Nitric oxide gas inhalation to prevent COVID-2019 in healthcare providers

IntroductionIn human hosts, SARS-CoV-2 causes a respiratory syndrome (named COVID-19) which can range from a mild involvement of the upper airways to a severe pneumonia with acute respiratory syndrome that requires mechanical ventilation in an intensive care unit (ICU). Hospital-associated transmission is an important route of spreading for the SARS-CoV-2 virus and healthcare providers are at the highest risk. As of February 2020, 1716, Chinese healthcare workers had confirmed SARS-CoV-2 infections and at least 6 died. Unfortunately, there is currently no vaccine or pharmacological prophylaxis to decrease the risk of healthcare providers contracting the infection. Methods and analysisWe will randomize 470 healthcare providers scheduled to work with COVID 19 patients to receive nitric oxide gas administration (NO group, n=235) or no gas administration (control group, n=235). The primary endpoint of this study is the incidence of subjects with COVID-19 disease at 14 days from enrollment. Secondary endpoints are the proportion of healthcare providers who present a positive real time RT-PCR test for SARS-CoV- 2 14 days after enrollment, the proportion of healthcare providers requiring quarantine, and the total number of quarantine days in the two groups. Ethics and disseminationThe trial protocol is under the approval of The Partners Human Research Committee of Massachusetts General Hospital (Boston, USA) and recruitment is expected to start in April 2020. The results of this study will be published in scientific journals and presented at scientific meetings.

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

Introductionthe 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 analysisThis 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 disseminationThe trial protocol has been approved at the Investigation Review Boards of Xijing Hospital (Xian, 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 registrationClinicaltrials.gov. NCT submitted

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).

IntroductionSevere acute respiratory syndrome due to novel Coronavirus (SARS-CoV-2) related infection (COVID-19) is characterized by severe ventilation perfusion mismatch leading to refractory hypoxemia. To date, there is no specific treatment available for COVID-19. 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 invitro 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 COVID-19. This is a multicenter randomized controlled trial with 1:1 individual allocation. Patients will be blinded to the treatment. Methods and analysisIntubated 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 disseminationThe study protocol has been approved by the Investigational Review Board of Xijing Hospital (Xian, China) and by 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 disease. Trial registrationClinicaltrials.gov. NCT04306393 Strengths and limitations of this study-- Supplementation with nitric oxide (NO) might improve oxygenation and survival of SARS-CoV-2-infected 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.