Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19

  1. Chong Lei
  2. Binxiao Su
  3. Hailong Dong
  4. Bijan Safaee Fakhr
  5. Luigi Giuseppe Grassi
  6. Raffaele Di Fenza
  7. Stefano Gianni
  8. Riccardo Pinciroli
  9. Emanuele Vassena
  10. Caio Cesar Araujo Morais
  11. Andrea Bellavia
  12. Stefano Spina
  13. Robert Kacmarek
  14. Lorenzo Berra

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Abstract

Introduction

the current worldwide outbreak of Coronavirus disease 2019 (COVID-19) due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities. Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value. To date there is still no available treatment for SARS-CoV-2. Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirus-mediated acute respiratory syndrome, and this can be related to its viricidal effect. The time from the symptoms’ onset to the development of severe respiratory distress is relatively long. We hypothesize that high concentrations of inhaled NO administered during early phases of COVID-19 infection can prevent the progression of the disease.

Methods and analysis

This is a multicenter randomized controlled trial. Spontaneous breathing patients admitted to the hospital for symptomatic COVID-19 infection will be eligible to enter the study. Patients in the treatment group will receive inhaled NO at high doses (140-180 parts per million) for 30 minutes, 2 sessions every day for 14 days in addition to the hospital care. Patient in the control group will receive only hospital care. The primary outcome is the percentage of patients requiring endotracheal intubation due to the progression of the disease in the first 28 days from enrollment in the study. Secondary outcomes include mortality at 28 days, proportion of negative test for SARS-CoV-2 at 7 days and time to clinical recovery.

Ethics and dissemination

The trial protocol has been approved at the Investigation Review Boards of Xijing Hospital (Xi’an, China) and The Partners Human Research Committee of Massachusetts General Hospital (Boston, USA) is pending. Recruitment is expected to start in March 2020. Results of this study will be published in scientific journals, presented at scientific meetings, and on related website or media in fighting this widespread contagious disease.

Trial registration

Clinicaltrials.gov . NCT submitted

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  1. ScreenIT

    SciScore for 10.1101/2020.03.10.20033522: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: The signed informed consent will be kept in a secure place for at least 5 years after study completion.
    RandomizationStudy design: Multicenter randomized clinical trial.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableCriteria of exclusion are pregnancy (all women in fertile age should be tested for pregnancy before being enrolled); presence of an open tracheostomy; therapy with high-flow nasal cannula; clinical contraindication to NO gas delivery, as judged by the attending physician; hospitalized and confirmed diagnosis of COVID-19 for more than 72 hours.

    Table 2: Resources

    Antibodies
    SentencesResources
    Diagnosis can also be obtained by detection of COVID-19 IgM/IgG antibodies in serum, plasma or whole blood sample.
    COVID-19 IgM/IgG
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04252664SuspendedA Trial of Remdesivir in Adults With Mild and Moderate COVID…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.03.10.20033522v1 on medRxiv