A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Ensifentrine; Placebo
Intervention description: Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks or 48 weeks; Dosage Formulation: Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks or 48 weeks
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 763.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: COPD

Summary:

      The purpose of this study is to evaluate the efficacy and safety of ensifentrine in patients
      with moderate to severe Chronic Obstructive Pulmonary Disease (COPD).
    

Eligibility criteria:

        Inclusion Criteria:

        Informed Consent

          1. 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 informed consent form (ICF).

             Age and Sex

          2. Age: Patient must be 40 to 80 years of age inclusive, at the time of Screening.

          3. Sex:

               -  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 at least one of the following conditions apply:

                    1. Not a woman of childbearing potential (WOCBP) as defined in Or

                    2. A WOCBP who agrees to follow the contraceptive guidance from Screening and
                       throughout the study and for at least 30 days after the last dose of blinded
                       study medication.

             Smoking History

          4. Smoking History: Current or former cigarette smokers with a history of cigarette
             smoking ≥10 pack years at Screening (Visit 0) [number of pack years = (number of
             cigarettes per day / 20) × number of years smoked (eg, 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 Visit 0. Smoking cessation programs are
             permitted during the study.

             COPD Diagnosis, Symptoms, Severity and Maintenance Therapy

          5. COPD Diagnosis: Patients 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.

          6. COPD Symptoms: A score of ≥2 on the Modified Medical Research Council (mMRC) Dyspnea
             Scale.

          7. COPD Severity:

               1. Pre- and Post-albuterol/salbutamol FEV1/FVC ratio of <0.70.

               2. Post-albuterol/salbutamol FEV1 ≥30 % and ≤70% of predicted normal calculated
                  using the National Health and Nutrition Examination Survey III.

          8. Maintenance Therapy: Patients on no maintenance/background therapy or patients on
             stable maintenance LAMA or LABA therapy are eligible. Patients taking maintenance LAMA
             or LABA therapy must demonstrate stable use of the maintenance LAMA or LABA therapy
             for at least 3 months prior to Screening and agree to continue use for the duration of
             the study. Background maintenance LAMA or LABA bronchodilator therapy will be capped
             at 50% of patients.

             Other Requirements for Inclusion

          9. Capable of withholding SABAs for 4 hours prior to initiation of any spirometry.
             Patients in the maintenance LAMA or LABA therapy stratum must be capable of
             withholding Twice-Daily maintenance LAMA or LABA for 24 hours and Once-Daily
             maintenance LAMA or LABA for 48 hours prior to initiation of any spirometry.

         10. Capable of using the study nebulizer correctly and complying with all study
             restrictions and procedures.

         11. Ability to perform acceptable spirometry in accordance with ATS/ERS guidelines.

        Inclusion Criteria at Randomization (RPL554-CO-301)

          1. Symptoms of COPD: A score of ≥2 on the mMRC Dyspnea Scale.

          2. Completion of the e-Diary at least 5 of the last 7 days of the Run-in period.

        Exclusion Criteria:

        Current Condition or Medical History

          1. History of life-threatening COPD including Intensive Care Unit admission and/or
             requiring intubation.

          2. Hospitalizations for COPD, pneumonia, or Corona Virus Disease 2019 (COVID-19) in the
             12 weeks prior to Screening and/or a positive COVID-19 test result indicating an
             active infection at Screening. Patients with COVID-19 antibodies from a previous
             exposure with no active infection are not excluded.

          3. COPD exacerbation requiring oral or parenteral steroids within 3 months of Screening.

          4. Previous lung resection or lung reduction surgery within 1-year of Screening.

          5. 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.

          6. Pulmonary rehabilitation, unless such treatment has been in a stable maintenance phase
             for 4 weeks prior to Visit 1 and remains stable during the study.

          7. Lower respiratory tract infection within 6 weeks of Screening.

          8. Other respiratory disorders including, but not limited to, a current diagnosis of
             asthma, active tuberculosis, lung cancer, sarcoidosis, lung fibrosis, interstitial
             lung diseases, unstable sleep apnea, known alpha-1 antitrypsin deficiency, core
             pulmonale, clinically significant pulmonary hypertension, clinically significant
             bronchiectasis, or other active pulmonary diseases.

          9. Major surgery (requiring general anesthesia) in the 6 weeks prior to Screening, lack
             of full recovery from surgery at Screening, or planned surgery through the end of the
             study.

         10. Historical or current evidence of clinically significant cardiovascular disease
             defined as any disease that in the opinion of the Investigator would put the safety of
             the patient at risk through participation or which could affect the efficacy or safety
             analysis if the disease/condition were to exacerbate during the study, including, but
             not limited to:

               -  Myocardial infarction or unstable angina within 6 months prior to Screening.

               -  Unstable or life-threatening cardiac arrhythmia requiring intervention within 3
                  months prior to Screening.

               -  Diagnosis of New York Heart Association Class III and Class IV heart failure.

         11. Chronic uncontrolled disease including, but not limited to, endocrine, active
             hyperthyroidism, neurological, hepatic, gastrointestinal, renal, hematological,
             urological, immunological, psychiatric, or ophthalmic diseases that the Investigator
             believes are clinically significant.

         12. Unstable liver disease defined by the presence of ascites, encephalopathy,
             coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice,
             cirrhosis, known biliary abnormalities (except for Gilbert's syndrome or asymptomatic
             gallstones).

         13. 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.

         14. Findings on physical examination that an investigator considers to be clinically
             significant at Screening.

             Prior/Concomitant Therapy

         15. Use of prohibited medications within the time intervals.

             History or Suspicion of Drug or Alcohol Abuse

         16. Current or history of past drug or alcohol abuse within the past 5 years.

             Laboratory and Other Diagnostic Parameters

         17. Glomerular Filtration Rate (eGFR) <30 mL/min. The Chronic Kidney Disease Epidemiology
             Collaboration Creatinine (2009) calculation will be used (Levey, 2009).

         18. Alanine aminotransferase (ALT) ≥ 2 x upper limit of normal (ULN), alkaline phosphatase
             and/or bilirubin > 1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin
             is fractionated and direct bilirubin <35%).

         19. Any other abnormal hematology, biochemistry, or viral serology deemed by an
             investigator to be clinically significantly abnormal. Abnormal chemistry and/or
             hematology may be repeated during Screening.

         20. Chest X-ray (CXR; posterior-anterior) at Screening, or in the 12 months prior to
             Screening with clinically significant abnormalities not attributable to COPD. If a CXR
             within the past 12 months is not available but a computerized tomography (CT) scan
             within the same time period is available, the CT scan may be reviewed in place of a
             CXR. For subjects in Germany, if a CXR or CT scan is not available in the 12 months
             prior to Screening, the subject is not eligible for the study.

         21. Electrocardiogram (ECG) finding that is significantly abnormal on the 12-lead ECG
             obtained at Screening.

             Other Exclusions

         22. Use of an experimental drug within 30 days or 5 half-lives of Screening, whichever is
             longer, and/or participation in a study treatment-free follow-up phase of a clinical
             study within 30 days prior to Screening.

         23. 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 Screening.

         24. Intolerance or hypersensitivity to albuterol/salbutamol or ensifentrine (RPL554) or
             any of its excipients/components.

         25. Prior receipt of blinded study medication in an ensifentrine (RPL554) study.

         26. 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.

         27. Inability to read, understand, and/or complete questionnaires (in the opinion of the
             Investigator).

         28. A disclosed history or one known to the Investigator of significant non-compliance in
             previous investigational studies or with prescribed medications.

         29. Any other reason that the Investigator considers makes the patient unsuitable to
             participate.

        Exclusion Criteria at Randomization (RPL554-CO-301)

          1. COPD exacerbation or lower respiratory tract infection between Screening and
             Randomization (defined as use of any additional treatment other than current treatment
             and rescue medication and/or emergency department or hospital visit). Patients with a
             severe COPD exacerbation that requires hospitalization may not be rescreened.

          2. Positive COVID-19 result at Screening or between Screening and Randomization.

          3. Prohibited medication use between Screening Visit 0 and Visit 1.

          4. Significantly abnormal ECG finding on the 12-lead ECG obtained at Screening as
             assessed by the investigator or site medical doctor/medically qualified person or on
             the pre-dose (prior to randomization) ECG obtained at Visit 1.

             In the event that the central ECG reviewer discovers a significant ECG abnormality on
             the Visit 1 ECG, the patient will be discontinued.

          5. Did not meet one or more of the Inclusion Criteria or met one or more of the Exclusion
             Criteria.