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

Phase 2

Withdrawn

• Conditions: Coronavirus Covid-19 Infection Variant Omicron; SARS (Severe Acute Respiratory Syndrome)
• Interventions: Drug: Nitric Oxide Gas; Other: The delivery system will be set up anyway without study gas administration

• Registration Number: NCT04290871
• Lead Sponsor: Xijing Hospital

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-02-27
• Study First Submitted QC: 2020-02-27
• Study First Posted: 2020-03-02
• Study Start: 2023-01-16
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-05
• Last Update Posted: 2023-02-08
• Primary Completion: 2023-12-31
• Study Completion: 2024-04-01

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Age ≥18 years
2. Diagnosed Covid-19 infection
3. Severe cases of Covid-19 infection needs mechanical ventilation

Exclusion Criteria

1. 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
2. Pregnant or positive pregnancy test in a pre-dose examination
3. mechanical ventilation initiated for more than 48 hrs
4. Rescue Use ECMO
5. With severe organ dysfunction or failure (Child Pugh≥12, eGFRC30 ml/min/1.73m2, on RRT or dialysis)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment Group	Nitric Oxide Gas	Nitric Oxide gas will be administered in the ventilatory circuit.
Control Group	The delivery system will be set up anyway without study gas administration	The delivery system will be set up anyway without study gas administration

Primary Outcome Measures

Name	Time	Method
Ventilation free days (VFDs)	28 days since beginning of treatment	count the days that patients do not need mechanical ventilation

Secondary Outcome Measures

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