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

An Open Label Safety Study of Inhaled Gaseous Nitric Oxide (gNO) for Adults & Adolescents With Non-Tuberculous Mycobacteria, Burkholderia Spp, Aspergillus Spp and Corona-like Viral (Sub-Study) 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).

COVID SubStudy Inclusion Criteria

• Capable of understanding and providing signed informed consent and ability to adhere to the requirements and restrictions of this protocol;
• Men and Women ≥ 19 years of age unless local laws dictate otherwise;
• English speaking;
• Suspected of exposure to SARS-CoV-2 with fatigue and at least a fever (>37.90 C) or cough or sore throat or a positive swab for SAR-CoV-2 within 5 days of the of enrollment;
• Must be willing to use an adequate form of contraception (or abstinence) from the time of the first dose with the IMP until after the last dose of IMP.

Exclusion Criteria

• Prior Tracheostomy;
• Concomitant treatment involving high flow nasal cannula;
• Any clinical contraindications, as judged by the attending physician;
• Mentally or neurologically disabled patients who are considered not fit to consent to their participation in the study;
• Prior COVID-19 infection or a positive swab for SARS-CoV-2 greater than 5 days from enrollment;
• Family members in the same household already on the study;
• Hydroxychloroquine, colchicine and other experimental antiviral medications;
• unwilling to practice a medically acceptable form of contraception from screening to Day 26 (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent).

Recruitment on hold for following Criteria during COVID-19 Pandemic

Inclusion Criteria:

• Written informed consent.

• Has been previously diagnosed with NTM, Burkholderia spp and Aspergillus spp. or Corona-like viral infection:

  1. NTM, Burkholderia spp and Aspergillus spp defined as positive culture(s) of at least one species of Mycobacterium avium Complex (MAC) or Mycobacterium abscessus Complex (MABSCor Burkholderia spp and Aspergillus spp) or Corona-like viral infection:
  2. History of repeatedly positive cultures (2 or more), irregardless of therapy

• Male or female ≥14 years of age.

• Female not pregnant at time of study.

• Has an FEV1 ≥ 30 % of predicted. c. Suspected corona-like viral infection

• Oxygen saturation on room air >92% at screening.

  a. Able to breathe without supplemental oxygen for 60 minutes

• Non-smoker for at least 6 months prior to screening and agrees not to smoke during the study.

• Willing and able to comply with the treatment schedule and procedures.

Exclusion Criteria:

• Use of an investigational drug within 30 days of screening

• History of frequent epistaxis (>1 episode/month)

• Significant hemoptysis within 30 days (≥ 5 mL of blood in one coughing episode or > 30 mL of blood in a 24 hour period)

• History of reactive pulmonary vascular hypertension

• Methemoglobin >3% at screening

• Liver function insufficiency (ALT/ AST >3 of normal values)

• Hemoglobin <11 g/dl

• Thrombocytopenia (platelet count <100,000/mm3) at screening

• Prothrombin time international ratio (INR) > 1.3 at screening

• Changes to antibiotics (e.g. azithromycin) from 7 days prior to screening through last treatment day. (Subjects may be taking antibiotics or antivirals during this time period, but they cannot start, stop or change doses during this time period)

• On supplemental oxygen during gNO treatment (SaO2 < 90% for 50 minutes while resting in a chair).

• For women of child bearing potential:

  1. positive pregnancy test at screening or
  2. lactating or
  3. unwilling to practice a medically acceptable form of contraception from screening to Day 36 (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent)

• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.