A Phase 3 Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD
NCT ID: NCT04542057
Last Updated: 2023-10-16
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
790 participants
INTERVENTIONAL
2020-09-22
2022-07-06
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Arm 1
Ensifentrine Nebulized Suspension; 3 mg twice daily for 24 weeks
Ensifentrine
Dosage Formulation:
Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks
Arm 2
Ensifentrine Placebo Nebulized Solution; twice daily for 24 weeks
Placebo
Dosage Formulation:
Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks
Interventions
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Ensifentrine
Dosage Formulation:
Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks
Placebo
Dosage Formulation:
Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks
Eligibility Criteria
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Inclusion Criteria
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). 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 (Celli BR, 2004) 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.
Randomization Criteria Criteria for Inclusion at Randomization
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
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.
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 trial 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 trial 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.
Criteria for Exclusion from Randomization
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.
40 Years
80 Years
ALL
No
Sponsors
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Iqvia Pty Ltd
INDUSTRY
Verona Pharma plc
INDUSTRY
Responsible Party
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Locations
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Wright Clinical Research, LLC
Alabaster, Alabama, United States
SEC Clinical Research
Andalusia, Alabama, United States
Jasper Summit Research LLC
Jasper, Alabama, United States
Pulmonary Associates Clinical Trials
Phoenix, Arizona, United States
Elite Clinical Studies LLC
Phoenix, Arizona, United States
Clinical Research Institute of Arizona, LLC
Sun City West, Arizona, United States
Premier Medical Group
Bakersfield, California, United States
Antelope Valley Clinical Trials
Lancaster, California, United States
Downtown LA Research Center, Inc.
Los Angeles, California, United States
UCLA Medical Center
Los Angeles, California, United States
California Medical Research Associates
Northridge, California, United States
Center for Clinical Trials of Sacramento, Inc.
Sacramento, California, United States
Integrated Research Center
San Diego, California, United States
Institute of HealthCare Assessment, Inc.
San Diego, California, United States
Alpine Clinical Research Center
Boulder, Colorado, United States
Innovative Research of West Florida
Clearwater, Florida, United States
Clinical Research of West Florida, Inc.
Clearwater, Florida, United States
Accel Research Sites - DeLand Clinical Research Unit
DeLand, Florida, United States
Riverside Clinical Research
Edgewater, Florida, United States
Medical Research of Central Florida
Leesburg, Florida, United States
Axcess Medical Research
Loxahatchee Groves, Florida, United States
Research Institute of South Florida
Miami, Florida, United States
Advanced Medical Research Institute
Miami, Florida, United States
Clinical Trials of Florida. LLC
Miami, Florida, United States
South Medical Research Group, Inc.
Miami, Florida, United States
ProCare Clinical Research
Miami Gardens, Florida, United States
HMD Research, LLC
Orlando, Florida, United States
Florida Institute for Clinical Research
Orlando, Florida, United States
Sarasota Clinical Research
Sarasota, Florida, United States
Coastal Pulmonary Critical Care
St. Petersburg, Florida, United States
Pasadena Center for Medical Research, LLC
St. Petersburg, Florida, United States
Clinical Research of West Florida, Inc.
Tampa, Florida, United States
Clinical Research Trials of Florida, Inc.
Tampa, Florida, United States
Florida Pulmonary Research Institute, LLC
Winter Park, Florida, United States
AMR New Orleans
New Orleans, Louisiana, United States
Genesis Clin RES& Consulting
Fall River, Massachusetts, United States
Minnesota Lung Center
Edina, Minnesota, United States
Minnesota Lung Center
Woodbury, Minnesota, United States
Midwest Chest Consultants
Saint Charles, Missouri, United States
Montana Medical Research Inc.
Missoula, Montana, United States
Mid Hudson Medical Research
New Windsor, New York, United States
CHEAR Center LLC
The Bronx, New York, United States
Carolina Clinical Research
Charlotte, North Carolina, United States
American Health Research
Charlotte, North Carolina, United States
Clinical Research of Gastonia
Gastonia, North Carolina, United States
PharmQuest LLC
Greensboro, North Carolina, United States
Monroe Biomedical Research
Monroe, North Carolina, United States
Clinical Research of Lake Norman
Mooresville, North Carolina, United States
Carolina Research Center, Inc.
Shelby, North Carolina, United States
Aventiv Research Inc.
Columbus, Ohio, United States
Remington Davis Clinical Research
Columbus, Ohio, United States
Aventiv Research
Dublin, Ohio, United States
OK Clinical Research, LLC
Edmond, Oklahoma, United States
Velocity Clinical Research, Medford (Crisor, LLC)
Medford, Oregon, United States
Safe Harbor Clinical Research
East Providence, Rhode Island, United States
VitaLink Research Anderson
Anderson, South Carolina, United States
Lowcountry Lung and Critical Care, P.A.
Charleston, South Carolina, United States
VitaLink Research Columbia
Columbia, South Carolina, United States
Piedmont Research Partners
Fort Mill, South Carolina, United States
VitaLink Research Gaffney
Gaffney, South Carolina, United States
VitaLink Research - Greenville
Greenville, South Carolina, United States
Clinical Research of Rock Hill
Rock Hill, South Carolina, United States
Spartanburg Medical Research
Spartanburg, South Carolina, United States
VitaLink Research Spartanburg
Spartanburg, South Carolina, United States
CU Pharmaceutical Research
Union, South Carolina, United States
MultiSpecialty Clinical Research, Inc.
Johnson City, Tennessee, United States
New Phase Research Development
Knoxville, Tennessee, United States
PnP Research
Amarillo, Texas, United States
TTS Research
Boerne, Texas, United States
Corsicana Medical Research, PLLC
Corsicana, Texas, United States
Houston Pulmonary and Sleep Allergy and Asthma Associates
Cypress, Texas, United States
Metroplex Pulmonary and Sleep Center
McKinney, Texas, United States
Diagnostics Research Group
San Antonio, Texas, United States
Element Research Group
San Antonio, Texas, United States
Sherman Clinical Research
Sherman, Texas, United States
DM Clinical Research
Tomball, Texas, United States
Manassas Clinical Research Center
Manassas, Virginia, United States
UZA
Edegem, , Belgium
C.H.R. de la Citadelle
Liège, , Belgium
Private Practice RESPISOM Namur
Namur, , Belgium
AZ Delta
Roeselare, , Belgium
MHAT 'Puls' AD
Blagoevgrad, , Bulgaria
Medical Centre "Asklepii", OOD
Dupnitsa, , Bulgaria
MHAT 'Dr. Stamen Iliev', AD
Montana, , Bulgaria
SHATPPD - Pazardzhik, EOOD
Pazardzhik, , Bulgaria
SHATPD Pernik
Pernik, , Bulgaria
Medical Center- Prolet Ltd
Rousse, , Bulgaria
SHATPPD-Ruse EOOD
Rousse, , Bulgaria
University First MHAT-Sofia, "St. Joan Krastitel" EAD
Sofia, , Bulgaria
Fifth MHAT - Sofia EAD
Sofia, , Bulgaria
NMTH "Tsar Boris III"
Sofia, , Bulgaria
MHAT "Lyulin", EAD
Sofia, , Bulgaria
DCC "Alexandrovska", EOOD
Sofia, , Bulgaria
Diagnostic Consultation Center CONVEX EOOD
Sofia, , Bulgaria
Medical Center "Nov Rehabilitatsionen Tsentar", EOOD
Stara Zagora, , Bulgaria
Medical Center "ResearchExpert", OOD
Varna, , Bulgaria
MC "Tara", OOD
Veliko Tarnovo, , Bulgaria
SHATPPD "Dr. Treyman" EOOD
Veliko Tarnovo, , Bulgaria
SHATPPD - Vratsa, EOOD
Vratsa, , Bulgaria
ALTA Clinical Research Inc.
Edmonton, Alberta, Canada
Synergy Respiratory Care
Sherwood Park, Alberta, Canada
Dynamic Drug Advancement
Ajax, Ontario, Canada
Respirology and Rheumatology Associates
Windsor, Ontario, Canada
C.I.C. Mauricie Inc.
Trois-Rivières, Quebec, Canada
Hvidovre Hospital
Hvidovre, , Denmark
Odense Universitetshospital
Odense C, , Denmark
Zealand University Hospital, Roskilde
Roskilde, , Denmark
Tartu University Hospital, Lung Clinic
Tartu, , Estonia
Dr. Kenessey Albert Kórház-Rendelőintézet, Pulmonológiai Osztály
Balassagyarmat, , Hungary
Komlói Egészségcentrum, Bányászati Utókezelő és Éjjeli Szanatórium Egészségügyi Központ
Komló, , Hungary
Da Vinci Klinika Infer-Med Kft. Tüdőgyógyászat
Pécs, , Hungary
Szarvasi Tüdőgyógyász Kft
Szarvas, , Hungary
Csanád-Csongrád Megyei Mellkasi Betegségek Szakkórháza, Tüdőgondozó Intézet
Szeged, , Hungary
Szent Borbála Kórház, Tüdőgyógyászat
Tatabánya, , Hungary
Centrum Medyczne All-Med
Krakow, , Poland
Małopolskie Centrum Alergologii
Krakow, , Poland
ETG Łódź
Lodz, , Poland
Ostrowieckie Centrum Medyczne spółka cywilna Anna Olech-Cudzik, Krzysztof Cudzik
Ostrowiec Świętokrzyski, , Poland
Prywatny Gabinet Lekarski
Rzeszów, , Poland
Gabinet Pulmonologii i Diagnostyki Chorób Alergicznych
Szczecin, , Poland
Centrum Badań Klinicznych Piotr Napora Lekarze Spółka Partnerska
Wroclaw, , Poland
"ALL-MED" Specjalistyczna Opieka Medyczna, Medyczny Instytut Badawczy
Wroclaw, , Poland
Pneumologicko-ftizeologická ambulancia, Pneumomed, s.r.o
Bratislava, , Slovakia
Zeleznicna nemocnica s poliklinikou
Košice, , Slovakia
Ambulancia pneumologie a ftizeologie, ZAPA JJ, s.r.o.
Levice, , Slovakia
Univerzitna nemocnica Martin, Klinika pneumologie a ftizeologie
Martin, , Slovakia
Hospital Vithas Internacional Xanit
Benalmádena, Málaga, Spain
Institut Catala de Serveis Medics
Girona, , Spain
Hospital Clinico Universitario Virgen de la Victoria
Málaga, , Spain
Hospital Clinico Universitario de Valencia
Valencia, , Spain
Countries
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References
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Dransfield M, Marchetti N, Kalhan R, Reyner D, Dixon AL, Rheault T, Rickard KA, Anzueto A. Ensifentrine in COPD patients taking long-acting bronchodilators: A pooled post-hoc analysis of the ENHANCE-1/2 studies. Chron Respir Dis. 2025 Jan-Dec;22:14799731251314874. doi: 10.1177/14799731251314874.
Sciurba FC, Christenson SA, Rheault T, Bengtsson T, Rickard K, Barjaktarevic IZ. Effect of Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine on Exacerbation Rate and Risk in Patients With Moderate to Severe COPD. Chest. 2025 Feb;167(2):425-435. doi: 10.1016/j.chest.2024.07.168. Epub 2024 Aug 27.
Mahler DA, Bhatt SP, Rheault T, Reyner D, Bengtsson T, Dixon A, Rickard K, Singh D. Effect of ensifentrine on dyspnea in patients with moderate-to-severe chronic obstructive pulmonary disease: pooled analysis of the ENHANCE trials. Expert Rev Respir Med. 2024 Aug;18(8):645-654. doi: 10.1080/17476348.2024.2389960. Epub 2024 Aug 8.
Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, Sciurba F. Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials). Am J Respir Crit Care Med. 2023 Aug 15;208(4):406-416. doi: 10.1164/rccm.202306-0944OC.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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RPL554-CO-302
Identifier Type: -
Identifier Source: org_study_id
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