A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Inhaled CHF6333 After Single Doses in Healthy Volunteers and After Single and Repeated Doses in Subjects With Bronchiectasis

Exclusion Criteria

• •1. Participation in another clinical study where investigational drug was received and the last investigations were performed less than 3 months prior to randomisation;
• •2. Clinically relevant and uncontrolled respiratory, cardiac, hepatic, gastrointestinal, renal, endocrine, hematologic, metabolic, neurological, or psychiatric disorders that may interfere with successful completion of this protocol, according to the investigator's judgment;
• •3. Clinically relevant abnormal laboratory values at screening suggesting an unknown disease and requiring further clinical investigation or which may impact the safety of the subject or the evaluation of the results of the study, according to the investigator's judgment;
• •4. History of respiratory diseases;
• •5. Positive human immunodeficiency virus (HIV) 1 or HIV2 serology results at screening;
• •6. Hepatitis serology results which indicate acute or chronic hepatitis B (HB) or hepatitis C virus (HCV) at screening;
• •7. Documented coronavirus disease 2019 (COVID-19) diagnosis within 2 weeks prior to screening or prior to randomisation, or associated complications/symptoms, which have not resolved within 2 weeks prior to screening;
• •8. Blood donation or blood loss (equal or more than 450 mL) less than 2 months prior to screening or prior to randomisation;
• •9. Abnormal liver enzymes at screening or prior to randomisation (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] or bilirubin: \>1.5× upper limit of normal \[ULN\]);
• •10. Positive urine test for cotinine at screening or prior to randomisation;
• •11. Documented history of alcohol abuse within 12 months prior to screening or a positive alcohol breath test at screening or prior to randomisation;
• •12. Documented history of drug abuse within 12 months prior to screening or a positive urine drug screen at screening or prior to randomisation;
• •13. Treatment with prohibited concomitant medications or if the subject is expected to take prohibited concomitant medications during the study;
• •14. Presence of any current infection, or previous infection that resolved less than 7 days prior to screening or prior to randomisation;
• •15. Known intolerance and/or hypersensitivity to any of the excipients contained in the formulation used in the study;
• •16. Unsuitable veins for repeated venepuncture;
• •17. Heavy caffeine drinker;
• •18. For females only: pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive serum human chorionic gonadotropin laboratory test. A serum pregnancy test is to be performed at screening and a urine pregnancy test is to be performed prior to randomisation;
• •19. Use of any kind of electronic smoking devices within 6 months prior to screening.
• •1. History of a clinically meaningful unstable or uncontrolled chronic comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the subject;
• •2. Acute symptomatic respiratory tract infection which constitutes an increase from the subject's baseline, per the investigator's judgment, within 4 weeks prior to randomisation;
• •3. Abnormal and clinically significant 12-lead ECG at screening or prior to randomisation that results in an active medical problem, which may impact the safety of the subject, per the investigator's judgment. Male subjects with QTcF \>450 ms and female subjects with QTcF \>470 ms cannot be enrolled;
• •4. Clinically significant abnormal laboratory values at screening that, in the opinion of the investigator, may put the subject at risk by participating in the study, or interfere with the subject's treatment or assessment, or influence the results of the study;
• •5. Participation in another clinical study, where investigational drug was received less than 30 days or less than 5 half-lives of the previous administered product (whichever is longer) prior to screening; participation in another clinical study is also not allowed between screening and randomisation;
• •6. Primary diagnosis of asthma, as determined by the investigator;
• •7. Concomitant diagnosis of cystic fibrosis;
• •8. Diagnosis of chronic obstructive pulmonary disease (COPD) made by a clinician, with airflow obstruction (post-bronchodilator FEV1/FVC ratio \<0.7) and at least a 10 pack-year smoking history; subjects with documented COPD but without airflow obstruction or smoking history will be permitted;
• •9. Current smokers; ex-smokers must have stopped for at least 1 year prior to screening (≥6 months for electronic smoking devices);
• •10. Subjects with an active tuberculous mycobacteria (TM) or non-tuberculous mycobacteria (NTM) infection requiring or receiving antibiotic treatment, an active allergic bronchopulmonary aspergillosis requiring treatment with corticosteroids or anti-fungal therapy, and/or a connective tissue disease (CTD) receiving an immunosuppressive treatment equivalent to \>10 mg prednisolone daily or systemic immunosuppression;
• •11. Diagnosis of common variable immunodeficiency (CVID) or other immunodeficiencies requiring immunoglobulin treatment, based on subject history;
• •12. Diagnosis of rheumatoid arthritis;
• •13. Malignancy that has not been in complete remission for at least 1 year or any untreated localised carcinomas;
• •14. History of solid organ/haematological transplantation and receiving immunosuppressive therapy;
• •15. Use of any antimicrobials (oral, inhaled, or intravenous) within 4 weeks prior to randomisation, except for subjects who are on stable treatment with macrolide antibiotics (for at least 3 months);
• •16. Medical history of discontinuation of previous inhaled therapy due to bronchospasm or intolerance;
• •17. Documented COVID-19 diagnosis within 4 weeks prior to randomisation, or associated complications/symptoms;
• •18. Diagnosis of alpha-1-antitrypsin (AAT) deficiency defined as an AAT serum level \<110 mg/dL; a prior test result of AAT serum level to confirm the diagnosis will be acceptable. In the event that a prior result is not available, a new test will be performed during the screening period and the result considered for the eligibility at randomisation.
• •19. Treatment with prohibited concomitant medications or if the subject is expected to take prohibited concomitant medications during the study;
• •20. Subjects treated with monoclonal antibodies (mAbs) for any respiratory conditions;
• •21. Subjects with traction BE;
• •22. For females only: pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive serum human chorionic gonadotropin laboratory test. A serum pregnancy test is to be performed at screening, and a urine pregnancy test is to be performed prior to randomisation;
• •23. Positive HIV1 or HIV2 serology results at screening;
• •24. Hepatitis serology results which indicate acute or chronic HB or HCV at screening;
• •25. BMI ≤17 kg/m2 at screening.
• •See the list of criteria in Part I for subjects with BE (Cohort B), except the exclusion criterion below: