RPL554-NCFB-220, Ensifentrine, NCFBE

Inclusion Criteria:
*  Males are eligible to participate if they agree to use contraception as described in the contraceptive guidance from Screening and throughout the study and for at least 30 days after the last dose of blinded study medication
*  Females are eligible to participate if they are not pregnant, not breastfeeding, and 1 of the following conditions apply: 1. Not a woman of childbearing potential (WOCBP) OR 2. A WOCBP who agrees to follow the contraceptive guidance from Screening throughout the study and for at least 30 days after the last dose of blinded study medication
*  Clinical history consistent with bronchiectasis (cough, chronic sputum production, and/or recurrent respiratory infections) confirmed by chest CT demonstrating bronchiectasis affecting 1 or more lobes. Confirmation may be based on prior chest CT within the prior 5 years; subjects whose past CT image records are not available will require chest CT scan during screening Notes: If a subject has no clinical history consistent with bronchiectasis, they may not be re-screened
*  Current sputum producer with a history of chronic expectoration and able to provide sputum sample spontaneously at the clinic during screening
*  ≥ 1 documented pulmonary exacerbation defined by an antibiotic prescription by a physician for the signs and symptoms of respiratory infections in the past 12 months before screening
*  Capable of using the study nebulizer correctly
*  Ability to perform acceptable spirometry in accordance with American Thoracic Society and European Respiratory Society guidelines

Exclusion Criteria:
*  A diagnosis of COPD or a primary diagnosis of asthma, as judged by the investigator
*  Bronchiectasis due to cystic fibrosis, hypogammaglobulinemia common variable immunodeficiency, severe immunodeficiency, or requirement for treatment with intravenous immunoglobulin
*  Current smoker defined as by the Centers for Disease Control and Prevention (CDC)
*  Former cigarette smokers with a history of cigarette smoking ≥ 10 pack years at Screening \[number of pack years = (number of cigarettes per day / 20) × number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. Pipe and/or cigar use cannot be used to calculate pack-year history. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Screening
*  A diagnosis of primary ciliary dyskinesia
*  Current treatment for nontuberculous mycobacterial lung infection, allergic bronchopulmonary aspergillosis, or tuberculosis
*  Presence of acute exacerbation or acute infection that required acute treatment within 28 days of randomization
*  Use of the following prohibited medications within the designated time periods: 1. Immunomodulatory agents for any indication (including but not limited to the following: methotrexate, systemic corticosteroids, see adalimumab, azathioprine, dupilumab, cyclosporine) within 90 days prior to signing the ICF 2. CFTR modulators (e.g., ivacaftor, lumacaftor, tezacaftor) within 1 week prior to signing the ICF 3. Theophylline and PDE4 inhibitors (e.g., roflumilast, apremilast, crisaborole) within 48 hours prior to signing the ICF 4. Brensocatib within 3 months or 5 half-lives, whichever is longer, prior to signing the ICF 5. Ohtuvayre at any time prior to signing the ICF
*  Initiated or altered therapy within 90 days of randomization with: 1. oral or inhaled antibiotics as chronic treatment 2. Cyclic antibiotics: defined as prescribed regular cycles of on antibiotic treatment and off antibiotic treatment (for example, but not limited to, 28 days on an antibiotic and 28 days off an antibiotic). Note: Subjects on cyclic antibiotics must be actively taking antibiotics for at least 7 days prior to randomization and through the day of randomization
*  Initiated or altered therapy with ICS within 4 weeks prior to randomization
*  Unable to withhold short-acting beta-agonists or short-acting muscarinic antagonists for ≥ 4 hours prior to spirometry
*  Significant hemoptysis (≥ 300 mL or requiring blood transfusion) within 6 weeks prior to randomization
*  Currently participating in or scheduled to participate in an intensive pulmonary rehabilitation program (a maintenance rehabilitation program is allowed if their schedule and procedure will be consistent for the duration of the study)
*  Current or chronic history of unstable liver disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice, cirrhosis, or known hepatic or biliary abnormalities except for a diagnosis of Gilbert syndrome or asymptomatic gallstones Note: Chronic stable hepatitis B and C is not exclusionary if the subject otherwise meets study entry criteria
*  History of or current malignancy of any organ system, treated or untreated within the past 5 years, except for localized basal or squamous cell carcinoma of the skin
*  Estimated glomerular filtration rate (eGFR) \< 30 mL/min
*  Alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN), aspartate aminotransferase (AST) ≥ 2 × ULN, alkaline phosphatase and/or bilirubin \> 1.5 × ULN (isolated bilirubin \> 1.5 × ULN is acceptable only in subjects with a diagnosis of Gilbert's syndrome)
*  Participation in any other interventional, clinical studies (drugs or devices) within 30 days before Day 1, or 5 half-lives, whichever is longer
*  Intolerance of or hypersensitivity to ensifentrine or any of its excipients/components
*  Current or history of drug or alcohol abuse within the past 5 years
*  Significantly abnormal ECG finding