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)

  1. Chong Lei
  2. Binxiao Su
  3. Hailong Dong
  4. Andrea Bellavia
  5. Raffaele Di Fenza
  6. Bijan Safaee Fakhr
  7. Stefano Gianni
  8. Luigi Giuseppe Grassi
  9. Riccardo Pinciroli
  10. Emanuele Vassena
  11. Lorenzo Berra

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Abstract

Introduction

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.

Methods and analysis

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. The primary outcome evaluates levels of oxygenation between the two groups at 48 hours. Secondary outcomes include rate of survival rate at 28 and 90 days in the two groups, time to resolution of severe hypoxemia, time to achieve negativity of SARS-CoV-2 RT-PCR tests.

Ethics and dissemination

The study protocol has been approved by the Investigational Review Board of Xijing Hospital (Xi’an, China) and pending the Partners Human Research Committee (Boston, USA). Recruitment will start after approval of both IRBs and local IRBs at other enrolling centers. Results of this study will be published in scientific journals, presented at scientific meetings, reported through flyers and posters, and published on related website or media in combating against this widespread contagious diseases.

Trial registration

Clinicaltrials.gov . NCT submitted

Strengths and limitations of this study

  • — Supplementation with nitric oxide (NO) might improve oxygenation and survival of SARS-CoV-2 patients.

  • — The antiviral activity of NO inhalation will be explored by measuring the time difference between the two groups to reach SARS-CoV-2 RT- PCR negativity.

  • — The spread of the disease worldwide determines the geographic areas of study and the recruitment rate of patients.

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    1. ScreenIT

      SciScore for 10.1101/2020.03.09.20033530: (What is this?)

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

      Table 1: Rigor

      Institutional Review Board StatementConsent: To obtain informed consent, the details of the study are presented to the patient’s healthcare proxy.
      RandomizationStudy Setting: This is a multicenter, randomized (1:1) controlled, parallel-arm clinical trial.
      BlindingBlinding: The study will be blinded to the patient.
      Power Analysisnot detected.
      Sex as a biological variablenot detected.

      Table 2: Resources

      Software and Algorithms
      SentencesResources
      A predetermined block randomization method (fixed block size of 10) is used to ensure equal distribution of participants to treatment arms and will be uploaded on REDCap.
      REDCap
      suggested: (REDCap, RRID:SCR_003445)

      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
      NCT04306393RecruitingNitric Oxide Gas Inhalation in Severe Acute Respiratory Synd…

      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

      SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

    2. Version published to 10.1101/2020.03.09.20033530v2 on medRxiv
    3. Version published to 10.1101/2020.03.09.20033530v1 on medRxiv