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Nitric Oxide Gas Inhalation Therapy for Mild/Moderate COVID-19 (NoCovid)

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ClinicalTrials.gov Identifier: NCT04305457
Recruitment Status : Recruiting
First Posted : March 12, 2020
Last Update Posted : May 27, 2020
Sponsor:
Collaborators:
Xijing Hospital
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Information provided by (Responsible Party):
Lorenzo Berra, MD, Massachusetts General Hospital

Brief Summary:
The scientific community is in search for novel therapies that can help to face the ongoing epidemics of novel Coronavirus (SARS-Cov-2) originated in China in December 2019. At present, there are no proven interventions to prevent progression of the disease. Some preliminary data on SARS pneumonia suggest that inhaled Nitric Oxide (NO) could have beneficial effects on SARS-CoV-2 due to the genomic similarities between this two coronaviruses. In this study we will test whether inhaled NO therapy prevents progression in patients with mild to moderate COVID-19 disease.

Condition or disease Intervention/treatment Phase
Coronavirus Infections Pneumonia, Viral Acute Respiratory Distress Syndrome Drug: Nitric Oxide Phase 2

Detailed Description:

To date, no targeted therapeutic treatments for the ongoing COVID-19 outbreak have been identified. Antiviral combined with adjuvant therapies are currently under investigation. The clinical spectrum of the infection is wide, ranging from mild signs of upper respiratory tract infection to severe pneumonia and death.

In the patients who progress, the time period from symptoms onset to development of dyspnea is reported to be between 5 to 10 days, and that one to severe respiratory distress syndrome from 10 to 14 days. Globally, 15 to 18% of patients deteriorates to the need of mechanical ventilation, despite the use of non-invasive ventilatory support in the earliest phases of the disease. Probability of progression to end stage disease is unpredictable, with the majority of these patients dying from multi-organ failure. Preventing progression in spontaneously breathing patients with mild to moderate disease would translate in improved morbidity and mortality and in a lower use of limited healthcare resources.

In 2004, during the SARS-coronavirus (SARS-CoV) outbreak, a pilot study showed that low dose ( max 30 ppm) inhaled NO for 3 days was able to shorten the time of ventilatory support. At the same time, NO donor compound S-nitroso-N-acetylpenicillamine increased survival rate in an in-vitro model of SARS-CoV infected epithelial cells.Based on the genetic similarities between the two viruses, similar effects of NO on SARS-CoV-2 can be hypothesized. While further in-vitro testing is recommended, we proposed a randomized clinical trial to test the effectiveness of inhaled NO in preventing the progression of SARS-CoV-2 related disease, when administered at an early stage.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients With Mild/Moderate COVID-19: a Randomized Clinical Trial
Actual Study Start Date : March 21, 2020
Estimated Primary Completion Date : April 1, 2021
Estimated Study Completion Date : April 1, 2022


Arm Intervention/treatment
Experimental: Nitric Oxide inhalation
Nitric Oxide will be delivered through a non invasive CPAP system (with minimal pressure support to decrease discomfort due to the facial mask) or through a non-rebreathing mask system.
Drug: Nitric Oxide
Nitric Oxide (NO) will be delivered together with the standard of care for a period of 20-30 minutes 2 times per day for 14 consecutive days from time of enrollment. Targeted No inhaled concentration will be maintained between 140 and 180 ppm. The gas will be delivered through a CPAP circuit ensuring an end-expiratory pressure between 2 and 10 cmH2O or through a non-rebreathing mask without positive end-expiratory pressure, depending on the clinical needs of the patient.
Other Name: Nitric Oxide inhalation

No Intervention: Control
Patients assigned to the control group will not receive any gas therapy.



Primary Outcome Measures :
  1. Reduction in the incidence of patients with mild/moderate COVID-19 requiring intubation and mechanical ventilation [ Time Frame: 28 days ]
    The primary outcome will be the reduction in the incidence of patients requiring intubation and mechanical ventilation, as a marker of deterioration from a mild to a severe form of COVID-19. Patients with indication to intubation and mechanical ventilation but concomitant DNI (Do Not Intubate) or not intubated for any other reason external to the clinical judgment of the attending physician will be considered as meeting the criteria for the primary endpoint.


Secondary Outcome Measures :
  1. Mortality [ Time Frame: 28 days ]
    Proportion of deaths from all causes

  2. Time to clinical recovery [ Time Frame: 28 days ]
    Time from initiation of the study to discharge or to normalization of fever (defined as <36.6°C from axillary site, or < 37.2°C from oral site or < 37.8°C from rectal or tympanic site), respiratory rate (< 24 bpm while breathing room air), alleviation of cough (defined as mild or absent in a patient reported scale of severe >>moderate>>mild>>absent) and resolution of hypoxia (defined as SpO2 ≥ 93% in room air or P/F ≥ 300 mmHg). All these improvements must be sustained for 72 hours.


Other Outcome Measures:
  1. Negative conversion of COVID-19 RT-PCR from upper respiratory tract [ Time Frame: 7 days ]
    Proportion of patients with a negative conversion of RT-PCR from an oropharyngeal or oropharyngeal swab.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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. Laboratory confirmed COVID19 infection defined with a positive RT-PCR from any specimen and/or detection of SARS-CoV-2 IgM/IgG antibodies.
  2. Hospital admission with at least one of the following:

    1. fever ≥ 36.6 °C from axillary site; or ≥ 37.2°C from oral site; or ≥ 37.6°C from tympanic or rectal site.
    2. Respiratory rate ≥ 24 bpm
    3. cough
  3. Spontaneous breathing with or without hypoxia of any degree. Gas exchange and ventilation maybe assisted by any continuous continuous airway pressure (CPAP), or any system of Non Invasive Ventilation (NIV), with Positive End-Expiratory Pressure (PEEP) ≤ 10 cmH2O.

Exclusion Criteria:

  1. Tracheostomy
  2. Therapy with high flow nasal cannula
  3. Any clinical contraindications, as judged by the attending physician
  4. Patients enrolled in another interventional study
  5. Hospitalized and confirmed diagnosis of COVID-19 for more than 72 hours
  6. Previous intubation for COVID-19
  7. Patient not committed to full support (DNR, DNI or CMO)
  8. Patient requiring oxygen at home for lung comorbidities
  9. Primary cause of hopitalization not due to COVID-19

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): NCT04305457


Contacts
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Contact: Lorenzo Berra +16176437733 lberra@mgh.harvard.edu
Contact: Lei Chong +86 8629011362 crystalleichong@126.com

Locations
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United States, Louisiana
Louisiana State University Health Shreveport Recruiting
Shreveport, Louisiana, United States, 71103
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114-2621
Contact: Lorenzo Berra, MD       lberra@mgh.harvard.edu   
Sponsors and Collaborators
Massachusetts General Hospital
Xijing Hospital
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
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Responsible Party: Lorenzo Berra, MD, Medical Doctor, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04305457    
Other Study ID Numbers: NOgas mildCOVID-19
First Posted: March 12, 2020    Key Record Dates
Last Update Posted: May 27, 2020
Last Verified: May 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
Keywords provided by Lorenzo Berra, MD, Massachusetts General Hospital:
COVID-19
ARDS
Mechanical Ventilation
Nitric Oxide
Additional relevant MeSH terms:
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Nitric Oxide
Coronavirus Infections
Severe Acute Respiratory Syndrome
Pneumonia, Viral
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Lung Injury
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