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

Coronavirus Clinical Trial

— NOSARSCOVID  

Official title:

Nitric Oxide Gas Inhalation Therapy for Mechanically Ventilated Patients With Severe Acute Respiratory Syndrome Caused by SARS-CoV2: a Randomized Clinical Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04306393
• Other study ID #: NO-SARS-COVID-19
• Status: Completed
• Phase: Phase 2
• Start date: March 21, 2020
• Est. completion date: June 15, 2022

Study information

• Verified date: June 2022
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Severe acute respiratory syndrome (SARS-CoV2) due to novel Coronavirus (2019-nCoV) related infection (COVID-19) is characterized by severe ventilation perfusion mismatch leading to refractory hypoxemia. To date, there is no specific treatment available for 2019-nCoV. Nitric oxide is a selective pulmonary vasodilator gas used in as a rescue therapy in refractory hypoxemia due to acute respiratory distress syndrome (ARDS). In-vitro and clinical evidence indicate that inhaled nitric oxide gas (iNO) has also antiviral activity against other strains of coronavirus. The primary aim of this study is to determine whether inhaled NO improves oxygenation in patients with hypoxic SARS-CoV2. This is a multicenter single-blinded randomized controlled trial with 1:1 individual allocation

Description:

Severe acute respiratory syndrome (SARS-CoV-2) due to novel Coronavirus (2019-nCoV) related infection (COVID-19) is characterized by severe ventilation perfusion mismatch leading to refractory hypoxemia. To date, there is no specific treatment available for 2019-nCoV. Nitric oxide is a selective pulmonary vasodilator gas used as a rescue therapy in refractory hypoxemia due to acute respiratory distress syndrome (ARDS). In has also shown in-vitro and clinical evidence that inhaled nitric oxide gas (iNO) has antiviral activity against other strains of coronavirus.

The primary aim of this study is to determine whether inhaled NO improves oxygenation in patients with hypoxic SARS-CoV2.

This is a multicenter randomized controlled trial with 1:1 individual allocation. Patients will be blinded to the treatment.

Intubated patients admitted to the intensive care unit with confirmed SARS-CoV-2 infection and severe hypoxemia will be randomized to receive inhalation of NO (treatment group) or not (control group). Treatment will be stopped when patients are free from hypoxemia for more than 24 hours.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: June 15, 2022
• Est. primary completion date: December 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion criteria: (1) Adult patients, >/= 18 year-old; (2) Patients admitted to the ICU; (3) Patients who are intubated and mechanically ventilated; (4) Confirmed diagnosis of SARS-CoV2 by positive rt-PCR.

Exclusion criteria: (1) Patients intubated for more than 72 hours from initiation of the treatment gas; (2) Subjects enrolled in another interventional research study; (3) Physician of record opposed to enrolling the patient due to perceived safety concerns; or any condition that does not allow the protocol to be followed safely; (4) Subjects with past medical history of lung malignancy or pneumonectomy or lung transplant; (5) Subjects receiving a tidal volume < 3 cc/kg of ideal body weight at the time of enrollment; (6) Subjects with severe burns involving more than 40% of Total Body Surface Area; (7) Subjects that have experienced cardiac arrest with CPR for longer than 30 minutes; (8) Subjects with a presumed severe deficit in cerebral function with fixed dilated pupil; (9) Subjects receiving renal replacement therapy at the time of enrollment; (10) Subjects who have an impaired ability to ventilate without assistance; (11) Subjects who have a history of malignancy or other irreversible disease/conditions with a 6-month mortality > 50%; (12) Subjects not fully committed to full support at the time of enrollment; (13) Subject receiving inhaled nitric oxide gas prior to enrollment; (14) Subject's hospital admission unrelated to COVID-19.

Related Conditions & MeSH terms

• Coronavirus
• SARS (Severe Acute Respiratory Syndrome)
• Severe Acute Respiratory Syndrome
• Syndrome

Intervention

Drug:
• Nitric Oxide Gas
80 ppm of inhaled nitric oxide for 48 hours, followed by 40 ppm, followed by weaning before stop. Weaning criteria: maintenance of a PaO2/FiO2 ratio >/= 300 for at least 24 hours consecutively.

Locations

Country	Name	City	State
Sweden	Danderyd Sjukhus AB	Danderyd	Stockholm
United States	University of Alabama	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Louisiana State University Health Shreveport	Shreveport	Louisiana

Sponsors (4)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Niguarda Hospital, Xijing Hospital

Countries where clinical trial is conducted

United States,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Daily oxygenation in the two groups until day 28	Expressed as PaO2/FiO2 ratio within each group and comparison between groups.	28 days
Other	Need for new renal replacement therapy during the first 28 days	Proportion of patients needing RRT within each group and comparison between groups.	28 days
Other	Mechanical support of circulation during the first 28 days	Proportion of patients needing mechanical support of circulation (i.e., ECMO, intra-aortic balloon pump, VADs) within each group and comparison between groups.	28 days
Other	Days free of vasopressors during the first 28 days	Average days without need for vasopressors within each group and comparison between groups.	28 days
Other	Ventilator-free days at 28 days	Average days without need for mechanical ventilation within each group and comparison between groups.	28 days
Other	Time to SARS-CoV-2 rt-PCR negative in upper respiratory tract specimen	Time to obtain first negative upper respiratory tract sample in the 2019-nCoV rt-PCR assay. Average within groups and comparison between groups.	28 days
Other	ICU-free days at 28 days	Average days out of ICU within each group and comparison between groups.	28 days
Other	ICU length of stay	Average days of ICU admission within each group and comparison between groups.	90 days
Other	SARS-CoV-2 Viral Load in Sputum	Number of copies of SARS-CoV-2 Viral Load measured with rt-PCR on sputum samples within each group and comparison between groups.	28 days
Other	SARS-CoV-2 Viral Load in Plasma	Number of copies of SARS-CoV-2 Viral Load measured with rt-PCR on blood samples within each group and comparison between groups.	28 days
Other	Acute Kidney Injury at 28 days	Proportion of patients with acute kidney injury and severity of acute kidney injury within each group and comparison between groups.	28 days
Other	Daily Vasoactive Inotropic Score	Daily calculation of the vasoactive inotropic score in each group and comparison between groups.	28 days
Other	Requirement for VV-ECMO	Proportion of patients requiring venous-venous extracorporeal membrane oxygenation within each group and comparison between groups.	28 days
Other	Daily Sequential Organ Failure Assessment	Daily calculation of the sequential organ failure assessment within each group and comparison between groups.	28 days
Other	Hospital-free days at 28 days	Average days after hospital discharge within each group and comparison between groups.	28 days
Other	Hospital length of stay	Average days of hospital stay within each group and comparison between groups.	90 days
Primary	Change of arterial oxygenation at 48 hours from enrollment	Difference within groups in terms of PaO2/FiO2 ratio. If a patient dies during the first 48 hours of treatment, the last available blood gas analysis will be used.	48 hours
Secondary	Time to reach normoxemia during the first 28 days after enrollment	Time to recover gas exchange to a PaO2/FiO2 =/> 300 for at least 24 hours during the first 28 days after enrollment, within each group and comparison between groups. If the patient dies before day 28, the patient will be considered as "never recovered".	28 days
Secondary	Proportion of SARS-nCoV-2 free patients during the first 28 days after enrollment	Daily proportion of patients with a PaO2/FiO2 ratio > 300 for at least 24 hours within each group and comparison between groups. If a patient dies before day 28, the patient will be considered as "never recovered".	28 days
Secondary	Survival at 28 days from enrollment	Proportion of patients surviving at 28 days within each group and comparison between groups.	28 days
Secondary	Survival at 90 days from enrollment	Proportion of patients surviving at 90 days within each group and comparison between groups.	90 days