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

• ClinicalTrials.gov Identifier: NCT04306393
• Recruitment Status: Completed
• First Posted: March 12, 2020
• Last Update Posted: June 22, 2022
• Sponsor: Massachusetts General Hospital
• Collaborators: Xijing Hospital; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; Niguarda Hospital
• Information provided by (Responsible Party): Lorenzo Berra, MD, Massachusetts General Hospital

Study Description

Brief 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

Condition or disease	Intervention/treatment	Phase
SARS (Severe Acute Respiratory Syndrome); Coronavirus	Drug: Nitric Oxide Gas	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Masking Description: The patient is blinded to the treatment.
• Primary Purpose: Treatment
• Official Title: Nitric Oxide Gas Inhalation Therapy for Mechanically Ventilated Patients With Severe Acute Respiratory Syndrome Caused by SARS-CoV2: a Randomized Clinical Trial.
• Actual Study Start Date: March 21, 2020
• Actual Primary Completion Date: December 21, 2021
• Actual Study Completion Date: June 15, 2022

Arms and Interventions

Arm	Intervention/treatment
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.
No Intervention: Control Group

Outcome Measures

Primary Outcome Measures :

1. Change of arterial oxygenation at 48 hours from enrollment [ Time Frame: 48 hours ]
   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.

Secondary Outcome Measures :

1. Time to reach normoxemia during the first 28 days after enrollment [ Time Frame: 28 days ]
   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".
2. Proportion of SARS-nCoV-2 free patients during the first 28 days after enrollment [ Time Frame: 28 days ]
   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".
3. Survival at 28 days from enrollment [ Time Frame: 28 days ]
   Proportion of patients surviving at 28 days within each group and comparison between groups.
4. Survival at 90 days from enrollment [ Time Frame: 90 days ]
   Proportion of patients surviving at 90 days within each group and comparison between groups.

Other Outcome Measures:

1. Daily oxygenation in the two groups until day 28 [ Time Frame: 28 days ]
   Expressed as PaO2/FiO2 ratio within each group and comparison between groups.
2. Need for new renal replacement therapy during the first 28 days [ Time Frame: 28 days ]
   Proportion of patients needing RRT within each group and comparison between groups.
3. Mechanical support of circulation during the first 28 days [ Time Frame: 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.
4. Days free of vasopressors during the first 28 days [ Time Frame: 28 days ]
   Average days without need for vasopressors within each group and comparison between groups.
5. Ventilator-free days at 28 days [ Time Frame: 28 days ]
   Average days without need for mechanical ventilation within each group and comparison between groups.
6. Time to SARS-CoV-2 rt-PCR negative in upper respiratory tract specimen [ Time Frame: 28 days ]
   Time to obtain first negative upper respiratory tract sample in the 2019-nCoV rt-PCR assay. Average within groups and comparison between groups.
7. ICU-free days at 28 days [ Time Frame: 28 days ]
   Average days out of ICU within each group and comparison between groups.
8. ICU length of stay [ Time Frame: 90 days ]
   Average days of ICU admission within each group and comparison between groups.
9. SARS-CoV-2 Viral Load in Sputum [ Time Frame: 28 days ]
   Number of copies of SARS-CoV-2 Viral Load measured with rt-PCR on sputum samples within each group and comparison between groups.
10. SARS-CoV-2 Viral Load in Plasma [ Time Frame: 28 days ]
    Number of copies of SARS-CoV-2 Viral Load measured with rt-PCR on blood samples within each group and comparison between groups.
11. Acute Kidney Injury at 28 days [ Time Frame: 28 days ]
    Proportion of patients with acute kidney injury and severity of acute kidney injury within each group and comparison between groups.
12. Daily Vasoactive Inotropic Score [ Time Frame: 28 days ]
    Daily calculation of the vasoactive inotropic score in each group and comparison between groups.
13. Requirement for VV-ECMO [ Time Frame: 28 days ]
    Proportion of patients requiring venous-venous extracorporeal membrane oxygenation within each group and comparison between groups.
14. Daily Sequential Organ Failure Assessment [ Time Frame: 28 days ]
    Daily calculation of the sequential organ failure assessment within each group and comparison between groups.
15. Hospital-free days at 28 days [ Time Frame: 28 days ]
    Average days after hospital discharge within each group and comparison between groups.
16. Hospital length of stay [ Time Frame: 90 days ]
    Average days of hospital stay within each group and comparison between groups.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama

Birmingham, Alabama, United States, 35294

United States, Louisiana

Louisiana State University Health Shreveport

Shreveport, Louisiana, United States, 71103

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

Sweden

Danderyd Sjukhus AB

Danderyd, Stockholm, Sweden, 18288

Sponsors and Collaborators

Massachusetts General Hospital

Xijing Hospital

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Niguarda Hospital

Investigators

• Study Director: Lorenzo Berra, MD; Massachusetts General Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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, Di Fenza R, Safaee Fakhr B, Gianni S, Grassi LG, Kacmarek R, Araujo Morais CC, 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. 2020 Mar 13:2020.03.09.20033530. doi: 10.1101/2020.03.09.20033530. Preprint.

• Responsible Party: Lorenzo Berra, MD, Medical Doctor, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT04306393
• Other Study ID Numbers: NO-SARS-COVID-19
• First Posted: March 12, 2020
• Last Update Posted: June 22, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Severe Acute Respiratory Syndrome; Syndrome; Disease; Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Diseases; Respiratory Tract Infections; Nitric Oxide; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Free Radical Scavengers; Antioxidants; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Endothelium-Dependent Relaxing Factors; Vasodilator Agents; Gasotransmitters; Protective Agents