PaO2/FiO2 ≥300 at room air | through oxygenation improvement, an average of 2 days | 
| MODS needs life support | Incidence of organ failure need support of RRT, VA-ECMO, LVAD, IABP, Prone ventilation, etc | 28 days | 
| duration of mechanical ventilation | days when mechanical ventilation are used | through wean of mechanical ventilation, an average of 10 days | 
| Length of ICU stay and hospital stay | count days when patients stay in ICU and hospital | through discharge from ICU or hospital, an average of 20 days | 
| SOFA score | Sequential (sepsis-related) organ failure assessment (SOFA) score. | at 48 hours, 72 hours, and 7 days after randomization |