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

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

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

Study Overview

• Status: Completed
• Conditions: Coronavirus; SARS (Severe Acute Respiratory Syndrome)
• Intervention / Treatment: Drug: Nitric Oxide Gas

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Stockholm County
    • Danderyd, Stockholm County, Sweden, 18288
      • Danderyd Sjukhus AB
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Shreveport
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control Group
Experimental: Treatment Group; Inhaled Nitric Oxide until PaO2/FiO2 >/= 300 mmHg	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Proportion of SARS-nCoV-2 Free Patients During the First 28 Days After Enrollment	Proportion of patients in each group who achieved a PaO₂/FiO₂ ratio >300 for at least 24 consecutive hours during the first 28 days after enrollment. Patients who died before day 28 were classified as "never recovered."	28 days
Survival at 28 Days From Enrollment	Proportion of patients surviving at 28 days within each group and comparison between groups.	28 days
Survival at 90 Days From Enrollment	Proportion of patients surviving at 90 days within each group and comparison between groups.	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Daily Vasoactive Inotropic Score	Daily calculation of the vasoactive inotropic score in each group and comparison between groups.	28 days
Requirement for VV-ECMO	Proportion of patients requiring venous-venous extracorporeal membrane oxygenation within each group and comparison between groups.	28 days
Daily Sequential Organ Failure Assessment	Daily calculation of the sequential organ failure assessment within each group and comparison between groups.	28 days
Daily Oxygenation in the Two Groups Until Day 28	Expressed as PaO2/FiO2 ratio within each group and comparison between groups.	28 days
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
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
Days Free of Vasopressors During the First 28 Days	Average days without need for vasopressors within each group and comparison between groups.	28 days
Ventilator-free Days at 28 Days	Average days without need for mechanical ventilation within each group and comparison between groups.	28 days
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
ICU-free Days at 28 Days	Average days out of ICU within each group and comparison between groups.	28 days
ICU Length of Stay	Average days of ICU admission within each group and comparison between groups.	90 days
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
Hospital-free Days at 28 Days	Average days after hospital discharge within each group and comparison between groups.	28 days
Hospital Length of Stay	Average days of hospital stay within each group and comparison between groups.	90 days

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Xijing Hospital; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; Niguarda Hospital
• Investigators: Study Director: Lorenzo Berra, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Gibson LE, Fenza RD, Lang M, Capriles MI, Li MD, Kalpathy-Cramer J, Little BP, Arora P, Mueller AL, Ichinose F, Bittner EA, Berra L, G Chang M. Right Ventricular Strain Is Common in Intubated COVID-19 Patients and Does Not Reflect Severity of Respiratory Illness. J Intensive Care Med. 2021 Aug;36(8):900-909. doi: 10.1177/08850666211006335. Epub 2021 Mar 30.
• Lei C, Su B, Dong H, Bellavia A, Fenza RD, Fakhr BS, Gianni S, Grassi LG, Kacmarek R, Morais CCA, Pinciroli R, Vassena E, Berra L. Protocol of a randomized controlled trial testing inhaled Nitric Oxide in mechanically ventilated patients with severe acute respiratory syndrome in COVID-19 (SARS-CoV-2). medRxiv [Preprint]. 2020 May 24:2020.03.09.20033530. doi: 10.1101/2020.03.09.20033530.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2020
• Primary Completion (Actual): December 21, 2021
• Study Completion (Actual): June 15, 2022

Study Registration Dates

• First Submitted: March 10, 2020
• First Submitted That Met QC Criteria: March 10, 2020
• First Posted (Actual): March 12, 2020

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Coronaviridae Infections; Nidovirales Infections; Coronavirus Infections; Severe Acute Respiratory Syndrome; Vasodilator Agents; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Cardiovascular Agents; Endothelium-Dependent Relaxing Factors
• Other Study ID Numbers: NO-SARS-COVID-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No