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

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ClinicalTrials.gov Identifier: NCT04306393
Recruitment Status : Active, not recruiting
First Posted : March 12, 2020
Last Update Posted : May 25, 2021
Sponsor:
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  ICMJE March 10, 2020
First Posted Date  ICMJE March 12, 2020
Last Update Posted Date May 25, 2021
Actual Study Start Date  ICMJE March 21, 2020
Estimated Primary Completion Date December 21, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE 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  ICMJE Nitric Oxide Gas Inhalation in Severe Acute Respiratory Syndrome in COVID-19
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Masking Description:
The patient is blinded to the treatment.
Primary Purpose: Treatment
Condition  ICMJE
  • SARS (Severe Acute Respiratory Syndrome)
  • Coronavirus
Intervention  ICMJE 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  ICMJE
  • Experimental: Treatment Group
    Inhaled Nitric Oxide until PaO2/FiO2 >/= 300 mmHg
    Intervention: Drug: Nitric Oxide Gas
  • No Intervention: Control Group
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 10, 2020)
200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 21, 2022
Estimated Primary Completion Date December 21, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04306393
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Lorenzo Berra, MD, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE
  • Xijing Hospital
  • Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
  • Niguarda Hospital
Investigators  ICMJE
Study Director: Lorenzo Berra, MD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP