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

This study is a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of ensifentrine inhalation suspension (3 mg) delivered twice daily via standard jet nebulizer over at least 24 weeks, compared to placebo, in subjects with non-cystic fibrosis bronchiectasis (NCFBE).

The primary objective of this study is to assess the effect of ensifentrine vs placebo in addition to standard of care on pulmonary exacerbations, symptoms and quality of life in participants with NCFBE. The study is designed as a pulmonary exacerbation event-driven study where participants will be treated for ≥ 24 weeks and until 120 subjects have experienced at least 1 protocol-defined pulmonary exacerbation. Participants will be randomized to receive either ensifentrine suspension or placebo via standard jet nebulizer during the treatment period and neither participants nor study staff will know which a participant is receiving.

Eligibility Criteria:
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 another acute infection that required antibiotic treatment within 4 weeks of screening (or within 12 weeks of screening if the antibiotic prescription is a macrolide).
* Use of the following prohibited medications within the designated time periods:

  1. Immunomodulatory agents (e.g., bortezomib, ixazomib, thalidomide, dupilumab) within 3 months prior to signing the ICF.
  2. CFTR modulators (e.g., ivacaftor, lumacaftor, tezacaftor) within 1 week prior to signing the ICF.
  3. Treated with doses of cyclic antibiotics 90 days prior to signing the ICF.
  4. Theophylline and PDE4 inhibitors (e.g., roflumilast, apremilast, crisaborole) within 48 hours prior to signing the ICF.
  5. Brensocatib within 3 months or 5 half-lives, whichever is longer, prior to signing the ICF.
  6. Ohtuvayre at any time prior to signing the ICF.
* Initiated or altered therapy with oral or inhaled antibiotics as chronic treatment for NCFBE within 3 months prior to signing the ICF.
* Initiated or altered therapy with ICS within 4 weeks prior to Screening.
* 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 Day 1.
* 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 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 if fractionated bilirubin \< 35%).
* Participation in any other interventional, clinical studies (drugs or devices) within 3 months 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