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

Primary Purpose

SARS (Severe Acute Respiratory Syndrome), Coronavirus

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Nitric Oxide Gas
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for SARS (Severe Acute Respiratory Syndrome)

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama
  • Louisiana State University Health Shreveport
  • Massachusetts General Hospital
  • Beth Israel Deaconess Medical Center
  • Danderyd Sjukhus AB

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Treatment Group

Control Group

Arm Description

Inhaled Nitric Oxide until PaO2/FiO2 >/= 300 mmHg

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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".
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".
Survival at 28 days from enrollment
Proportion of patients surviving at 28 days within each group and comparison between groups.
Survival at 90 days from enrollment
Proportion of patients surviving at 90 days within each group and comparison between groups.

Full Information

First Posted
March 10, 2020
Last Updated
June 20, 2022
Sponsor
Massachusetts General Hospital
Collaborators
Xijing Hospital, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Niguarda Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04306393
Brief Title
Nitric Oxide Gas Inhalation in Severe Acute Respiratory Syndrome in COVID-19
Acronym
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.
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
March 21, 2020 (Actual)
Primary Completion Date
December 21, 2021 (Actual)
Study Completion Date
June 15, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Xijing Hospital, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Niguarda Hospital

4. Oversight

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
Data Monitoring Committee
Yes

5. 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
SARS (Severe Acute Respiratory Syndrome), Coronavirus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
Masking Description
The patient is blinded to the treatment.
Allocation
Randomized
Enrollment
200 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment Group
Arm Type
Experimental
Arm Description
Inhaled Nitric Oxide until PaO2/FiO2 >/= 300 mmHg
Arm Title
Control Group
Arm Type
No Intervention
Intervention Type
Drug
Intervention Name(s)
Nitric Oxide Gas
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change of arterial oxygenation at 48 hours from enrollment
Description
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.
Time Frame
48 hours
Secondary Outcome Measure Information:
Title
Time to reach normoxemia during the first 28 days after enrollment
Description
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".
Time Frame
28 days
Title
Proportion of SARS-nCoV-2 free patients during the first 28 days after enrollment
Description
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".
Time Frame
28 days
Title
Survival at 28 days from enrollment
Description
Proportion of patients surviving at 28 days within each group and comparison between groups.
Time Frame
28 days
Title
Survival at 90 days from enrollment
Description
Proportion of patients surviving at 90 days within each group and comparison between groups.
Time Frame
90 days
Other Pre-specified Outcome Measures:
Title
Daily oxygenation in the two groups until day 28
Description
Expressed as PaO2/FiO2 ratio within each group and comparison between groups.
Time Frame
28 days
Title
Need for new renal replacement therapy during the first 28 days
Description
Proportion of patients needing RRT within each group and comparison between groups.
Time Frame
28 days
Title
Mechanical support of circulation during the first 28 days
Description
Proportion of patients needing mechanical support of circulation (i.e., ECMO, intra-aortic balloon pump, VADs) within each group and comparison between groups.
Time Frame
28 days
Title
Days free of vasopressors during the first 28 days
Description
Average days without need for vasopressors within each group and comparison between groups.
Time Frame
28 days
Title
Ventilator-free days at 28 days
Description
Average days without need for mechanical ventilation within each group and comparison between groups.
Time Frame
28 days
Title
Time to SARS-CoV-2 rt-PCR negative in upper respiratory tract specimen
Description
Time to obtain first negative upper respiratory tract sample in the 2019-nCoV rt-PCR assay. Average within groups and comparison between groups.
Time Frame
28 days
Title
ICU-free days at 28 days
Description
Average days out of ICU within each group and comparison between groups.
Time Frame
28 days
Title
ICU length of stay
Description
Average days of ICU admission within each group and comparison between groups.
Time Frame
90 days
Title
SARS-CoV-2 Viral Load in Sputum
Description
Number of copies of SARS-CoV-2 Viral Load measured with rt-PCR on sputum samples within each group and comparison between groups.
Time Frame
28 days
Title
SARS-CoV-2 Viral Load in Plasma
Description
Number of copies of SARS-CoV-2 Viral Load measured with rt-PCR on blood samples within each group and comparison between groups.
Time Frame
28 days
Title
Acute Kidney Injury at 28 days
Description
Proportion of patients with acute kidney injury and severity of acute kidney injury within each group and comparison between groups.
Time Frame
28 days
Title
Daily Vasoactive Inotropic Score
Description
Daily calculation of the vasoactive inotropic score in each group and comparison between groups.
Time Frame
28 days
Title
Requirement for VV-ECMO
Description
Proportion of patients requiring venous-venous extracorporeal membrane oxygenation within each group and comparison between groups.
Time Frame
28 days
Title
Daily Sequential Organ Failure Assessment
Description
Daily calculation of the sequential organ failure assessment within each group and comparison between groups.
Time Frame
28 days
Title
Hospital-free days at 28 days
Description
Average days after hospital discharge within each group and comparison between groups.
Time Frame
28 days
Title
Hospital length of stay
Description
Average days of hospital stay within each group and comparison between groups.
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lorenzo Berra, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Louisiana State University Health Shreveport
City
Shreveport
State/Province
Louisiana
ZIP/Postal Code
71103
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Danderyd Sjukhus AB
City
Danderyd
State/Province
Stockholm
ZIP/Postal Code
18288
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33783269
Citation
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.
Results Reference
derived
PubMed Identifier
32511534
Citation
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.
Results Reference
derived

Learn more about this trial

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

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