A Phase 3 Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD

Chronic Obstructive Pulmonary Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04542057
• Other study ID #: RPL554-CO-302
• Status: Completed
• Phase: Phase 3
• Start date: September 22, 2020
• Est. completion date: July 6, 2022

Study information

• Verified date: October 2023
• Source: Verona Pharma plc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 790
• Est. completion date: July 6, 2022
• Est. primary completion date: May 3, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Ensifentrine
Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks
• Placebo
Dosage Formulation: Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Verona Pharma plc	Iqvia Pty Ltd

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Canada,  Denmark,  Estonia,  Hungary,  Poland,  Slovakia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 (40 minutes before first administration on Day 1) and Week 12
Secondary	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 (40 minutes before first administration on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
Secondary	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 (average of 7 days before first administration on Day 1) and Weeks 6, 12, and 24
Secondary	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 (40 minutes before first administration on Day 1) and Weeks 6, 12, and 24
Secondary	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 (40 minutes before first administration on Day 1) and Weeks 6, 12, and 24
Secondary	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 (40 minutes before first administration on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
Secondary	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
Secondary	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 (average of 7 days before first administration on Day 1) and Weeks 6, 12, and 24
Secondary	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
Secondary	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 (40 minutes before first administration on Day 1) and Week 12