Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD, bronchodilator, ensifentrine-glycopyrrolate
Brief summary
This study will assess the safety and efficacy of fixed dose combinations of ensifentrine with two different glycopyrrolate dose levels compared to placebo and to the individual components of the fixed dose combinations, each administered twice a day via standard jet nebulizer, in adult participants with chronic obstructive pulmonary disease (COPD).
Detailed description
Enrolled participants will be expected to participate for approximately 7 weeks: 1 to 2 weeks for screening, 4 weeks of treatment, and 1 week of follow up. Participants will be randomized to one of 6 treatment arms: two fixed dose combinations of ensifentrine (3 mg) and glycopyrrolate (either 21.25 or 42.5 mcg), the 3 individual components as monotherapies, or placebo. All treatments will be administered twice a day via oral inhalation by a standard jet nebulizer. The primary objective of this study is to evaluate the bronchodilator effects of the fixed dose combinations compared to each of the individual components and to placebo.
Interventions
Administered by a standard jet nebulizer, twice daily for 28 consecutive days
DRUGGlycopyrrolate 21.25 mcg
Administered by a standard jet nebulizer, twice daily for 28 consecutive days
Administered by a standard jet nebulizer, twice daily for 28 consecutive days
DRUGPlacebo
Administered by a standard jet nebulizer, twice daily for 28 consecutive days
Sponsors
Verona Pharma, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Males are eligible to participate if they agree to use contraception or abstinence, and refrain from donating fresh unwashed semen during the study and for at least 30 days post-study * Females are eligible to participate if they are not pregnant, breastfeeding and if one of the following conditions apply: 1. Not a woman of child-bearing potential OR 2. Agrees to follow the contraceptive guidance from screening throughout the study and for at least 30 days post-study 3. Agrees not to donate eggs for the purpose of reproduction from screening throughout the study and for at least 30 days post-study * Current of former cigarette smokers with a history of smoking ≥ 10 pack years at the time of signing informed consent \[number of pack years = (number of cigarettes per day / 20) × number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. 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 informed consent. Smoking cessation programs are permitted during the study * Participants with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines with symptoms compatible with COPD * A score of ≥ 2 on the Modified Medical Research Council (mMRC) Dyspnea Scale at the Screening Visit * Post-bronchodilator (4 puffs of albuterol) spirometry during the Screening Period demonstrating both the following: 1. FEV1/forced vital capacity (FVC) ratio of \< 0.70 AND 2. FEV1 ≥ 30 % and ≤ 70% of predicted normal * A posterior-anterior chest x-ray (CXR) during the Screening Period or within 12 months of signing the Informed Consent Form (ICF) showing no clinically significant abnormalities unrelated to COPD. If a CXR within the past 12 months is not available but a computed tomography (CT) scan within the same time period is available, the CT scan may be reviewed in place of a CXR * Participants on no maintenance/background therapy or participants on stable maintenance as either long-acting β2-agonist (LABA) or long-acting β2-agonist/Inhaled corticosteroid (LABA/ICS) therapy are eligible. Subjects taking maintenance therapy must demonstrate regular use of maintenance therapy, in any form, for at least 60 days prior to signing informed consent and agree to continue use of their current permitted LABA or LABA/ICS medication for the duration of the screening and treatment period * Capable of withholding from short-acting bronchodilators for 4 hours prior to spirometry testing. Participants receiving maintenance therapy with a LABA or LABA/ICS must be capable of withholding twice-daily maintenance therapy for 24 hours and once-daily maintenance therapy for 48 hours prior to initiation of any spirometry * Capable of using the study jet nebulizer correctly * Ability to perform acceptable spirometry in accordance with ATS/ERS guidelines * Willing and able to attend all study visits and adhere to all study assessments and procedures
Exclusion criteria
* Concomitant clinically significant pulmonary disease other than COPD (i.e., asthma, tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, sleep apnea (unless controlled with stable continuous positive airway pressure \[CPAP\] use), known alpha-1 antitrypsin deficiency, core pulmonale or other non-specific pulmonary disease * Within 6 months prior to randomization, a COPD exacerbation requiring hospitalization * Within 3 months prior to randomization, use of oral or systemic therapies for COPD exacerbations (for example, oral, intravenous, or intramuscular glucocorticoids, antibiotics, theophylline, and roflumilast) * History of life-threatening COPD, including Intensive Care Unit admission and/or requiring intubation * Severe comorbidities including 1. unstable cardiac disease (myocardial infarction within 1 year prior to randomization, unstable angina within 6 months prior to randomization, unstable or life-threatening arrhythmia requiring intervention within 3 months prior to randomization, diagnosis of New York Heart Association (NYHA) class III or IV heart disease, or 2. any other clinically significant medical conditions including uncontrolled diseases (e.g., endocrine, neurological, hepatic, gastrointestinal, renal, hematological, urological, immunological, psychiatric \[e.g. untreated significant depression, anxiety or history of suicidality\], or ophthalmic diseases) that would, in the opinion of the Investigator, preclude the participant from safely completing the required tests or the study, or is likely to result in disease progression that would require withdrawal of the participant * History of or clinically significant on-going bladder outflow obstruction or history of catheterization for relief of bladder outflow obstruction within 6 months prior to randomization * History of narrow angle glaucoma * History of hypersensitivity or intolerance to aerosol medications, albuterol, ensifentrine, or glycopyrrolate or any of its excipients/components, anticholinergic agents, or sympathomimetic amines * History of or current malignancy of any organ system, treated or untreated within the 5 years prior to randomization, except for localized basal or squamous cell carcinoma of the skin * Other significant psychiatric disease that would likely result in the participant not being able to complete the study, in the opinion of the Investigator * Findings on physical examination that an investigator considers to be clinically significant or abnormal during the Screening Period including hematology, biochemistry, viral serology, and ECG * Prior or current use of Ohtuvayre (ensifentrine) * Previous lung resection or lung reduction surgery within 1-year of randomization * Long term oxygen use defined as oxygen therapy prescribed for greater than 12 hours per day. As needed oxygen use (≤ 12 hours per day) is not exclusionary * Pulmonary rehabilitation unless such treatment has been stable from 4 weeks prior to signing the ICF and plans to remain stable during the study. Pulmonary rehabilitation programs should not be started or completed during participation in the study * Major surgery (requiring general anesthesia) in the 6 weeks prior randomization, lack of full recovery from surgery at randomization, or planned surgery through the end of the study * Current or history of drug or alcohol abuse within the 5 years prior to randomization * Estimated glomerular filtration rate (eGFR) \< 30 mL/min as tested during the Screening Period * Alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN), aspartate aminotransferase (AST) ≥ 2 × ULN, alkaline phosphatase and/or total bilirubin \> 1.5 × ULN (participants with Gilbert's syndrome can be included with total bilirubin \>1.5 × ULN as long as direct bilirubin is ≤ 1.5 × ULN) * Use of an experimental drug within 30 days or 5 half-lives of signing the ICF, whichever is longer, and/or participation in a study treatment-free follow-up phase of a clinical study within 30 days prior to signing the ICF * Use of an experimental medical device or participation in a follow-up phase of an experimental medical device clinical study within 30 days prior to informed consent * Affiliation with the investigator site, including an Investigator, Sub-Investigator, study coordinator, study nurse, other employee of participating investigator or study site or a family member of the aforementioned
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Average Forced Expiry Volume in 1 Second (FEV1) Area Under the Curve Versus Time From Time 0 to 4 Hours (AUC0-4h) | Baseline and Day 28 | Spirometry will be performed to determine the FEV1. Change from baseline in average FEV1 area under the curve from 0 to 4 hours on Day 28 will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak FEV1 Measured Over 4 Hours Post-Dose | Baseline and Day 28 | Spirometry will be performed to determine the FEV1. Change from baseline in peak FEV1 over 4 hours following dosing on Day 28 will be reported. |
| Change From Baseline in Average FEV1 Area Under the Curve Versus Time From Time 0 to 12 Hours (AUC0-12h) | Baseline and Day 28 | Spirometry will be performed to determine the FEV1. Change from baseline in average FEV1 area under the curve from 0 to 12 hours on Day 28 will be reported. |
| Change From Baseline in Morning Trough FEV1 on Day 29 | Baseline and Day 29 | Spirometry will be performed to determine the FEV1. Change from baseline in morning trough FEV1 measured on Day 29 will be reported. |
| Change From Baseline in Evening Trough FEV1 on Day 28 | Baseline and Day 28 | Spirometry will be performed to determine the FEV1. Change from baseline in evening trough FEV1 measured on Day 28 will be reported. |
| Change From Baseline in Morning Trough FEV1 on Day 28 | Baseline and Day 28 | Spirometry will be performed to determine the FEV1. Change from baseline in morning trough FEV1 measured on Day 28 will be reported. |
| Change From Baseline in Average FEV1 AUC0-4h Measured After First Dose on Day 14 | Baseline and Day 14 | Spirometry will be performed to determine the FEV1. Change from baseline in average FEV1 area under the curve from 0 to 4 hours following the first dose on Day 14 will be reported. |
| Change From Baseline in Peak FEV1 Measured Over 4 Hours After First Dose on Day 14 | Baseline and Day 14 | Spirometry will be performed to determine the FEV1. Change from baseline in peak FEV1 over 4 hours following the first dose on Day 14 will be reported. |
| Change From Baseline in Average FEV1 AUC0-4h Measured After First Dose on Day 1 | Baseline and Day 1 | Spirometry will be performed to determine the FEV1. Change from baseline in average FEV1 area under the curve from 0 to 4 hours following the first dose on Day 1 will be reported. |
| Change from Baseline in Peak FEV1 Measured Over 4 Hours After First Dose on Day 1 | Baseline and Day 1 | Spirometry will be performed to determine the FEV1. Change from baseline in peak FEV1 over 4 hours following the first dose on Day 1 will be reported. |
| Change in Symptoms of Dyspnea from Baseline as Measured by Transition Dyspnea Index (TDI) Score on Day 14 | Baseline and Day 14 | The TDI measures the change in dyspnea symptom severity from the baseline as measured by the Baseline Dyspnea Index (BDI). It is based on three components, functional impairment, magnitude of task, and magnitude of effort, that evoke dyspnea in activities of daily living. The BDI score ranges from 0 (very severe impairment) to 4 (no impairment) for each domain and are summed to determine the BDI focal score (0-12). The TDI score ranges from -3 (major deterioration) to +3 (major improvement) for each domain. The sum of all domains yields the TDI focal score (-9 to +9). Change from baseline in TDI score on Day 14 will be reported. |
| Change in Symptoms of Dyspnea from Baseline as Measured by TDI Score on Day 28 | Baseline and Day 28 | The TDI measures the change in dyspnea symptom severity from the baseline as measured by the BDI. It is based on three components, functional impairment, magnitude of task, and magnitude of effort, that evoke dyspnea in activities of daily living. The BDI score ranges from 0 (very severe impairment) to 4 (no impairment) for each domain and are summed to determine the BDI focal score (0-12). The TDI score ranges from -3 (major deterioration) to +3 (major improvement) for each domain. The sum of all domains yields the TDI focal score (-9 to +9). Change from baseline in TDI score on Day 28 will be reported. |
| Change From Baseline in Health-Related Quality of Life as Measured by Saint George's Respiratory Questionnaire (SGRQ) Total Score | Baseline and Day 28 | The SGRQ Patient Reported Outcome (PRO) measure is a 50- item questionnaire designed to assess health-related quality of life in patients with COPD in terms of symptoms, daily activity limitation, and psychosocial well-being. The total score ranges from 0 to 100, with lower scores indicating better health status. Change from baseline in health-related quality of life as assessed using SGRQ total score on Day 28 will be reported. |
| Number of Participants who Experience at Least one Treatment Emergent Adverse Event (TEAE) | Up to approximately 5 weeks | An AE is any untoward medical occurrence in a subject, temporally associated with the use of the study medication, whether or not considered related to the study medication. Number of participants who experience at least one TEAE will be reported. |
| Number of Participants With Markedly Abnormal Changes in Hematology Parameters | Up to approximately Day 28 | Number of participants with markedly abnormal changes in hematology parameters will be reported. |
| Number of Participants With Markedly Abnormal Changes in Blood Chemistry Parameters | Up to approximately Day 28 | Number of participants with markedly abnormal changes in blood chemistry parameters will be reported. |
| Number of Participants With Markedly Abnormal Changes in QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF) | Up to approximately Day 28 | Number of participants with markedly abnormal changes in QTcF measurements will be reported. |
| Number of Participants With Markedly Abnormal Changes in Heart Rate | Up to approximately Day 28 | Number of participants with markedly abnormal changes in heart rate will be reported. |
| Number of Participants With Markedly Abnormal Changes in Blood Pressure | Up to approximately Day 28 | Number of participants with markedly abnormal changes in blood pressure will be reported. |
| Number of Participants With Markedly Abnormal Changes in Pulse Rate | Up to approximately Day 28 | Number of participants with markedly abnormal changes in pulse rate will be reported. |
| Area Under the Concentration-Time Curve from Time 0 to 12 Hours (AUC0-12hrs) of Ensifentrine | Predose and at designated timepoints up to 12 hours postdose | Blood samples will be collected to determine the AUC0-12hrs of ensifentrine. |
| Maximum Plasma Concentration (Cmax) of Ensifentrine | Predose and at designated timepoints up to day 28 postdose | Blood samples will be collected to determine the Cmax of ensifentrine. |
| Plasma Trough Concentration (Ctrough) of Ensifentrine | Day 28 | Blood samples will be collected to determine the Ctrough of ensifentrine. |
| Average Plasma Concentrations (Cavg) of Ensifentrine | Day 28 | Blood samples will be collected to determine the Cavg of ensifentrine. |
| Time to Maximum Plasma Concentration (Tmax) of Ensifentrine | Predose and at designated timepoints up to day 28 postdose | Blood samples will be collected to determine the Tmax of ensifentrine. |
| Apparent Clearance (CL/F) of Ensifentrine | Day 28 | Blood samples will be collected to determine the CL/F of ensifentrine. |
| Accumulation Ratio Cmax (ARCmax) of Ensifentrine | Predose and at designated timepoints up to day 28 postdose | Blood samples will be collected to determine the ARCmax of ensifentrine. |
| Accumulation Ratio AUC (ARAUCs) of Ensifentrine | Predose and at designated timepoints up to day 28 postdose | Blood Samples Will be Collected to Determine the ARAUC of Ensifentrine. |
| Area Under the Concentration-Time Curve from Time 0 to 12 Hours (AUC0-12hrs) of Glycopyrronium | Predose and at designated timepoints up to 12 hours postdose | Blood samples will be collected to determine the AUC0-12hrs of glycopyrronium. |
| Maximum Plasma Concentration (Cmax) of Glycopyrronium | Predose and at designated timepoints up to day 28 postdose | Blood samples will be collected to determine the Cmax of glycopyrronium. |
| Plasma Trough Concentration (Ctrough) of Glycopyrronium | Day 28 | Blood samples will be collected to determine the Ctrough of glycopyrronium. |
| Average Plasma Concentrations (Cavg) of Glycopyrronium | Day 28 | Blood samples will be collected to determine the Cavg of glycopyrronium. |
| Time to Maximum Plasma Concentration (Tmax) of Glycopyrronium | Predose and at designated timepoints up to day 28 postdose | Blood samples will be collected to determine the Tmax of glycopyrronium. |
| Apparent Clearance (CL/F) of Glycopyrronium | Day 28 | Blood samples will be collected to determine the CL/F of glycopyrronium. |
| Accumulation Ratio Cmax (ARCmax) of Glycopyrronium | Predose and at designated timepoints up to day 28 postdose | Blood samples will be collected to determine the ARCmax of glycopyrronium. |
| Accumulation Ratio AUC (ARAUCs) of Glycopyrronium | Predose and at designated timepoints up to day 28 postdose | Blood Samples Will be Collected to Determine the ARAUC of glycopyrronium. |
Countries
United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed