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)

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

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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.