Clinical trial NCT04305457: Nitric Oxide Gas Inhalation Therapy for Mild/Moderate COVID-19
Official title: Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients With Mild/Moderate COVID-19: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Coronavirus Infections
Pneumonia, Viral
Acute Respiratory Distress Syndrome
Keywords: COVID-19
ARDS
Mechanical Ventilation
Nitric Oxide
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: University of Alabama at Birmingham
First posted: 2020-03-12
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study includes a randomized, parallel arm clinical trial in which subjects will be randomized to receive either inhaled nitric oxide (in addition to the standard of care) or the standard of care alone.

In a third arm, COVID-19 subjects will be enrolled at Providence HealthCare Network, Anchorage (AK). Subjects in this arm will not be randomized and will all receive nitric oxide gas either as an inpatient or outpatient.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Reduction in the incidence of patients with mild/moderate COVID-19 requiring intubation and mechanical ventilation
timeFrame: 28 days
Secondary outcomes:
measure: Mortality
timeFrame: 28 days
measure: Time to clinical recovery
timeFrame: 28 days
Other outcomes:
measure: Negative conversion of COVID-19 RT-PCR from upper respiratory tract
timeFrame: 7 days
Locations:
city: Anchorage
country: United States
facility: Providence HealthCare Network
state: Alaska
city: Shreveport
country: United States
facility: Louisiana State University Health Shreveport
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Lorenzo Berra, MD
role: PRINCIPAL_INVESTIGATOR
References: