A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD
NCT ID: NCT04535986
Last Updated: 2023-11-13
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
763 participants
INTERVENTIONAL
2020-09-29
2022-12-02
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 BID
Ensifentrine
Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks or 48 weeks
Arm 2
Placebo Nebulized BID
Placebo
Dosage Formulation: Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks or 48 weeks
Interventions
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Ensifentrine
Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks or 48 weeks
Placebo
Dosage Formulation: Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks or 48 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) 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.
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 (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.
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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Phoenix Medical Group
Peoria, Arizona, United States
AMR Tempe
Tempe, Arizona, United States
Beach Physicians Medical Group
Huntington Beach, California, United States
Downtown LA Research Center, Inc.
Los Angeles, California, United States
Clinical Research of West Florida, Inc.
Clearwater, Florida, United States
St. Francis Medical Institute
Clearwater, Florida, United States
Qway Research, LLC
Hialeah, Florida, United States
Multi-Specialty Research Associates, Inc.
Lake City, Florida, United States
Elite Clinical Research
Miami, Florida, United States
Global Research Solutions Corp
Miami, Florida, United States
Phoenix Medical Research
Miami, Florida, United States
Florida Institute for Clinical Research
Orlando, Florida, United States
Precision Clinical Research
Sunrise, Florida, United States
Clinical Research of West Florida, Inc.
Tampa, Florida, United States
iResearch Atlanta, LLC
Decatur, Georgia, United States
IACT Health
Rincon, Georgia, United States
In-Quest Medical Research, LLC
Suwanee, Georgia, United States
John Hopkins University School of Medicine
Baltimore, Maryland, United States
Pulmonary Research Institute of SE Michigan
Farmington Hills, Michigan, United States
Midwest Chest Consultants
Saint Charles, Missouri, United States
The Clinical Research Center, LLC
St Louis, Missouri, United States
Sierra Clinical Research
Las Vegas, Nevada, United States
Alliance for Multispecialty Research, LLC
Las Vegas, Nevada, United States
IMA Clinical Research, LLC
New York, New York, United States
Monroe Biomedical Research
Monroe, North Carolina, United States
Remington Davis Clinical Research
Columbus, Ohio, United States
Velocity Clinical Research - Grants Pass
Grants Pass, Oregon, United States
Clinical Research Associates of Central PA, LLC
DuBois, Pennsylvania, United States
University of Pittsburgh Physicians, Emphysema/COPD Research Center
Pittsburgh, Pennsylvania, United States
Medtrial
Columbia, South Carolina, United States
MDFirst Research
Lancaster, South Carolina, United States
Chattanooga Research & Medicine (CHARM)
Chattanooga, Tennessee, United States
MultiSpecialty Clinical Research, Inc.
Johnson City, Tennessee, United States
New Phase Research Development
Knoxville, Tennessee, United States
West Houston Clinical Research Services
Houston, Texas, United States
LinQ Research, LLC
Pearland, Texas, United States
Sherman Clinical Research
Sherman, Texas, United States
Pulmonary Research of Abingdon, LLC
Abingdon, Virginia, United States
TPMG Clinical Research Williamsburg
Williamsburg, Virginia, United States
SHATPPD - Haskovo, EOOD
Haskovo, , Bulgaria
Medical center Medconsult Pleven OOD
Pleven, , Bulgaria
UMHAT-Plovdiv AD
Plovdiv, , Bulgaria
Medical Center Hera EOOD
Sofia, , Bulgaria
MC "Sv. Ivan Rilski", OOD
Vidin, , Bulgaria
MUDr. I. Cierna Peterova s.r.o.
Brandýs nad Labem, , Czechia
Fakultni nemocnice Brno, Dept of Klinika nemoci plicnich a tuberkulozy
Brno, , Czechia
EDUMED s.r.o.
Broumov, , Czechia
MUDr. Petr Pravda
Hlučín, , Czechia
MediTrial s.r.o.
Jindřichův Hradec, , Czechia
Plicni ambulance Kralupy s.r.o.
Kralupy nad Vltavou, , Czechia
CEFISPIRO s.r.o.
Lovosice, , Czechia
Odborná plicní ambulance Opava s.r.o.
Opava, , Czechia
DAWON spol. s.r.o., Plicni ambulance
Prague, , Czechia
Plicni centrum s.r.o.
Prague, , Czechia
MUDr. Josef Veverka, Plicni ambulacne
Rokycany, , Czechia
Plicni stredisko Teplice s.r.o.
Teplice, , Czechia
MECS GmbH Cottbus
Cottbus, Brandenburg, Germany
Clinical Studies Pankow Dr Dr Evelin Liefring/Ishak Teber
Berlin, City state Bremen, Germany
Praxis Dr. Keller
Frankfurt am Main, Hesse, Germany
IKF Pneumologie GmbH & Co. KG
Frankfurt am Main, Hesse, Germany
Dr. Christian Schlenska
Peine, Lower Saxony, Germany
Zentrum fur Klinische Forschung
Cologne, North Rhine-Westphalia, Germany
Framol-med GmbH, Pneumologische Gemeinschaftspraxis Rheine
Rheine, North Rhine-Westphalia, Germany
Pneumologische Praxis Dr. Falk Brunner
Leipzig, Saxony, Germany
Salvus-Klinische Studien GmbH.
Leipzig, Saxony, Germany
SMO.MD GmbH
Magdeburg, Saxony-Anhalt, Germany
PRI Pulmonary Research Institute, Pneumologisches Forschungsinstitut GmbH
Großhansdorf, Schleswig-Holstein, Germany
KLB Gesundheitsforschung Luebeck GmbH; Praxis Dr. med. Jens Becker
Lübeck, Schleswig-Holstein, Germany
Studienpraxis Berlin-Brandenburg
Berlin, , Germany
Praxis an der Oper.
Berlin, , Germany
Ballenberger, Freytag, Wenisch Institut für klinische Forschung
Neu-Isenburg, , Germany
General Hospital of Athens of Chest Diseases "SOTIRIA", 7th Respiratory Clinic
Athens, , Greece
University General Hospital of Heraklion, Pulmonary Clinic
Heraklion, , Greece
University General Hospital of Ioannina, University Respiratory Clinic
Ioannina, , Greece
University General Hospital of Larissa, University Pulmonary Clinic
Larissa, , Greece
Clinexpert Kft.
Budapest, , Hungary
Szalay János Rendelőintézet Tüdőgyógyászati Szakrendelés
Hajdúnánás, , Hungary
Bajcsy-Zsilinszky Kórház és Rendelőintézet Monori Rendelőintézete
Monor, , Hungary
Karolina Kórház-Rendelőintézet, Tüdőgyógyászat
Mosonmagyaróvár, , Hungary
Püspökladányi Egészségügyi Szolgáltató Nonprofit Kft.
Püspökladány, , Hungary
Markusovszky Egyetemi Oktatókórház Tüdőgondozó
Szombathely, , Hungary
NZOZ Centrum Medyczne KERmed
Bydgoszcz, , Poland
Uniwersyteckie Centrum Kliniczne
Gdansk, , Poland
Centrum Alergologii Sp. z o. o.
Lublin, , Poland
ETG Siedlce
Siedlce, , Poland
NASZ LEKARZ Ośrodek Badań Klinicznych
Torun, , Poland
ETG Warszawa
Warsaw, , Poland
S.C Centrul Medical Unirea S.R.L, Campus Medical Brasov
Brasov, , Romania
S.C Centrul Medical de Diagnostic si Tratament Ambulator Neomed S.R.L
Brasov, , Romania
Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca
Brasov, , Romania
Quantum Medical Center S.R.L.
Bucharest, , Romania
Institutul de Pneumoftiziologie "Marius Nasta"
Bucharest, , Romania
S.C Cardiomed S.R.L
Cluj-Napoca, , Romania
Impatiens SRL
Codlea, , Romania
Fundatia Cardioprevent
Timișoara, , Romania
Spitalul Clinic de Boli Infectioase si Pneumoftiziologie "Dr. Victor Babes" Timisoara
Timișoara, , Romania
NSHI "Departmental CH on St. Barnaul of JSCO "Russian Railways"
Barnaul, , Russia
SBHI "Regional Clinical Hospital #3"
Chelyabinsk, , Russia
FSBI "Scientific-research Institute for Complex Problems of cardiovascular disease"
Kemerovo, , Russia
LLC "Novosibirsk GastroCenter"
Novosibirsk, , Russia
SBIH of Novosibirsk Region "Clinical Emergency Hospital #2"
Novosibirsk, , Russia
City Clinical Hospital #25
Novosibirsk, , Russia
SPb SBHI "Vvedenskaya hospital"
Saint Petersburg, , Russia
"LEC at the LLC "LLC "Energiy Zdorovya"
Saint Petersburg, , Russia
LLC "Institute of Medical Examinations"
Saint Petersburg, , Russia
Research center Eco-safety, LLC
Saint Petersburg, , Russia
Pavlov First Saint Petersburg State Medical University
Saint Petersburg, , Russia
SPb SBIH "City Hospital # 40 of Kurortnyi region"
Sestroretsk, , Russia
SBHI of Yaroslavl Region "Clinical Hospital # 2"
Yaroslavl, , Russia
SBHI of Yaroslavl Region "Clinical Hospital # 2"
Yaroslavl, , Russia
SBHI Outpatient 2
Yaroslavl, , Russia
LLC MA New Hospital
Yekaterinburg, , Russia
City Hospital #6
Yekaterinburg, , Russia
Nemocnica s poliklinikou Sv. Jakuba, n.o. Bardejov
Bardejov, , Slovakia
Inspiro, s.r.o.
Humenné, , Slovakia
Plucna ambulancia Hrebenar, s.r.o.
Spišská Nová Ves, , Slovakia
Yeungnam University Hospital
Daegu, , South Korea
Kyung Hee University Hospital
Seoul, , South Korea
Asan Medical Center
Seoul, , South Korea
The Catholic University of Korea, Seoul St. Mary's Hospital
Seoul, , South Korea
The Catholic University of Korea, Yeouido St.Mary's Hospital
Seoul, , South Korea
Respiratory Clinical Trials Ltd
London, Greater London, United Kingdom
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-301
Identifier Type: -
Identifier Source: org_study_id
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