A Phase II Study of Ensifentrine in Non-Cystic Fibrosis Bronchiectasis

Prior treatment

• Meets a., b., OR c. below: a. A diagnosis of COPD: OR b.Meets both the following i. i. 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 signing the ICF . AND ii. Evidence within 1 year prior to randomization of obstructed lung function as shown by forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of < 0.70. OR c. A primary diagnosis of asthma, as judged by the PI.
• Initiated or altered therapy with ICS within 4 weeks prior to randomization.
• Presence of acute exacerbation or acute infection that required acute treatment within 28 days of randomization. Note: If a subject suffers an exacerbation or infection requiring acute treatment after signing the ICF but prior to randomization, the subject will be considered a screen failure but may be rescreened once this criterion is no longer met (Section 5.3).
• Use of the following prohibited medications within the designated time periods: a. Chronic, systemic Immunomodulatory agents for any chronic indication within 90 days prior to signing the ICF.b. CFTR modulators within 1 week prior to signing the ICF. c. Theophylline and oral PDE4 inhibitors (e.g., roflumilast, apremilast, crisaborole) within 48 hours prior to signing the ICF.e. Ohtuvayre at any time prior to signing the ICF.
• Initiated or altered therapy within 90 days prior to randomization with: a. Oral or inhaled antibiotics as chronic treatment (including macrolides) b. Cyclic antibiotics c. Dipeptidyl peptidase 1 (DPP1) or cathepsin C (CatC) inhibitor (e.g., brensocatib)
• Unable to withhold short-acting beta-agonists or short-acting muscarinic antagonists for ≥ 4 hours prior to spirometry.
• Significant hemoptysis within 6 weeks prior to randomization.
• History of or current malignancy of any organ system, treated or untreated within the 5 years prior to signing the ICF, except for localized basal or squamous cell carcinoma of the skin.
• Bronchiectasis due to cystic fibrosis, primary hypogammaglobulinemia common variable immunodeficiency, severe immunodeficiency, or requirement for treatment with intravenous immunoglobulin.
• Current or history of drug or alcohol abuse within the 5 years prior to signing the ICF.

Other illness

• Current treatment for nontuberculous mycobacterial (NTM) lung infection, allergic bronchopulmonary aspergillosis, or tuberculosis.
• Current or chronic history of clinically significant, 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 Gilbert syndrome or asymptomatic gallstones.
• Current diagnosis or history of severe depression or suicidal ideation or other significant psychiatric disease that would likely result in the subject not being able to complete the study, in the opinion of the PI.
• Intolerance of or hypersensitivity to ensifentrine or any of its excipients/components.

Lab values

• eGFR < 30 mL/min .
• Screening ALT ≥ 2 × ULN, 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).

Other

• Affiliation with the PI site, including an PI, Sub-PI, study coordinator, study nurse, other employee of participating PI or study site or a family member of the aforementioned.
• Current smoker defined as by the CDC.
• A diagnosis of primary ciliary dyskinesia (PCD) is NOT exclusionary. Subjects with a diagnosis of PCD are permitted to be enrolled, but the proportion of subjects with PCD enrolled in the study may be limited
• Currently participating in or scheduled to participate in an intensive pulmonary rehabilitation program.
• Subject has clinically significant findings on physical examination that may increase the risk associated with study participation, study treatment administration, or may interfere with the interpretation of study results, and in judgement of the PI would make the subject inappropriate for entry into this study.
• Not applicable. Deleted with Protocol Version 8.0.
• Any other abnormal hematology, biochemistry, or viral serology deemed by the PI to be clinically significant. Abnormal chemistry and/or hematology may be repeated during the Screening Period.
• ECG finding that is significantly abnormal as defined in Appendix 4 on a 12-lead ECG obtained during the Screening Period (including the Visit 2 pre-dose ECG if obtained before the subject has been randomized
• Participation in any other interventional, clinical studies within 30 days, or 5 half-lives, whichever is longer.

• Capable of giving informed consent indicating that they understand the purpose of the study and study procedures and agree to comply with the requirements and restrictions listed in the inform consent form (ICF) and in this protocol.
• Willing and able to attend all study visits and adhere to all study assessments and procedures.
• Age: Subject must be 18 to 80 years of age, inclusive, at the time of signing the ICF.
• Sex: • Males are eligible to participate if they agree to use contraception as described in the contraceptive guidance (Appendix 7) from signing the ICF, 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: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 7. OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 7 from signing the ICF, 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 5 years prior to signing the ICF; subjects whose past CT image records are not available will require chest CT scan during screening. Note: 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 at the clinic during screening. Note: If a subject is unable to produce sputum spontaneously during the Screening Period, the subject is considered a screen failure and may be re-screened only once with Medical Monitor approval .
• ≥ 1 documented pulmonary exacerbation defined by an antimicrobial prescription (i.e., antibiotic or antiviral) by a physician for the signs and symptoms of respiratory infections in the past 12 months prior to signing the ICF. Note: The number of subjects randomized with exactly 1 documented pulmonary exacerbation in the past 12 months prior to signing the ICF will be capped at approximately 30% for the entire study population.
• Capable of using the study nebulizer correctly.
• Ability to perform acceptable spirometry in accordance with American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines as assessed by the Investigator (Graham et al.) 2019). Note: Subjects who need to repeat spirometry because they did not meet the acceptability criteria will be allowed to repeat the test up to 2 times without being rescreened. Historical spirometry tests performed within 90 days of signing the ICF may be used to meet this criterion if the test was performed according to the ATS/ERS guidelines (Graham et al. 2019)