A Phase 3 Clinical 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 (With a 48-week Safety Subset) in Subjects With Moderate to Severe COPD

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04535986
• Other study ID #: RPL554-CO-301
• Status: Completed
• Phase: Phase 3
• Start date: September 29, 2020
• Est. completion date: December 2, 2022

Study information

• Verified date: November 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 evaluate the efficacy and safety of ensifentrine in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 763
• Est. completion date: December 2, 2022
• Est. primary completion date: September 12, 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) 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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Ensifentrine
Dosage Formulation: Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks or 48 weeks
• Placebo
Dosage Formulation: Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks or 48 weeks

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Verona Pharma plc	Iqvia Pty Ltd

Countries where clinical trial is conducted

United States,  Bulgaria,  Czechia,  Germany,  Greece,  Hungary,  Korea, Republic of,  Poland,  Romania,  Russian Federation,  Slovakia,  United Kingdom, 

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 (pre-dose 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 (pre-dose 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 (pre-dose 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 (pre-dose 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 (pre-dose 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 (pre-dose 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 (pre-dose 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 (pre-dose on Day 1) and Week 12