Nebulised RESP30X Nitric Oxide Formulations in NCFB Patients with Pseudomonas Aeruginosa (Pa) (NOPA)

Prior treatment

• Currently receiving therapy with any inhaled antibiotic therapy. Patients who have previously received inhaled antibiotic therapy may be eligible if therapy was discontinued at least 28-days prior to screening.
• Asthma which requires treatment with Global Initiative for Asthma steps 4–5 suggested medications for the previous year, or systemic corticosteroids for ≥50% of the previous year.
• Patients with a current diagnosis of pulmonary TB based on clinical testing or symptoms. Patients with a history of pulmonary TB who have completed a course or eradication therapy at least 2 years prior to screening may be eligible if there is no clinical suspicion of recurrence. Patients with latent pulmonary TB are eligible provided they have received adequate treatment per local country guidelines.
• Taking medications that may induce methaemoglobinaemia or have received these within 30 days of screening.
• Patients with a diagnosis, or suspected diagnosis, of nontuberculous mycobacteria infection. Patients with a previous positive culture that is suspected to be a contaminant are eligible.
• Treatment with systemic anti-infective therapy within 28-days prior to screening. Treatment with azithromycin may be permitted only if in accordance with Protocol Section 4.4.1.
• Participation in other clinical studies with investigational agents within 8 weeks prior to screening.
• Treatment with NO and other NO donor agents, phosphodiesterase inhibitors and lung surfactant drugs, within 30 days prior to screening.
• Treatment with immunosuppressive medications within 2 weeks prior to screening, or systemic corticosteroids, or immunoglobulin therapy for> 7 days within 2 weeks prior to screening.

Other illness

• Known allergy to active substance or any excipients or to auxiliary product.
• In the opinion of the investigator, any other clinically relevant active respiratory disease with the potential to compromise patient safety or confound interpretation of safety or efficacy outcomes.
• Patients with a diagnosis of pulmonary hypertension.
• Conditions of increased risk for MetHb formation, significant anaemia or haemoglobinopathy.
• Known hypersensitivity to NO.
• Symptomatic gastroesophageal reflux disease (GERD) causing NCFB disease.
• History of solid organ transplantation.
• History of malignancy or treatment for malignancy within the past year.
• History of anaphylaxis to any medication or hospitalisation due to an adverse drug reaction (ADR)
• HIV positive AND: • CD4 < 350 cells/mm3
• History of methaemoglobinaemia.

Lab values

• Baseline-corrected QTcF >450 msec (males) or 470 msec (females) or history of congenital long QT syndrome, Torsades de Pointes or other clinically significant abnormal ECG at Screening screening or Baseline baseline.
• Patients with the following toxicities at screening as defined by the enhanced CTCAE toxicity table version 5.0, 27Nov2017. See protocol.
  • 30.Baseline-corrected QTcF >450 msec (males) or 470 msec (females) or history of congenital long QT syndrome, Torsades de Pointes or other clinically significant abnormal ECG at screening or baseline.

Other

• In the opinion of the investigator, patients with an acute exacerbation of NCFB
• Baseline SpMet >5%.
• Current smokers of tobacco products, marijuana, e-cigarettes/vaping.
• Patients with a diagnosis of primary ciliary dyskinesia
• Patients who are pregnant or breast-feeding.
• Patients planning to conceive a child within the anticipated period of study participation and for at least 90 days after the last dose of IMP in the study.
• FEV1 <55% predicted at the screening visit.
• Significant haemoptysis within 60 days of screening defined as an estimated volume of 50ml in a single occurrence.

• Provide written, informed consent prior to all study-related procedures and agree to undergo all study procedures.
• Aged between 18 and 75 years, inclusive.
• Clinical history of bronchiectasis affecting 1 or more lobes based on symptoms (cough, sputum productive and/or recurrent lower respiratory tract infections) as confirmed by historical computerised tomography (CT) scan and radiology report performed within the last 5 years.
• Confirmed high-titre respiratory PPMs (Part 1: Pa only) at screening ≥10^⁵ CFU/mL (as determined by central laboratory microbiological cultures).
• Individuals of childbearing potential (IOCBP) and their partners who engage in heterosexual intercourse must agree to use protocol defined method(s) of contraception.
• Patients who can produce spontaneous sputum on a daily basis.
• Patients who are able to self-administer the SABA inhaler and study nebuliser for IMP administration effectively in the investigator’s opinion, following training.
• Patients appropriately vaccinated against influenza and pneumococcus at least 14-days prior to Day 1. This applies only if the screening visit falls between September and March and the Influenza vaccine/pneumococcal vaccine for that year is available.