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

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).

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Ensifentrine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 763
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Haskovo, Bulgaria, 6300
    • SHATPPD - Haskovo, EOOD
  • Pleven, Bulgaria, 5800
    • Medical center Medconsult Pleven OOD
  • Plovdiv, Bulgaria, 4003
    • UMHAT-Plovdiv AD
  • Sofia, Bulgaria, 1510
    • Medical Center Hera Eood
  • Vidin, Bulgaria, 3700
    • MC "Sv. Ivan Rilski", OOD
• Czechia
  • Brandýs Nad Labem, Czechia, 25001
    • MUDr. I. Cierna Peterova s.r.o.
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno, Dept of Klinika nemoci plicnich a tuberkulozy
  • Broumov, Czechia, 550 01
    • EDUMED s.r.o.
  • Hlučín, Czechia, 74801
    • MUDr. Petr Pravda
  • Jindřichův Hradec, Czechia, 377 01
    • MediTrial s.r.o.
  • Kralupy Nad Vltavou, Czechia, 278 01
    • Plicni ambulance Kralupy s.r.o.
  • Lovosice, Czechia, 41002
    • CEFISPIRO s.r.o.
  • Opava, Czechia, 74601
    • Odborná plicní ambulance Opava s.r.o.
  • Praha 4, Czechia, 149 00
    • DAWON spol. s.r.o., Plicni ambulance
  • Praha 5, Czechia, 15300
    • Plicni centrum s.r.o.
  • Rokycany, Czechia, 33701
    • MUDr. Josef Veverka, Plicni ambulacne
  • Teplice, Czechia, 41501
    • Plicní středisko Teplice s.r.o.
• Germany
  • Berlin, Germany, 10119
    • Studienpraxis Berlin-Brandenburg
  • Berlin, Germany, 10625
    • Praxis an der Oper.
  • Neu Isenburg, Germany, 63263
    • Ballenberger, Freytag, Wenisch Institut für klinische Forschung
  • Brandenburg
    • Cottbus, Brandenburg, Germany, 03050
      • MECS GmbH Cottbus
  • Bremen
    • Berlin, Bremen, Germany, 13187
      • Clinical Studies Pankow Dr Dr Evelin Liefring/Ishak Teber
  • Hessen
    • Frankfurt, Hessen, Germany, 60389
      • Praxis Dr. Keller
    • Frankfurt am Main, Hessen, Germany, 60596
      • IKF Pneumologie GmbH & Co. KG
  • Niedersachsen
    • Peine, Niedersachsen, Germany, 31224
      • Dr. Christian Schlenska
  • Nordrhein Westfalen
    • Koeln, Nordrhein Westfalen, Germany, 51069
      • Zentrum für klinische Forschung
    • Rheine, Nordrhein Westfalen, Germany, 48431
      • Framol-med GmbH, Pneumologische Gemeinschaftspraxis Rheine
  • Sachsen
    • Leipzig, Sachsen, Germany, 04157
      • Pneumologische Praxis Dr. Falk Brunner
    • Leipzig, Sachsen, Germany, 04207
      • Salvus-Klinische Studien GmbH.
  • Sachsen Anhalt
    • Magdeburg, Sachsen Anhalt, Germany, 39120
      • SMO.MD GmbH
  • Schleswig Holstein
    • Großhansdorf, Schleswig Holstein, Germany, 22927
      • PRI Pulmonary Research Institute, Pneumologisches Forschungsinstitut GmbH
    • Luebeck, Schleswig Holstein, Germany, 23552
      • KLB Gesundheitsforschung Luebeck GmbH; Praxis Dr. med. Jens Becker
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens of Chest Diseases "SOTIRIA", 7th Respiratory Clinic
  • Heraklion, Greece, 71110
    • University General Hospital of Heraklion, Pulmonary Clinic
  • Ioánnina, Greece, 45500
    • University General Hospital of Ioannina, University Respiratory Clinic
  • Larissa, Greece, 41110
    • University General Hospital of Larissa, University Pulmonary Clinic
• Hungary
  • Budapest, Hungary, 1033
    • Clinexpert Kft.
  • Hajdúnánás, Hungary, 4080
    • Szalay János Rendelőintézet Tüdőgyógyászati Szakrendelés
  • Monor, Hungary, 2200
    • Bajcsy-Zsilinszky Kórház és Rendelőintézet Monori Rendelőintézete
  • Mosonmagyaróvár, Hungary, 9200
    • Karolina Kórház-Rendelőintézet, Tüdőgyógyászat
  • Püspökladány, Hungary, 4150
    • Puspokladanyi Egeszsegugyi Szolgaltato Nonprofit Kft.
  • Szombathely, Hungary, 9700
    • Markusovszky Egyetemi Oktatókórház Tüdőgondozó
• Korea, Republic of
  • Daegu, Korea, Republic of, 42415
    • Yeungnam University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 02447
    • Kyung Hee University Hospital
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of, 07345
    • The Catholic University of Korea, Yeouido St.Mary's Hospital
• Poland
  • Bydgoszcz, Poland, 85-231
    • NZOZ Centrum Medyczne KERmed
  • Gdańsk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne
  • Lublin, Poland, 20-552
    • Centrum Alergologii Sp. z o. o.
  • Siedlce, Poland, 08-110
    • ETG Siedlce
  • Toruń, Poland, 87-100
    • Nasz Lekarz Osrodek Badan Klinicznych
  • Warsaw, Poland, 02-793
    • Etg Warszawa
• Romania
  • Braşov, Romania, 500091
    • S.C Centrul Medical Unirea S.R.L, Campus Medical Brasov
  • Braşov, Romania, 500283
    • S.C Centrul Medical de Diagnostic si Tratament Ambulator Neomed S.R.L
  • Braşov, Romania, 500366
    • Spitalul Clinic De Pneumoftiziologie "Leon Daniello" Cluj-Napoca
  • Bucuresti, Romania, 012071
    • Quantum Medical Center S.R.L.
  • Bucuresti, Romania, 050159
    • Institutul de Pneumoftiziologie "Marius Nasta"
  • Cluj-Napoca, Romania, 400371
    • S.C Cardiomed S.R.L
  • Codlea, Romania, 505100
    • Impatiens SRL
  • Timişoara, Romania, 300134
    • Fundatia CardioPrevent
  • Timişoara, Romania, 300310
    • Spitalul Clinic de Boli Infectioase si Pneumoftiziologie "Dr. Victor Babes" Timisoara
• Russian Federation
  • Barnaul, Russian Federation, 656038
    • NSHI "Departmental CH on St. Barnaul of JSCO "Russian Railways"
  • Chelyabinsk, Russian Federation, 454091
    • SBHI "Regional Clinical Hospital #3"
  • Ekaterinburg, Russian Federation, 620109
    • LLC MA New Hospital
  • Ekaterinburg, Russian Federation, 620149
    • City Hospital #6
  • Kemerovo, Russian Federation, 650002
    • FSBI "Scientific-research Institute for Complex Problems of cardiovascular disease"
  • Novosibirsk, Russian Federation, 630007
    • LLC "Novosibirsk GastroCenter"
  • Novosibirsk, Russian Federation, 630008
    • SBIH of Novosibirsk Region "Clinical Emergency Hospital #2"
  • Novosibirsk, Russian Federation, 630075
    • City Clinical Hospital #25
  • Saint Petersburg, Russian Federation, 191180
    • SPb SBHI "Vvedenskaya hospital"
  • Saint Petersburg, Russian Federation, 194156
    • "LEC at the LLC "LLC "Energiy Zdorovya"
  • Saint Petersburg, Russian Federation, 196084
    • LLC "Institute of Medical Examinations"
  • Saint Petersburg, Russian Federation, 196143
    • Research Center Eco-Safety, LLC
  • Saint Petersburg, Russian Federation, 197022
    • Pavlov First Saint Petersburg State Medical University
  • Sestroretsk, Russian Federation, 197706
    • SPb SBIH "City Hospital # 40 of Kurortnyi region"
  • Yaroslavl, Russian Federation, 1500030
    • SBHI of Yaroslavl Region "Clinical Hospital # 2"
  • Yaroslavl, Russian Federation, 150010
    • SBHI of Yaroslavl Region "Clinical Hospital # 2"
  • Yaroslavl, Russian Federation, 150047
    • SBHI Outpatient 2
• Slovakia
  • Bardejov, Slovakia, 08501
    • Nemocnica s poliklinikou Sv. Jakuba, n.o. Bardejov
  • Humenné, Slovakia, 06601
    • Inspiro, s.r.o.
  • Spišská Nová Ves, Slovakia, 05201
    • Plucna ambulancia Hrebenar, s.r.o.
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, W1T6AH
      • Respiratory Clinical Trials Ltd
• United States
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Phoenix Medical Group
    • Tempe, Arizona, United States, 85281
      • AMR Tempe
  • California
    • Huntington Beach, California, United States, 92647
      • Beach Physicians Medical Group
    • Los Angeles, California, United States, 90017
      • Downtown LA Research Center, Inc.
  • Florida
    • Clearwater, Florida, United States, 33765
      • Clinical Research of West Florida, Inc.
    • Clearwater, Florida, United States, 33765
      • St. Francis Medical Institute
    • Hialeah, Florida, United States, 33010
      • Qway Research, LLC
    • Lake City, Florida, United States, 32055
      • Multi-Specialty Research Associates, Inc.
    • Miami, Florida, United States, 33144
      • Elite Clinical Research
    • Miami, Florida, United States, 33144
      • Global Research Solutions Corp
    • Miami, Florida, United States, 33165
      • Phoenix Medical Research
    • Orlando, Florida, United States, 32825
      • Florida Institute For Clinical Research
    • Sunrise, Florida, United States, 33351
      • Precision Clinical Research
    • Tampa, Florida, United States, 33606
      • Clinical Research of West Florida, Inc.
  • Georgia
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta, LLC
    • Rincon, Georgia, United States, 31326
      • IACT Health
    • Suwanee, Georgia, United States, 30024
      • In-Quest Medical Research, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • John Hopkins University School of Medicine
  • Michigan
    • Farmington Hills, Michigan, United States, 48336
      • Pulmonary Research Institute of SE Michigan
  • Missouri
    • Saint Charles, Missouri, United States, 63301
      • Midwest Chest Consultants
    • Saint Louis, Missouri, United States, 63141
      • The Clinical Research Center, LLC
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Sierra Clinical Research
    • Las Vegas, Nevada, United States, 89119
      • Alliance For multispecialty Research, LLC
  • New York
    • New York, New York, United States, 10036
      • IMA Clinical Research, LLC
  • North Carolina
    • Monroe, North Carolina, United States, 28112
      • Monroe Biomedical Research
  • Ohio
    • Columbus, Ohio, United States, 43215
      • Remington Davis Clinical Research
  • Oregon
    • Grants Pass, Oregon, United States, 97527
      • Velocity Clinical Research - Grants Pass
  • Pennsylvania
    • DuBois, Pennsylvania, United States, 15801
      • Clinical Research Associates of Central Pa, LLC
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Physicians, Emphysema/COPD Research Center
  • South Carolina
    • Columbia, South Carolina, United States, 29204
      • Medtrial
    • Lancaster, South Carolina, United States, 29720
      • MDFirst Research
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Research & Medicine (CHARM)
    • Johnson City, Tennessee, United States, 37601
      • MultiSpecialty Clinical Research, Inc.
    • Knoxville, Tennessee, United States, 37909
      • New Phase Research Development
  • Texas
    • Houston, Texas, United States, 77055
      • West Houston Clinical Research Services
    • Pearland, Texas, United States, 77584
      • LinQ Research, LLC
    • Sherman, Texas, United States, 75092
      • Sherman Clinical Research
  • Virginia
    • Abingdon, Virginia, United States, 24210
      • Pulmonary Research of Abingdon, LLC
    • Williamsburg, Virginia, United States, 23188
      • TPMG Clinical Research Williamsburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Ensifentrine Nebulized Suspension; 3 mg BID	Drug: Ensifentrine; Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks or 48 weeks
Placebo Comparator: Arm 2; Placebo Nebulized BID	Drug: Placebo; Dosage Formulation: Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks or 48 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Average FEV1 AUC0-12h was defined as AUC over 12 hours of the FEV1, divided by 12 hours. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines.	Baseline (pre-dose on Day 1) and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of SGRQ Responders at Weeks 6, 12 and 24	The SGRQ questionnaire consists of 17 questions, split into 2 parts. Part 1 consisted of the first 8 questions and was related to the symptoms subdomain. The remaining 9 questions were in Part 2, which were related to the activity and impacts subdomains. The total score was calculated by dividing the summed weights by the maximum possible weight for all items in the questionnaire and expressing the result as a percentage. Responder was a patient with an improvement from baseline in SGRQ total score of 4 or more. Percentage of SGRQ responders are reported.	Weeks 6, 12 and 24
LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 6, 12 and 24	The TDI is a questionnaire that focused on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome. Change from baseline was assessed with the Baseline Dyspnea Index.	Weeks 6, 12 and 24
LS Mean Change From Baseline FEV1 to Peak FEV1 at Day 1 and Weeks 6, 12 and 24	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Peak FEV1 is the maximum value in the 4 hours after dosing. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
LS Mean Change From Baseline to the Mean Weekly Evaluating-Respiratory Symptoms (E-RS) Total Score at Weeks 6, 12 and 24	The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS total score was derived as the sum of the raw scores of the 11 items ranging from 0 to 40. Higher scores indicates severe respiratory symptoms. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS was collected daily by electronic diary (e-diary). Baseline is the mean over the 7 days prior to the first intake of study medication, using only days where data was recorded.	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
LS Mean Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Weeks 6, 12 and 24	The SGRQ questionnaire consists of 17 questions, split into 2 parts. Part 1 consisted of the first 8 questions and was related to the symptoms subdomain. The remaining 9 questions were in Part 2, which were related to the activity and impacts subdomains. The total score was calculated by dividing the summed weights by the maximum possible weight for all items in the questionnaire and expressing the result as a percentage. Score ranging from 0 to 100 and higher scores indicated a worse outcome. Baseline is the score calculated on Day 1 prior to 4 hour post-dose spirometry.	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 6, 12 and 24	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Morning trough FEV1 was the last value collected prior to the morning dose. Baseline FEV1 is the mean of the two measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
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	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Average FEV1 AUC0-4h was defined as area under the curve over 4 hours of the FEV1, divided by 4 hours. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
LS Mean Change From Baseline to the Mean Weekly Rescue Medication Use at Weeks 6, 12 and 24	Use of rescue medication (albuterol/salbutamol) per week was calculated as the LS mean use daily over 7 days. Daily rescue medication use was collected in an e-diary throughout the study. Baseline is the mean over the 7 days prior to the first intake of study medication, calculated as the sum of puffs taken, divided by number of days data has been recorded.	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
LS Mean Change From Baseline FEV1 to Evening Trough FEV1 at Week 12	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Evening trough FEV1 was the value collected at 12 hours post-morning dose and prior to the evening dose. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (pre-dose on Day 1) and Week 12

Collaborators and Investigators

• Sponsor: Verona Pharma plc
• Collaborators: Iqvia Pty Ltd

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2020
• Primary Completion (Actual): September 12, 2022
• Study Completion (Actual): December 2, 2022

Study Registration Dates

• First Submitted: August 19, 2020
• First Submitted That Met QC Criteria: September 1, 2020
• First Posted (Actual): September 2, 2020

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 7, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: COPD
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Chronic Disease; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: RPL554-CO-301

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No