A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD

A Phase III Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ensifentrine Over 24 Weeks (With a 48-week Safety Subset) in Subjects With Moderate to Severe COPD

Sponsors

Lead Sponsor: Verona Pharma plc

Collaborator: Iqvia Pty Ltd

Source Verona Pharma plc
Brief Summary

The purpose of this study is to determine if ensifentrine is safe and effective for the treatment of patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD).

Overall Status Recruiting
Start Date September 29, 2020
Completion Date August 2022
Primary Completion Date July 2022
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h 12 weeks
Secondary Outcome
Measure Time Frame
Average FEV1 AUC0-4h post-dose at Week 12 12 weeks
Peak FEV1 over 4 hours post dose at Week 12 12 weeks
Weekly average of Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24 24 weeks
St. George's Respiratory Questionnaire (SGRQ) total score at Week 24 24 weeks
Morning trough FEV1 at Week 12 12 weeks
St. George's Respiratory Questionnaire (SGRQ) 24 weeks
Rescue medication use at Week 24 24 weeks
Transitional Dyspnea Index (TDI) at Week 24 24 weeks
Evening trough FEV1 at Week 12 12 weeks
Peak FEV1 at Week 6 and Week 24 6 and 24 weeks
Morning trough FEV1 at Week 6 and Week 24 6 and 24 weeks
Evening trough FEV1 at Week 6 and Week 24 6 and 24 weeks
FEV1 AUC0-4h at Week 6 and Week 24 6 and 24 weeks
Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 6 and Week 12 6 and 12 weeks
St. George's Respiratory Questionnaire (SGRQ) responder analysis at Week 6 and Week 12 6 and 12 weeks
TDI at Week 6 and Week 12 6 and 12 Weeks
St. George's Respiratory Questionnaire (SGRQ) total score at Weeks 6 and 12 6 Weeks and 12 weeks
Rescue medication use at Weeks 6 and 12 12 weeks
Enrollment 800
Condition
Intervention

Intervention Type: Drug

Intervention Name: Ensifentrine

Description: • Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily Study to randomize 800 patients in total Subjects randomized to the 24-week subset will enroll 400 patients (1:1 ensifentrine (3 mg): placebo) Subjects randomized to the 48-week subset will enroll approximately 400 patients randomized 3:1 ensifentrine (3 mg): placebo.

Arm Group Label: Arm 1

Intervention Type: Drug

Intervention Name: Placebo

Description: • Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily Study to randomize 800 patients in total Subjects randomized to the 24-week subset will enroll 400 patients (1:1 ensifentrine (3 mg): placebo) Subjects randomized to the 48-week subset will enroll approximately 400 patients randomized 3:1 ensifentrine (3 mg): placebo.

Arm Group Label: Arm 2

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. Hepatitis B antibody:

- Positive findings for both Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (anti-HBc) are excluded, as this indicates acute or chronic infection.

- Negative findings for HBsAg and Hepatitis B surface antibody (anti-HBs) but positive findings for anti-HBc are excluded as this may indicate current or resolving infection.

- Positive findings for anti-HBc and anti-HBs but negative findings for HBsAg are not excluded, as this indicates immunity due to natural infection.

- Positive findings for anti-HBs but negative findings for HBsAg and anti-HBc are not excluded, as this indicates immunity due to hepatitis B vaccination.

20. Hepatitis C antibody positive.

21. 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.

22. 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.

23. Electrocardiogram (ECG) finding that is significantly abnormal on the 12-lead ECG obtained at Screening.

Other Exclusions

24. 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.

25. 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.

26. Intolerance or hypersensitivity to albuterol/salbutamol or ensifentrine (RPL554) or any of its excipients/components.

27. Prior receipt of blinded study medication in an ensifentrine (RPL554) study.

28. 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.

29. Inability to read, understand, and/or complete questionnaires (in the opinion of the Investigator).

30. A disclosed history or one known to the Investigator of significant non-compliance in previous investigational studies or with prescribed medications.

31. 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.

Gender: All

Minimum Age: 40 Years

Maximum Age: 80 Years

Healthy Volunteers: No

Overall Contact

Last Name: Nancy Herje

Phone: 646-951-0961

Email: [email protected]

Location
Facility: Status: Contact: Investigator:
Pulmonary Research Institute of SE Michigan | Farmington Hills, Michigan, 48336, United States Recruiting Gary Ferguson, MD 248-478-6561 [email protected] Gary Ferguson Principal Investigator
Sierra Clinical Research | Las Vegas, Nevada, 89106, United States Recruiting Naresh Singh, MD 702-384-5101 [email protected] Naresh Singh, MD Principal Investigator
Location Countries

United States

Verification Date

October 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Arm 1

Type: Experimental

Description: Ensifentrine Nebulized Suspension; 3 mg BID

Label: Arm 2

Type: Placebo Comparator

Description: Placebo Nebulized BID

Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Double (Participant, Investigator)

Source: ClinicalTrials.gov