Clinical trial NCT06559150: A Phase II Study of Ensifentrine in Non-Cystic Fibrosis Bronchiectasis
Official title: A Phase II, Randomized, Double-Blind, Placebo- Controlled Study of Ensifentrine in Subjects With Non-Cystic Fibrosis Bronchiectasis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Non-cystic Fibrosis Bronchiectasis
Lead sponsor: Verona Pharma plc
Sponsor class: INDUSTRY
First posted: 2024-08-19
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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

Primary outcomes:
measure: Rate of protocol-defined pulmonary exacerbations (number of events per subject-year)
timeFrame: Through study completion (a maximum of 3 years from the date of randomization)
Secondary outcomes:
measure: Time to the onset of the first protocol-defined pulmonary exacerbation
timeFrame: Through study completion (a maximum of 3 years from the date of randomization)
measure: Mean change from Baseline in Evaluating Respiratory Symptoms (E-RS) Cough and Sputum Domain score
timeFrame: Baseline, Week 6, Week 12, and Week 24
measure: Mean change from Baseline in Saint George's Respiratory Questionnaire (SGRQ) score
timeFrame: Baseline, Week 6, Week 12, and Week 24
measure: Mean change from Baseline in quality of life - bronchiectasis questionnaire (QOL-B) Respiratory Symptoms Domain score
timeFrame: Baseline, Week 6, Week 12, and Week 24
measure: Mean change from Baseline in Chronic Airways Assessment Test (CAAT) score
timeFrame: Baseline, Week 6, Week 12, and Week 24
measure: Mean change from Baseline in Percent of the predicted forced expiratory volume over 1 second (FEV1)
timeFrame: Baseline, Week 12, and Week 24
measure: Mean change from Baseline in quality of life - bronchiectasis questionnaire (QOL-B) total score
timeFrame: Baseline, Week 6, Week 12, and Week 24
measure: Incidence of Adverse Events
timeFrame: Through study completion (a maximum of 3 years from the date of randomization)
measure: PK Sub-study only: Ensifentrine area under the curve from time 0 to 12 hours (AUC 0 -12)
timeFrame: Week 12, Week 18, and Week 24
measure: PK Sub-study only: Ensifentrine maximum plasma drug concentration (Cmax)
timeFrame: Week 12, Week 18, and Week 24
measure: Pharmacokinetic (PK) Sub-study only: Ensifentrine time to Cmax (tmax) post morning dose
timeFrame: Week 12, Week 18, and Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Kirklin Clinic of UAB Hospital
state: Alabama
city: Los Angeles
country: United States
facility: So Cal Institute for Respiratory Diseases, Inc.
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Denver
country: United States
facility: National Jewish Health Main Campus
state: Colorado
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University at Saint Joseph Pulmonary Clinic
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Hammond
country: United States
facility: ASHA Clinical Research
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center-Kansas City
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital- 55 Fruit St
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: NYU Langone Health Pulmonary and Critical Care Associates, P.C. - BRANY - PPDS
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Wilmington
country: United States
facility: Accellacare of Wilmington
state: North Carolina
city: Winston-Salem
country: United States
facility: Southeastern Research Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC) - PPDS
state: South Carolina
city: Tyler
country: United States
facility: UT Texas Health Science at Tyler
state: Texas
city: Williamsburg
country: United States
facility: TPMG Clinical Research
state: Virginia
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
state: Lombardi
city: A Coruña
country: Spain
facility: Hospital Universitario A Coruña
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Dundee
country: United Kingdom
facility: Ninewells Hospital - PPDS
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital - PPDS
Study officials:
References: