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

• ClinicalTrials.gov Identifier: NCT04306393
• Recruitment Status: Active, not recruiting
• First Posted: March 12, 2020
• Last Update Posted: May 25, 2021
• 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

Tracking Information

• First Submitted Date: March 10, 2020
• First Posted Date: March 12, 2020
• Last Update Posted Date: May 25, 2021
• Actual Study Start Date: March 21, 2020
• Estimated Primary Completion Date: December 21, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 11, 2020)

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.

Original Primary Outcome Measures (submitted: March 10, 2020)

Improvement 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.

Current Secondary Outcome Measures (submitted: March 10, 2020)

• 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".
• 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".
• Survival at 28 days from enrollment [ Time Frame: 28 days ]
  Proportion of patients surviving at 28 days within each group and comparison between groups.
• Survival at 90 days from enrollment [ Time Frame: 90 days ]
  Proportion of patients surviving at 90 days within each group and comparison between groups.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: May 21, 2021)

• 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.
• 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.
• 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.
• 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.
• Ventilator-free days at 28 days [ Time Frame: 28 days ]
  Average days without need for mechanical ventilation within each group and comparison between groups.
• 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.
• ICU-free days at 28 days [ Time Frame: 28 days ]
  Average days out of ICU within each group and comparison between groups.
• ICU length of stay [ Time Frame: 90 days ]
  Average days of ICU admission within each group and comparison between groups.
• 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.
• 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.
• 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.
• Daily Vasoactive Inotropic Score [ Time Frame: 28 days ]
  Daily calculation of the vasoactive inotropic score in each group and comparison between groups.
• Requirement for VV-ECMO [ Time Frame: 28 days ]
  Proportion of patients requiring venous-venous extracorporeal membrane oxygenation within each group and comparison between groups.
• Daily Sequential Organ Failure Assessment [ Time Frame: 28 days ]
  Daily calculation of the sequential organ failure assessment within each group and comparison between groups.
• Hospital-free days at 28 days [ Time Frame: 28 days ]
  Average days after hospital discharge within each group and comparison between groups.
• Hospital length of stay [ Time Frame: 90 days ]
  Average days of hospital stay within each group and comparison between groups.

Original Other Pre-specified Outcome Measures (submitted: March 10, 2020)

• 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.
• 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.
• Mechanical support of circulation during the first 28 days [ Time Frame: 28 days ]
  Proportion of patients needing (i.e., ECMO, intra-aortic balloon pump, VADs) within each group and comparison between groups.
• 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.
• Ventilator-free days at 28 days [ Time Frame: 28 days ]
  Average days without need for mechanical ventilation within each group and comparison between groups.
• Time to SARS-CoV-2 rt-PCR negative in upper respiratory tract specimen [ Time Frame: 28 days ]
  Time to obtain first negative upper respiratory trait sample in the 2019-nCoV rt-PCR assay. Average within groups and comparison between groups.
• ICU-free days at 28 days [ Time Frame: 28 days ]
  Average days out of ICU within each group and comparison between groups.

Descriptive Information

• Brief Title: Nitric Oxide Gas Inhalation in Severe Acute Respiratory Syndrome in COVID-19
• Official Title: Nitric Oxide Gas Inhalation Therapy for Mechanically Ventilated Patients With Severe Acute Respiratory Syndrome Caused by SARS-CoV2: a Randomized Clinical Trial.
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Masking Description:

The patient is blinded to the treatment.

Primary Purpose: Treatment

Condition

• SARS (Severe Acute Respiratory Syndrome)
• Coronavirus

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.

Study Arms

• Experimental: Treatment Group
  Inhaled Nitric Oxide until PaO2/FiO2 >/= 300 mmHg
  Intervention: Drug: Nitric Oxide Gas
• No Intervention: Control Group

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, 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. pii: 2020.03.09.20033530. doi: 10.1101/2020.03.09.20033530.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 10, 2020): 200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 21, 2022
• Estimated Primary Completion Date: December 21, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Sweden, United States

Administrative Information

• NCT Number: NCT04306393
• Other Study ID Numbers: NO-SARS-COVID-19
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Lorenzo Berra, MD, Massachusetts General Hospital
• Study 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

• PRS Account: Massachusetts General Hospital
• Verification Date: May 2021