Inhaled Gaseous Nitric Oxide (gNO) Antimicrobial Treatment of Difficult Bacterial and Viral Lung (COVID-19) Infections

Non tuberculous mycobacteria (NTM), Burkholdria spp, Aspergillus in the lung are almost impossible to eradicate with conventional antibiotics. In addition COVID-19 has know current treatment. These patients have few options to treat their lung infection. Nitric oxide has broad bactericidal and virucidal properties. It has been shown that nitric oxide was safe to be inhaled for similar cystic fibrosis patients and reduced drug resistant bacteria in the lungs. Further, research indicates that clinical isolates of NTM, Burkholderia spp, Aspergillus spp and Corona-like viruses can be eradicated by 160ppm NO exposure in the laboratory petri dish. This is not the first time inhaled NO treatment has been used in patients with difficult lung infections. This study will provide more data to see if NO therapy can reduce the bacterial load in the lungs, help the patients breath better; and in the case of COVID-19 act as a anti-viral agent resulting in the reduction of incidence of oxygen therapy, mechanical assistance of BIPAP, CPAP, intubation and mechanical ventilation during the study period.

Main Study

Primary Objective: Assess the safety of inhaled NO (gNO) in adults \& adolescents with NTM, Burkholderia, Aspergillus Lung Infections and Viral Lung (COVID-19) Infections

Safety will be evaluated by unanticipated adverse events in clinical labs (hematology, coagulation, and serum chemistries); in vitals; in inspired concentration of NO, O2 and NO2 delivered to each subject and; in real time methemoglobin and oxygen saturation levels.

Primary Endpoint:

Determine the safety of gNO in the NTM population,

* as confirmed by no unanticipated adverse events * Absence of a deleterious mean change in FEV1% predicted (absolute) from baseline

Secondary safety Endpoint: Determine the efficacy of inhaled NO in adults with NTM, Burkholderia and Aspergillus Lung Infections

Efficacy will be evaluated by measuring the change in lung function with spirometry (specifically absolute change in FEV1 % predicted) from baseline to Days 5, 12, 19 and 26.

Secondary Efficacy Endpoint Determine the presence of an efficacy signal of gNO in the NTM, Burkholderia and Aspergillus Lung Infections

Efficacy will be assessed by the antimicrobial effect of inhaled NO on the density of NTM species and other microorganisms in sputum. Serial measurements of these microbial colony counts in sputum have been previously used as a measure of antimicrobial activity in other clinical trials of antibiotics in NTM.

• as confirmed by an improvement in pre-treatment bacterial colonization and post-treatment bacterial colonization on Days 19 and 26 as compared to baseline.

Efficacy will be assessed by change in Quality of Life Score.

* as assessed by an improvement in CRISS Score on Day 5, 19 and 26 as compared to baseline measurement; * as determined by improvement in six-minute walk test with one minute recovery as compared to baseline measurement.

COVID-19 Substudy

Primary Endpoint:

Efficacy will be evaluated by measuring reduction in the incidence of mechanical assistance of BIPAP, CPAP, intubation and mechanical ventilation during the study period.

Secondary Endpoints:

1. Proportion of patients with mild COVID2019 who deteriorate to a severe form of the disease requiring mechanical intervention like BIPAP/CPAP, intubation and mechanical ventilation; 2. Mortality from all causes during the study period; 3. Negative conversion of COVID-19 RT-PCR from upper respiratory tract measured as the proportion of patients with a negative conversion of RT-PCR from an oropharyngeal or a nasopahryngeal swab; 4. Time to clinical recovery defined as the time from initiation of the study to discharge or to normalization of fever (defined as \<36.6°C from axillary site, or \< 37.2°C from oral site or \< 37.8°C from rectal or tympanic site), respiratory rate (\< 24 bpm while breathing room air); 5. Alleviation of symptoms recorded in the Modified Jackson Cols score with particular definition of cough (defined as mild or absent in a patient reported scale of severity).