Clinical trial NCT04535986: A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Lead sponsor: Verona Pharma plc
Sponsor class: INDUSTRY
Collaborators: name: Iqvia Pty Ltd
First posted: 2020-09-02
Enrollment: 763
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Least Square (LS) Mean Change From Baseline in Average Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) at Week 12
timeFrame: Baseline (pre-dose on Day 1) and Week 12
Secondary outcomes:
measure: LS Mean Change From Baseline FEV1 to Peak FEV1 at Day 1 and Weeks 6, 12 and 24
timeFrame: Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
measure: LS Mean Change From Baseline to the Mean Weekly Evaluating-Respiratory Symptoms (E-RS) Total Score at Weeks 6, 12 and 24
timeFrame: Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
measure: LS Mean Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Weeks 6, 12 and 24
timeFrame: Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
measure: LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 6, 12 and 24
timeFrame: Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
measure: LS Mean Change From Baseline in Average FEV1 Area Under the Curve Over 4 Hours (AUC0-4h) at Day 1 and Weeks 6, 12 and 24
timeFrame: Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
measure: Percentage of SGRQ Responders at Weeks 6, 12 and 24
timeFrame: Weeks 6, 12 and 24
measure: LS Mean Change From Baseline to the Mean Weekly Rescue Medication Use at Weeks 6, 12 and 24
timeFrame: Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
measure: LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 6, 12 and 24
timeFrame: Weeks 6, 12 and 24
measure: LS Mean Change From Baseline FEV1 to Evening Trough FEV1 at Week 12
timeFrame: Baseline (pre-dose on Day 1) and Week 12
Other outcomes:
Locations:
city: Peoria
country: United States
facility: Phoenix Medical Group
state: Arizona
city: Tempe
country: United States
facility: AMR Tempe
state: Arizona
city: Huntington Beach
country: United States
facility: Beach Physicians Medical Group
state: California
city: Los Angeles
country: United States
facility: Downtown LA Research Center, Inc.
state: California
city: Clearwater
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: Clearwater
country: United States
facility: St. Francis Medical Institute
state: Florida
city: Hialeah
country: United States
facility: Qway Research, LLC
state: Florida
city: Lake City
country: United States
facility: Multi-Specialty Research Associates, Inc.
state: Florida
city: Miami
country: United States
facility: Elite Clinical Research
state: Florida
city: Miami
country: United States
facility: Global Research Solutions Corp
state: Florida
city: Miami
country: United States
facility: Phoenix Medical Research
state: Florida
city: Orlando
country: United States
facility: Florida Institute for Clinical Research
state: Florida
city: Sunrise
country: United States
facility: Precision Clinical Research
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: Decatur
country: United States
facility: iResearch Atlanta, LLC
state: Georgia
city: Rincon
country: United States
facility: IACT Health
state: Georgia
city: Suwanee
country: United States
facility: In-Quest Medical Research, LLC
state: Georgia
city: Baltimore
country: United States
facility: John Hopkins University School of Medicine
state: Maryland
city: Farmington Hills
country: United States
facility: Pulmonary Research Institute of SE Michigan
state: Michigan
city: Saint Charles
country: United States
facility: Midwest Chest Consultants
state: Missouri
city: Saint Louis
country: United States
facility: The Clinical Research Center, LLC
state: Missouri
city: Las Vegas
country: United States
facility: Sierra Clinical Research
state: Nevada
city: Las Vegas
country: United States
facility: Alliance for Multispecialty Research, LLC
state: Nevada
city: New York
country: United States
facility: IMA Clinical Research, LLC
state: New York
city: Monroe
country: United States
facility: Monroe Biomedical Research
state: North Carolina
city: Columbus
country: United States
facility: Remington Davis Clinical Research
state: Ohio
city: Grants Pass
country: United States
facility: Velocity Clinical Research - Grants Pass
state: Oregon
city: DuBois
country: United States
facility: Clinical Research Associates of Central PA, LLC
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Physicians, Emphysema/COPD Research Center
state: Pennsylvania
city: Columbia
country: United States
facility: Medtrial
state: South Carolina
city: Lancaster
country: United States
facility: MDFirst Research
state: South Carolina
city: Chattanooga
country: United States
facility: Chattanooga Research & Medicine (CHARM)
state: Tennessee
city: Johnson City
country: United States
facility: MultiSpecialty Clinical Research, Inc.
state: Tennessee
city: Knoxville
country: United States
facility: New Phase Research Development
state: Tennessee
city: Houston
country: United States
facility: West Houston Clinical Research Services
state: Texas
city: Pearland
country: United States
facility: LinQ Research, LLC
state: Texas
city: Sherman
country: United States
facility: Sherman Clinical Research
state: Texas
city: Abingdon
country: United States
facility: Pulmonary Research of Abingdon, LLC
state: Virginia
city: Williamsburg
country: United States
facility: TPMG Clinical Research Williamsburg
state: Virginia
city: Haskovo
country: Bulgaria
facility: SHATPPD - Haskovo, EOOD
city: Pleven
country: Bulgaria
facility: Medical center Medconsult Pleven OOD
city: Plovdiv
country: Bulgaria
facility: UMHAT-Plovdiv AD
city: Sofia
country: Bulgaria
facility: Medical Center Hera EOOD
city: Vidin
country: Bulgaria
facility: MC "Sv. Ivan Rilski", OOD
city: Brandýs Nad Labem
country: Czechia
facility: MUDr. I. Cierna Peterova s.r.o.
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno, Dept of Klinika nemoci plicnich a tuberkulozy
city: Broumov
country: Czechia
facility: EDUMED s.r.o.
city: Hlučín
country: Czechia
facility: MUDr. Petr Pravda
city: Jindřichův Hradec
country: Czechia
facility: MediTrial s.r.o.
city: Kralupy Nad Vltavou
country: Czechia
facility: Plicni ambulance Kralupy s.r.o.
city: Lovosice
country: Czechia
facility: CEFISPIRO s.r.o.
city: Opava
country: Czechia
facility: Odborná plicní ambulance Opava s.r.o.
city: Praha 4
country: Czechia
facility: DAWON spol. s.r.o., Plicni ambulance
city: Praha 5
country: Czechia
facility: Plicni centrum s.r.o.
city: Rokycany
country: Czechia
facility: MUDr. Josef Veverka, Plicni ambulacne
city: Teplice
country: Czechia
facility: Plicni stredisko Teplice s.r.o.
city: Cottbus
country: Germany
facility: MECS GmbH Cottbus
state: Brandenburg
city: Berlin
country: Germany
facility: Clinical Studies Pankow Dr Dr Evelin Liefring/Ishak Teber
state: Bremen
city: Frankfurt am Main
country: Germany
facility: IKF Pneumologie GmbH & Co. KG
state: Hessen
city: Frankfurt
country: Germany
facility: Praxis Dr. Keller
state: Hessen
city: Peine
country: Germany
facility: Dr. Christian Schlenska
state: Niedersachsen
city: Koeln
country: Germany
facility: Zentrum fur Klinische Forschung
state: Nordrhein Westfalen
city: Rheine
country: Germany
facility: Framol-med GmbH, Pneumologische Gemeinschaftspraxis Rheine
state: Nordrhein Westfalen
city: Magdeburg
country: Germany
facility: SMO.MD GmbH
state: Sachsen Anhalt
city: Leipzig
country: Germany
facility: Pneumologische Praxis Dr. Falk Brunner
state: Sachsen
city: Leipzig
country: Germany
facility: Salvus-Klinische Studien GmbH.
state: Sachsen
city: Großhansdorf
country: Germany
facility: PRI Pulmonary Research Institute, Pneumologisches Forschungsinstitut GmbH
state: Schleswig Holstein
city: Luebeck
country: Germany
facility: KLB Gesundheitsforschung Luebeck GmbH; Praxis Dr. med. Jens Becker
state: Schleswig Holstein
city: Berlin
country: Germany
facility: Studienpraxis Berlin-Brandenburg
city: Berlin
country: Germany
facility: Praxis an der Oper.
city: Neu Isenburg
country: Germany
facility: Ballenberger, Freytag, Wenisch Institut für klinische Forschung
city: Athens
country: Greece
facility: General Hospital of Athens of Chest Diseases "SOTIRIA", 7th Respiratory Clinic
city: Heraklion
country: Greece
facility: University General Hospital of Heraklion, Pulmonary Clinic
city: Ioánnina
country: Greece
facility: University General Hospital of Ioannina, University Respiratory Clinic
city: Larissa
country: Greece
facility: University General Hospital of Larissa, University Pulmonary Clinic
city: Budapest
country: Hungary
facility: Clinexpert Kft.
city: Hajdúnánás
country: Hungary
facility: Szalay János Rendelőintézet Tüdőgyógyászati Szakrendelés
city: Monor
country: Hungary
facility: Bajcsy-Zsilinszky Kórház és Rendelőintézet Monori Rendelőintézete
city: Mosonmagyaróvár
country: Hungary
facility: Karolina Kórház-Rendelőintézet, Tüdőgyógyászat
city: Püspökladány
country: Hungary
facility: Püspökladányi Egészségügyi Szolgáltató Nonprofit Kft.
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatókórház Tüdőgondozó
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Yeouido St.Mary's Hospital
city: Bydgoszcz
country: Poland
facility: NZOZ Centrum Medyczne KERmed
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lublin
country: Poland
facility: Centrum Alergologii Sp. z o. o.
city: Siedlce
country: Poland
facility: ETG Siedlce
city: Toruń
country: Poland
facility: NASZ LEKARZ Ośrodek Badań Klinicznych
city: Warsaw
country: Poland
facility: ETG Warszawa
city: Braşov
country: Romania
facility: S.C Centrul Medical Unirea S.R.L, Campus Medical Brasov
city: Braşov
country: Romania
facility: S.C Centrul Medical de Diagnostic si Tratament Ambulator Neomed S.R.L
city: Braşov
country: Romania
facility: Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca
city: Bucuresti
country: Romania
facility: Quantum Medical Center S.R.L.
city: Bucuresti
country: Romania
facility: Institutul de Pneumoftiziologie "Marius Nasta"
city: Cluj-Napoca
country: Romania
facility: S.C Cardiomed S.R.L
city: Codlea
country: Romania
facility: Impatiens SRL
city: Timişoara
country: Romania
facility: Fundatia Cardioprevent
city: Timişoara
country: Romania
facility: Spitalul Clinic de Boli Infectioase si Pneumoftiziologie "Dr. Victor Babes" Timisoara
city: Barnaul
country: Russian Federation
facility: NSHI "Departmental CH on St. Barnaul of JSCO "Russian Railways"
city: Chelyabinsk
country: Russian Federation
facility: SBHI "Regional Clinical Hospital #3"
city: Ekaterinburg
country: Russian Federation
facility: LLC MA New Hospital
city: Ekaterinburg
country: Russian Federation
facility: City Hospital #6
city: Kemerovo
country: Russian Federation
facility: FSBI "Scientific-research Institute for Complex Problems of cardiovascular disease"
city: Novosibirsk
country: Russian Federation
facility: LLC "Novosibirsk GastroCenter"
city: Novosibirsk
country: Russian Federation
facility: SBIH of Novosibirsk Region "Clinical Emergency Hospital #2"
city: Novosibirsk
country: Russian Federation
facility: City Clinical Hospital #25
city: Saint Petersburg
country: Russian Federation
facility: SPb SBHI "Vvedenskaya hospital"
city: Saint Petersburg
country: Russian Federation
facility: "LEC at the LLC "LLC "Energiy Zdorovya"
city: Saint Petersburg
country: Russian Federation
facility: LLC "Institute of Medical Examinations"
city: Saint Petersburg
country: Russian Federation
facility: Research center Eco-safety, LLC
city: Saint Petersburg
country: Russian Federation
facility: Pavlov First Saint Petersburg State Medical University
city: Sestroretsk
country: Russian Federation
facility: SPb SBIH "City Hospital # 40 of Kurortnyi region"
city: Yaroslavl
country: Russian Federation
facility: SBHI of Yaroslavl Region "Clinical Hospital # 2"
city: Yaroslavl
country: Russian Federation
facility: SBHI of Yaroslavl Region "Clinical Hospital # 2"
city: Yaroslavl
country: Russian Federation
facility: SBHI Outpatient 2
city: Bardejov
country: Slovakia
facility: Nemocnica s poliklinikou Sv. Jakuba, n.o. Bardejov
city: Humenné
country: Slovakia
facility: Inspiro, s.r.o.
city: Spišská Nová Ves
country: Slovakia
facility: Plucna ambulancia Hrebenar, s.r.o.
city: London
country: United Kingdom
facility: Respiratory Clinical Trials Ltd
state: Greater London
Study officials:
References: