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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04290871
Recruitment Status : Withdrawn (A new coordinating center has been defined (Massachusetts General Hospital))
First Posted : March 2, 2020
Last Update Posted : March 24, 2020
Sponsor:
Collaborators:
Massachusetts General Hospital
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Information provided by (Responsible Party):
chonglei, Xijing Hospital

Brief Summary:
The investigators will enroll 102 patients with a confirmed diagnosis of COVID-19. Patients will be randomized to receive either inhaled nitric oxide (per protocol) or placebo. ICU Standards of care will be the institution's own protocols (such as ventilation strategies and use and dose of antivirals and antimicrobials, steroids, inotropic and vasopressor agents).

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

Detailed Description:

2019-new Coronavirus (2019-nCoV) infection (COVID-19) is highly contagious and responsible for thousands of casualties. Originated in Wuhan (China), the 2019-nCoV is spreading to many countries, including Italy, Korea and Japan. While no targeted-treatment against 2019-nCoV virus is available to-date, inhaled nitric oxide gas (NO) has shown antiviral activity against Coronavirus during the 2003 SARS outbreak. The investigators designed this study to assess whether inhaled NO improves survival in patients affected with severe COVID-2019.

The clinical spectrum of symptomatic patients ranges from mild upper respiratory syndrome to severe diffuse viral pneumonia in the context of severe multiorgan dysfunction leading to death. In China, overall reported fatality rate is between 2.2% in patients with proven infection. In hospitalized patients with COVID-19, about 25% required admission to ICU. Of these, 61% of patients met clinical criteria for acute respiratory distress syndrome (ARDS). In another retrospective study in Wuhan (China) on 52 critically ill patients with COVID-19, the incidence of patients with pneumonia meeting ARDS criteria was 67%. ICU mortality reached 63%, with various profiles of combined organ failure in deceased patients (81% with ARDS, 37.5% with AKI, 28% with cardiac injury and 28% with liver failure).

In 2004, during the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) outbreak, it was demonstrated that treatment with NO reversed pulmonary hypertension, improved severe hypoxia and shortened the length of ventilatory support as compared to matched control patients with SARS-CoV. In a subsequent in-vitro study, NO donors (e.g. S-nitroso-N-acetylpenicillamine) greatly increased the survival rate of SARS-CoV-infected eukaryotic cells, suggesting direct antiviral effects of NO. Coronavirus responsible for SARS-CoV shares most of the genome of COVID-19 indicating potential effectiveness of inhaled NO therapy in these patients.

Here, the investigators propose a randomized clinical trial aimed to prevent progression of the disease in patients with severe acute respiratory syndrome.

Control group: the institutional standard of care will be delivered. Treatment group: in addition to standard therapy, the subjects will receive inhalation of NO. Inspired NO/N2 will be delivered at 80 parts per million (ppm) in the first 48 hours of enrollment. After that, NO levels will be decreased to 40 ppm until severe hypoxia resolves. Weaning from NO will start when patients improves the level of oxygenation to a PaO2/FiO2 > 300 mmHg or SpO2 > 93% for more than 24 hours consecutively. Physician will follow their own institutional weaning protocols. In the absence of institutional protocols, NO will be reduced every 4 hours in step-wise fashion starting from 40 ppm to 20, 10, 5, 3, 2 and 1 ppm. If hypoxemia (SpO2 < 93%) or acute hypotension (systolic blood pressure < 90 mmHg) occurs during weaning, NO should be increased to a prior higher concentration.

Safety: prolonged treatment with inhaled NO can lead to increased methemoglobin levels. Blood levels of methemoglobin will be monitored via a non-invasive CO-oximeter or MetHb levels in blood. If methemoglobin levels rise above 5% at any point of the study, inhaled NO concentration will be halved.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Nitric Oxide Gas Inhalation Therapy for Severe Acute Respiratory Syndrome Due to COVID-19.
Estimated Study Start Date : March 23, 2020
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : March 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment Group
Nitric Oxide gas will be administered in the ventilatory circuit.
Drug: Nitric Oxide Gas
Inspired NO will be delivered at 80 parts per million (ppm) in the first 48 hours of enrollment. After that, NO levels will be decreased to 40 ppm until severe hypoxia resolves. Weaning from NO will start when patients improves the level of oxygenation to a PaO2/FiO2 > 300 mmHg or SpO2 > 93% for more than 24 hours consecutively. Physician will follow their own institutional weaning protocols. In the absence of institutional protocols, NO will be reduced every 4 hours in step-wise fashion starting from 40 ppm to 20, 10, 5, 3, 2 and 1 ppm.
Other Name: Nitric Oxide inhalation

Sham Comparator: Control Group
The delivery system will be set up anyway without study gas administration
Drug: Nitric Oxide Gas
Inspired NO will be delivered at 80 parts per million (ppm) in the first 48 hours of enrollment. After that, NO levels will be decreased to 40 ppm until severe hypoxia resolves. Weaning from NO will start when patients improves the level of oxygenation to a PaO2/FiO2 > 300 mmHg or SpO2 > 93% for more than 24 hours consecutively. Physician will follow their own institutional weaning protocols. In the absence of institutional protocols, NO will be reduced every 4 hours in step-wise fashion starting from 40 ppm to 20, 10, 5, 3, 2 and 1 ppm.
Other Name: Nitric Oxide inhalation




Primary Outcome Measures :
  1. SARS-free patients at 14 days [ Time Frame: 14 days since beginning of treatment ]
    Percentage of patients that have a PaO2/FiO2 ratio steadily > 300 in ambient air


Secondary Outcome Measures :
  1. Survival at 28 days [ Time Frame: 28 days ]
  2. Survival at 90 days [ Time Frame: 90 days ]
  3. SARS-free days at 28 days [ Time Frame: 28 days ]
    Composite outcome in which: Death=0, Days of treatment =1

  4. SARS -free days at 90 days [ Time Frame: 90 days ]
    Composite outcome in which: Death=0, Days of treatment =1

  5. Renal Replacement Therapy [ Time Frame: 28 days ]
    Incidence

  6. Liver Failure [ Time Frame: 28 days ]
    Incidence

  7. Mechanical Support of Circulation [ Time Frame: 28 days ]
    Incidence of patients requiring VA-ECMO, LVAD, IABP

  8. PaO2/FiO2 ratio in ambient air [ Time Frame: daily for 28 days ]
    In ambient air if possible



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years
  2. Laboratory (RT-PCR) confirmed infection with 2019-nCoV
  3. PaO2/FiO2 < 300 or SpO2 below 93% breathing ambient air

Exclusion Criteria:

  1. Physician makes a decision that trial involvement is not in the patient's best interest, or any condition that does not allow the protocol to be followed safely
  2. Pregnant or positive pregnancy test in a pre-dose examination
  3. Use of high flow nasal cannula

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04290871


Sponsors and Collaborators
Xijing Hospital
Massachusetts General Hospital
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Investigators
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Principal Investigator: Chong Lei, MD, PhD Fourth Military Medical University
Principal Investigator: Lorenzo Berra, MD Massachusetts General Hospital
Publications:

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Responsible Party: chonglei, Chong Lei, MD, PhD, Xijing Hospital
ClinicalTrials.gov Identifier: NCT04290871    
Other Study ID Numbers: NO-SARS-COVID-19
First Posted: March 2, 2020    Key Record Dates
Last Update Posted: March 24, 2020
Last Verified: March 2020

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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:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Syndrome
Disease
Pathologic Processes
Respiratory Tract Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus 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