Clinical trial NCT04542057: A Phase 3 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 in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease
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: 2020-09-09
Enrollment: 790
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 determine if ensifentrine is safe and effective for the treatment of 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). 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:

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.
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.
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 (40 minutes before first administration 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 (40 minutes before first administration 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 (average of 7 days before first administration 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 (40 minutes before first administration 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 (40 minutes before first administration 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 (40 minutes before first administration 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 (average of 7 days before first administration 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 (40 minutes before first administration on Day 1) and Week 12
Other outcomes:
Locations:
city: Alabaster
country: United States
facility: Wright Clinical Research, LLC
state: Alabama
city: Andalusia
country: United States
facility: SEC Clinical Research
state: Alabama
city: Jasper
country: United States
facility: Jasper Summit Research LLC
state: Alabama
city: Phoenix
country: United States
facility: Pulmonary Associates Clinical Trials
state: Arizona
city: Phoenix
country: United States
facility: Elite Clinical Studies LLC
state: Arizona
city: Sun City West
country: United States
facility: Clinical Research Institute of Arizona, LLC
state: Arizona
city: Bakersfield
country: United States
facility: Premier Medical Group
state: California
city: Lancaster
country: United States
facility: Antelope Valley Clinical Trials
state: California
city: Los Angeles
country: United States
facility: Downtown LA Research Center, Inc.
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Northridge
country: United States
facility: California Medical Research Associates
state: California
city: Sacramento
country: United States
facility: Center for Clinical Trials of Sacramento, Inc.
state: California
city: San Diego
country: United States
facility: Integrated Research Center
state: California
city: San Diego
country: United States
facility: Institute of HealthCare Assessment, Inc.
state: California
city: Boulder
country: United States
facility: Alpine Clinical Research Center
state: Colorado
city: Clearwater
country: United States
facility: Innovative Research of West Florida
state: Florida
city: Clearwater
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: DeLand
country: United States
facility: Accel Research Sites - DeLand Clinical Research Unit
state: Florida
city: Edgewater
country: United States
facility: Riverside Clinical Research
state: Florida
city: Leesburg
country: United States
facility: Medical Research of Central Florida
state: Florida
city: Loxahatchee Groves
country: United States
facility: Axcess Medical Research
state: Florida
city: Miami Gardens
country: United States
facility: ProCare Clinical Research
state: Florida
city: Miami
country: United States
facility: Research Institute of South Florida
state: Florida
city: Miami
country: United States
facility: Advanced Medical Research Institute
state: Florida
city: Miami
country: United States
facility: Clinical Trials of Florida. LLC
state: Florida
city: Miami
country: United States
facility: South Medical Research Group, Inc.
state: Florida
city: Orlando
country: United States
facility: HMD Research, LLC
state: Florida
city: Orlando
country: United States
facility: Florida Institute for Clinical Research
state: Florida
city: Saint Petersburg
country: United States
facility: Coastal Pulmonary Critical Care
state: Florida
city: Saint Petersburg
country: United States
facility: Pasadena Center for Medical Research, LLC
state: Florida
city: Sarasota
country: United States
facility: Sarasota Clinical Research
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: Tampa
country: United States
facility: Clinical Research Trials of Florida, Inc.
state: Florida
city: Winter Park
country: United States
facility: Florida Pulmonary Research Institute, LLC
state: Florida
city: New Orleans
country: United States
facility: AMR New Orleans
state: Louisiana
city: Fall River
country: United States
facility: Genesis Clin RES& Consulting
state: Massachusetts
city: Edina
country: United States
facility: Minnesota Lung Center
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Lung Center
state: Minnesota
city: Saint Charles
country: United States
facility: Midwest Chest Consultants
state: Missouri
city: Missoula
country: United States
facility: Montana Medical Research Inc.
state: Montana
city: Bronx
country: United States
facility: CHEAR Center LLC
state: New York
city: New Windsor
country: United States
facility: Mid Hudson Medical Research
state: New York
city: Charlotte
country: United States
facility: Carolina Clinical Research
state: North Carolina
city: Charlotte
country: United States
facility: American Health Research
state: North Carolina
city: Gastonia
country: United States
facility: Clinical Research of Gastonia
state: North Carolina
city: Greensboro
country: United States
facility: PharmQuest LLC
state: North Carolina
city: Monroe
country: United States
facility: Monroe Biomedical Research
state: North Carolina
city: Mooresville
country: United States
facility: Clinical Research of Lake Norman
state: North Carolina
city: Shelby
country: United States
facility: Carolina Research Center, Inc.
state: North Carolina
city: Columbus
country: United States
facility: Aventiv Research Inc.
state: Ohio
city: Columbus
country: United States
facility: Remington Davis Clinical Research
state: Ohio
city: Dublin
country: United States
facility: Aventiv Research
state: Ohio
city: Edmond
country: United States
facility: OK Clinical Research, LLC
state: Oklahoma
city: Medford
country: United States
facility: Velocity Clinical Research, Medford (Crisor, LLC)
state: Oregon
city: East Providence
country: United States
facility: Safe Harbor Clinical Research
state: Rhode Island
city: Anderson
country: United States
facility: VitaLink Research Anderson
state: South Carolina
city: Charleston
country: United States
facility: Lowcountry Lung and Critical Care, P.A.
state: South Carolina
city: Columbia
country: United States
facility: VitaLink Research Columbia
state: South Carolina
city: Fort Mill
country: United States
facility: Piedmont Research Partners
state: South Carolina
city: Gaffney
country: United States
facility: VitaLink Research Gaffney
state: South Carolina
city: Greenville
country: United States
facility: VitaLink Research - Greenville
state: South Carolina
city: Rock Hill
country: United States
facility: Clinical Research of Rock Hill
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Medical Research
state: South Carolina
city: Spartanburg
country: United States
facility: VitaLink Research Spartanburg
state: South Carolina
city: Union
country: United States
facility: CU Pharmaceutical Research
state: South Carolina
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: Amarillo
country: United States
facility: PnP Research
state: Texas
city: Boerne
country: United States
facility: TTS Research
state: Texas
city: Corsicana
country: United States
facility: Corsicana Medical Research, PLLC
state: Texas
city: Cypress
country: United States
facility: Houston Pulmonary and Sleep Allergy and Asthma Associates
state: Texas
city: McKinney
country: United States
facility: Metroplex Pulmonary and Sleep Center
state: Texas
city: San Antonio
country: United States
facility: Diagnostics Research Group
state: Texas
city: San Antonio
country: United States
facility: Element Research Group
state: Texas
city: Sherman
country: United States
facility: Sherman Clinical Research
state: Texas
city: Tomball
country: United States
facility: DM Clinical Research
state: Texas
city: Manassas
country: United States
facility: Manassas Clinical Research Center
state: Virginia
city: Edegem
country: Belgium
facility: UZA
city: Liège
country: Belgium
facility: C.H.R. de la Citadelle
city: Namur
country: Belgium
facility: Private Practice RESPISOM Namur
city: Roeselare
country: Belgium
facility: AZ Delta
city: Blagoevgrad
country: Bulgaria
facility: MHAT 'Puls' AD
city: Dupnitsa
country: Bulgaria
facility: Medical Centre "Asklepii", OOD
city: Montana
country: Bulgaria
facility: MHAT 'Dr. Stamen Iliev', AD
city: Pazardzhik
country: Bulgaria
facility: SHATPPD - Pazardzhik, EOOD
city: Pernik
country: Bulgaria
facility: SHATPD Pernik
city: Ruse
country: Bulgaria
facility: Medical Center- Prolet Ltd
city: Ruse
country: Bulgaria
facility: SHATPPD-Ruse EOOD
city: Sofia
country: Bulgaria
facility: University First MHAT-Sofia, "St. Joan Krastitel" EAD
city: Sofia
country: Bulgaria
facility: Fifth MHAT - Sofia EAD
city: Sofia
country: Bulgaria
facility: NMTH "Tsar Boris III"
city: Sofia
country: Bulgaria
facility: MHAT "Lyulin", EAD
city: Sofia
country: Bulgaria
facility: DCC "Alexandrovska", EOOD
city: Sofia
country: Bulgaria
facility: Diagnostic Consultation Center CONVEX EOOD
city: Stara Zagora
country: Bulgaria
facility: Medical Center "Nov Rehabilitatsionen Tsentar", EOOD
city: Varna
country: Bulgaria
facility: Medical Center "ResearchExpert", OOD
city: Veliko Tarnovo
country: Bulgaria
facility: MC "Tara", OOD
city: Veliko Tarnovo
country: Bulgaria
facility: SHATPPD "Dr. Treyman" EOOD
city: Vratsa
country: Bulgaria
facility: SHATPPD - Vratsa, EOOD
city: Edmonton
country: Canada
facility: ALTA Clinical Research Inc.
state: Alberta
city: Sherwood Park
country: Canada
facility: Synergy Respiratory Care
state: Alberta
city: Ajax
country: Canada
facility: Dynamic Drug Advancement
state: Ontario
city: Windsor
country: Canada
facility: Respirology and Rheumatology Associates
state: Ontario
city: Trois-Rivières
country: Canada
facility: C.I.C. Mauricie Inc.
state: Quebec
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Roskilde
country: Denmark
facility: Zealand University Hospital, Roskilde
city: Tartu
country: Estonia
facility: Tartu University Hospital, Lung Clinic
city: Balassagyarmat
country: Hungary
facility: Dr. Kenessey Albert Kórház-Rendelőintézet, Pulmonológiai Osztály
city: Komló
country: Hungary
facility: Komlói Egészségcentrum, Bányászati Utókezelő és Éjjeli Szanatórium Egészségügyi Központ
city: Pécs
country: Hungary
facility: Da Vinci Klinika Infer-Med Kft. Tüdőgyógyászat
city: Szarvas
country: Hungary
facility: Szarvasi Tüdőgyógyász Kft
city: Szeged
country: Hungary
facility: Csanád-Csongrád Megyei Mellkasi Betegségek Szakkórháza, Tüdőgondozó Intézet
city: Tatabánya
country: Hungary
facility: Szent Borbála Kórház, Tüdőgyógyászat
city: Kraków
country: Poland
facility: Centrum Medyczne All-Med
city: Kraków
country: Poland
facility: Małopolskie Centrum Alergologii
city: Ostrowiec Świętokrzyski
country: Poland
facility: Ostrowieckie Centrum Medyczne spółka cywilna Anna Olech-Cudzik, Krzysztof Cudzik
city: Rzeszów
country: Poland
facility: Prywatny Gabinet Lekarski
city: Szczecin
country: Poland
facility: Gabinet Pulmonologii i Diagnostyki Chorób Alergicznych
city: Wrocław
country: Poland
facility: Centrum Badań Klinicznych Piotr Napora Lekarze Spółka Partnerska
city: Wrocław
country: Poland
facility: "ALL-MED" Specjalistyczna Opieka Medyczna, Medyczny Instytut Badawczy
city: Łódź
country: Poland
facility: ETG Łódź
city: Bratislava
country: Slovakia
facility: Pneumologicko-ftizeologická ambulancia, Pneumomed, s.r.o
city: Košice
country: Slovakia
facility: Zeleznicna nemocnica s poliklinikou
city: Levice
country: Slovakia
facility: Ambulancia pneumologie a ftizeologie, ZAPA JJ, s.r.o.
city: Martin
country: Slovakia
facility: Univerzitna nemocnica Martin, Klinika pneumologie a ftizeologie
city: Benalmádena
country: Spain
facility: Hospital Vithas Internacional Xanit
state: Málaga
city: Girona
country: Spain
facility: Institut Catala de Serveis Medics
city: Málaga
country: Spain
facility: Hospital Clinico Universitario Virgen de la Victoria
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
References: