Tiotropium+Olodaterol Fixed Dose Combination (FDC) Versus Tiotropium and Olodaterol in Chronic Obstructive Pulmonary Disease (COPD)

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

A Randomised, Double-blind, Parallel Group Study to Assess the Efficacy and Safety of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5 µg / 5 µg; 5 µg / 5 µg) (Delivered by the Respimat® Inhaler) Compared With the Individual Components (2.5 µg and 5 µg Tiotropium, 5 µg Olodaterol) (Delivered by the Respimat® Inhaler) in Patients With Chronic Obstructive Pulmonary Disease (COPD). [TOnado TM 1]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01431274
• Other study ID #: 1237.5
• Secondary ID: 2009-010668-40
• Status: Completed
• Phase: Phase 3
• First received: September 8, 2011
• Last updated: June 19, 2015
• Start date: September 2011
• Est. completion date: September 2013

Study information

• Verified date: June 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia MedicaAustralia: Responsible Ethics CommitteeBulgaria: Bulgarian Drug AgencyCanada: Health CanadaChina: Food and Drug AdministrationCzech Republic: State Institute for Drug ControlDenmark: The Danish Health and Medicines AuthorityEstonia: The State Agency of MedicineFinland: Finnish Medicines AgencyFrance: Agence Nationale sécurité médicament et des produits santéGermany: Federal Institute for Drugs and Medical DevicesGuatemala: Ministry of Public Health and Social AssistanceHungary: National Institute of PharmacyIndia: Drugs Controller General of IndiaItaly: Ethics CommitteeJapan: Ministry of Health, Labor and WelfareMexico: Federal Commission for Sanitary Risks ProtectionNetherlands: Central Committee Research Involving Human SubjectsNew Zealand: MedsafePortugal: National Pharmacy and Medicines InstituteRussia: Pharmacological Committee, Ministry of HealthSlovenia: Agency for Medicinal Products - Ministry of HealthSouth Korea: Ministry of Food and Drug Safety (MFDS)Turkey: Ministry of HealthUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The overall objective of this study is to assess the efficacy and safety of 52 weeks once daily treatment with orally inhaled tiotropium + olodaterol FDC (delivered by the RESPIMAT Inhaler) compared with the individual components ( tiotropium, olodaterol) (delivered by the RESPIMAT Inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2624
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion criteria:

1. Diagnosis of chronic obstructive pulmonary disease.

2. Relatively stable airway obstruction with post FEV1< 80% predicted normal and post FEV1/FVC <70%.

3. Male or female patients, 40 years of age or older.

4. Smoking history of more than 10 pack years.

Exclusion criteria:

1. Significant disease other than COPD

2. Clinically relevant abnormal lab values.

3. History of asthma.

4. Diagnosis of thyrotoxicosis

5. Diagnosis of paroxysmal tachycardia

6. History of myocardial infarction within 1 year of screening visit

7. Unstable or life-threatening cardiac arrhythmia.

8. Hospitalization for heart failure within the past year.

9. Known active tuberculosis.

10. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years

11. History of life-threatening pulmonary obstruction.

12. History of cystic fibrosis.

13. Clinically evident bronchiectasis.

14. History of significant alcohol or drug abuse.

15. Thoracotomy with pulmonary resection

16. Oral ß-adrenergics.

17. Oral corticosteroid medication at unstable doses

18. Regular use of daytime oxygen therapy for more than one hour per day

19. Pulmonary rehabilitation program in the six weeks prior to the screening visit

20. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit

21. Known hypersensitivity to ß-adrenergic drugs, anticholinergics, BAC, EDTA

22. Pregnant or nursing women.

23. Women of childbearing potential not using a highly effective method of birth control

24. Patients who are unable to comply with pulmonary medication restrictions

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• tiotropium + olodaterol
fixed dose combination
• tiotropium
low dose
• olodaterol
one dose only
• tiotropium
high dose
• tiotropium + olodaterol
fixed dose combination

Device:
• Respimat
Respimat inhaler

Locations

Country	Name	City	State
Argentina	1237.5.54010 Boehringer Ingelheim Investigational Site	Buenos Aires
Argentina	1237.5.54013 Boehringer Ingelheim Investigational Site	Caba
Argentina	1237.5.54016 Boehringer Ingelheim Investigational Site	Caba
Argentina	1237.5.54003 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	1237.5.54002 Boehringer Ingelheim Investigational Site	Cuidad Autonoma de Buenos Airess A
Argentina	1237.5.54006 Boehringer Ingelheim Investigational Site	Mar del Plata
Argentina	1237.5.54007 Boehringer Ingelheim Investigational Site	Mar del Plata
Argentina	1237.5.54009 Boehringer Ingelheim Investigational Site	Mendoza
Argentina	1237.5.54012 Boehringer Ingelheim Investigational Site	Monte Grande
Argentina	1237.5.54008 Boehringer Ingelheim Investigational Site	Quilmes
Argentina	1237.5.54005 Boehringer Ingelheim Investigational Site	Rosario
Argentina	1237.5.54004 Boehringer Ingelheim Investigational Site	San Miguel de Tucuma
Argentina	1237.5.54011 Boehringer Ingelheim Investigational Site	San Miguel de Tucuman
Australia	1237.5.61004 Boehringer Ingelheim Investigational Site	Frankston	Victoria
Australia	1237.5.61001 Boehringer Ingelheim Investigational Site	Toorak Gardens	South Australia
Australia	1237.5.61002 Boehringer Ingelheim Investigational Site	Woodville	South Australia
Bulgaria	1237.5.35905 Boehringer Ingelheim Investigational Site	Plovdiv
Bulgaria	1237.5.35901 Boehringer Ingelheim Investigational Site	Rousse
Bulgaria	1237.5.35906 Boehringer Ingelheim Investigational Site	Shumen
Bulgaria	1237.5.35902 Boehringer Ingelheim Investigational Site	Sofia
Bulgaria	1237.5.35904 Boehringer Ingelheim Investigational Site	Sofia
Bulgaria	1237.5.35903 Boehringer Ingelheim Investigational Site	Troyan
Bulgaria	1237.5.35908 Boehringer Ingelheim Investigational Site	Veliko Tarnovo
Canada	1237.5.02005 Boehringer Ingelheim Investigational Site	Burlington	Ontario
Canada	1237.5.02002 Boehringer Ingelheim Investigational Site	Calgary	Alberta
Canada	1237.5.02007 Boehringer Ingelheim Investigational Site	Grimsby	Ontario
Canada	1237.5.02011 Boehringer Ingelheim Investigational Site	Ottawa	Ontario
Canada	1237.5.02003 Boehringer Ingelheim Investigational Site	Quebec
Canada	1237.5.02006 Boehringer Ingelheim Investigational Site	Quebec
Canada	1237.5.02009 Boehringer Ingelheim Investigational Site	Saskatoon	Saskatchewan
Canada	1237.5.02008 Boehringer Ingelheim Investigational Site	Sherbrooke	Quebec
Canada	1237.5.02001 Boehringer Ingelheim Investigational Site	Vancouver	British Columbia
Canada	1237.5.02004 Boehringer Ingelheim Investigational Site	Winnipeg	Manitoba
China	1237.5.86003 Boehringer Ingelheim Investigational Site	Beijing
China	1237.5.86004 Boehringer Ingelheim Investigational Site	Beijing
China	1237.5.86011 Boehringer Ingelheim Investigational Site	Changsha
China	1237.5.86012 Boehringer Ingelheim Investigational Site	Changsha
China	1237.5.86014 Boehringer Ingelheim Investigational Site	Foshan
China	1237.5.86001 Boehringer Ingelheim Investigational Site	Guangzhou
China	1237.5.86015 Boehringer Ingelheim Investigational Site	Nan Ning
China	1237.5.86002 Boehringer Ingelheim Investigational Site	Shanghai
China	1237.5.86005 Boehringer Ingelheim Investigational Site	Shanghai
China	1237.5.86006 Boehringer Ingelheim Investigational Site	Shanghai
China	1237.5.86007 Boehringer Ingelheim Investigational Site	Shanghai
China	1237.5.86009 Boehringer Ingelheim Investigational Site	Shenyang
China	1237.5.86016 Boehringer Ingelheim Investigational Site	Wuhan
China	1237.5.86010 Boehringer Ingelheim Investigational Site	Xi'An
China	1237.5.86008 Boehringer Ingelheim Investigational Site	Yangzhou
China	1237.5.86017 Boehringer Ingelheim Investigational Site	Yinchuan
Czech Republic	1237.5.42004 Boehringer Ingelheim Investigational Site	Beroun
Czech Republic	1237.5.42002 Boehringer Ingelheim Investigational Site	Cvikov
Czech Republic	1237.5.42001 Boehringer Ingelheim Investigational Site	Praha 6
Czech Republic	1237.5.42005 Boehringer Ingelheim Investigational Site	Rokycany
Czech Republic	1237.5.42003 Boehringer Ingelheim Investigational Site	Znojmo
Denmark	1237.5.45002 Boehringer Ingelheim Investigational Site	Aalborg
Denmark	1237.5.45009 Boehringer Ingelheim Investigational Site	Hvidovre
Denmark	1237.5.45001 Boehringer Ingelheim Investigational Site	København NV
Denmark	1237.5.45007 Boehringer Ingelheim Investigational Site	Kolding
Denmark	1237.5.45011 Boehringer Ingelheim Investigational Site	Næstved
Denmark	1237.5.45006 Boehringer Ingelheim Investigational Site	Odense C
Denmark	1237.5.45008 Boehringer Ingelheim Investigational Site	Roskilde
Denmark	1237.5.45003 Boehringer Ingelheim Investigational Site	Silkeborg
Denmark	1237.5.45005 Boehringer Ingelheim Investigational Site	Sønderborg
Denmark	1237.5.45004 Boehringer Ingelheim Investigational Site	Vaerløse
Estonia	1237.5.37002 Boehringer Ingelheim Investigational Site	Tallin
Estonia	1237.5.37001 Boehringer Ingelheim Investigational Site	Tartu
Finland	1237.5.35801 Boehringer Ingelheim Investigational Site	Helsinki
Finland	1237.5.35804 Boehringer Ingelheim Investigational Site	Pori
Finland	1237.5.35802 Boehringer Ingelheim Investigational Site	Turku
France	1237.5.33004 Boehringer Ingelheim Investigational Site	Bethune Cedex
France	1237.5.33007 Boehringer Ingelheim Investigational Site	Montpellier cedex 5
France	1237.5.33005 Boehringer Ingelheim Investigational Site	Nantes
France	1237.5.33006 Boehringer Ingelheim Investigational Site	Nîmes cedex 9
France	1237.5.33008 Boehringer Ingelheim Investigational Site	Perpignan
France	1237.5.33001 Boehringer Ingelheim Investigational Site	Saint Pierre Cedex
France	1237.5.33002 Boehringer Ingelheim Investigational Site	Strasbourg
Germany	1237.5.49006 Boehringer Ingelheim Investigational Site	Bamberg
Germany	1237.5.49002 Boehringer Ingelheim Investigational Site	Berlin
Germany	1237.5.49003 Boehringer Ingelheim Investigational Site	Berlin
Germany	1237.5.49013 Boehringer Ingelheim Investigational Site	Berlin
Germany	1237.5.49011 Boehringer Ingelheim Investigational Site	Erfurt
Germany	1237.5.49005 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1237.5.49010 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1237.5.49009 Boehringer Ingelheim Investigational Site	Koblenz
Germany	1237.5.49014 Boehringer Ingelheim Investigational Site	Neu-Isenburg
Germany	1237.5.49012 Boehringer Ingelheim Investigational Site	Oschersleben
Germany	1237.5.49001 Boehringer Ingelheim Investigational Site	Rüdersdorf
Germany	1237.5.49004 Boehringer Ingelheim Investigational Site	Weinheim
Germany	1237.5.49008 Boehringer Ingelheim Investigational Site	Wiesloch
Guatemala	1237.5.50201 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	1237.5.50202 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	1237.5.50203 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	1237.5.50204 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	1237.5.50205 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	1237.5.50206 Boehringer Ingelheim Investigational Site	Guatemala
Guatemala	1237.5.50207 Boehringer Ingelheim Investigational Site	Guatemala
Hungary	1237.5.36005 Boehringer Ingelheim Investigational Site	Debrecen
Hungary	1237.5.36001 Boehringer Ingelheim Investigational Site	Deszk
Hungary	1237.5.36006 Boehringer Ingelheim Investigational Site	Kapuvar
Hungary	1237.5.36003 Boehringer Ingelheim Investigational Site	Szombathely
Hungary	1237.5.36002 Boehringer Ingelheim Investigational Site	Törökbalint
India	1237.5.91010 Boehringer Ingelheim Investigational Site	Ahmedabad
India	1237.5.91002 Boehringer Ingelheim Investigational Site	Bangalore
India	1237.5.91007 Boehringer Ingelheim Investigational Site	Bangalore
India	1237.5.91004 Boehringer Ingelheim Investigational Site	Coimbatore
India	1237.5.91011 Boehringer Ingelheim Investigational Site	Hyderabad
India	1237.5.91001 Boehringer Ingelheim Investigational Site	Jaipur
India	1237.5.91008 Boehringer Ingelheim Investigational Site	Jaipur
India	1237.5.91009 Boehringer Ingelheim Investigational Site	Mysore
India	1237.5.91006 Boehringer Ingelheim Investigational Site	Pune
Italy	1237.5.39008 Boehringer Ingelheim Investigational Site	Cagliari
Italy	1237.5.39002 Boehringer Ingelheim Investigational Site	Genova
Italy	1237.5.39006 Boehringer Ingelheim Investigational Site	Montescano (PV)
Italy	1237.5.39009 Boehringer Ingelheim Investigational Site	Monza
Italy	1237.5.39004 Boehringer Ingelheim Investigational Site	Parma
Italy	1237.5.39001 Boehringer Ingelheim Investigational Site	Pisa
Japan	1237.5.81003 Boehringer Ingelheim Investigational Site	Aoba-ku, Sendai, Miyagi
Japan	1237.5.81001 Boehringer Ingelheim Investigational Site	Asahikawa, Hokkaido
Japan	1237.5.81006 Boehringer Ingelheim Investigational Site	Bunkyo-ku, Tokyo
Japan	1237.5.81044 Boehringer Ingelheim Investigational Site	Chuo-ku, Kumamoto, Kumamoto
Japan	1237.5.81035 Boehringer Ingelheim Investigational Site	Gifu, Gifu
Japan	1237.5.81017 Boehringer Ingelheim Investigational Site	Hakata-ku, Fukuoka, Fukuoka
Japan	1237.5.81031 Boehringer Ingelheim Investigational Site	Hamamatsushi, Shizuoka
Japan	1237.5.81014 Boehringer Ingelheim Investigational Site	Himeji, Hyogo
Japan	1237.5.81037 Boehringer Ingelheim Investigational Site	Ikoma, Nara
Japan	1237.5.81024 Boehringer Ingelheim Investigational Site	Inashiki-gun, Ibaraki
Japan	1237.5.81008 Boehringer Ingelheim Investigational Site	Itabashi-ku, Tokyo
Japan	1237.5.81016 Boehringer Ingelheim Investigational Site	Jonan-ku, Fukuoka, Fukuoka
Japan	1237.5.81021 Boehringer Ingelheim Investigational Site	Kagoshima, Kagoshima
Japan	1237.5.81020 Boehringer Ingelheim Investigational Site	Kagoshima, Kagoshima,
Japan	1237.5.81005 Boehringer Ingelheim Investigational Site	Kamogawa, Chiba
Japan	1237.5.81011 Boehringer Ingelheim Investigational Site	Kishiwada, Osaka
Japan	1237.5.81018 Boehringer Ingelheim Investigational Site	Kitakyusyu,Fukuoka
Japan	1237.5.81042 Boehringer Ingelheim Investigational Site	Koga, Fukuoka
Japan	1237.5.81032 Boehringer Ingelheim Investigational Site	Komaki, Aichi
Japan	1237.5.81033 Boehringer Ingelheim Investigational Site	Komaki, Aichi
Japan	1237.5.81019 Boehringer Ingelheim Investigational Site	Koshi, Kumamoto
Japan	1237.5.81027 Boehringer Ingelheim Investigational Site	koto-ku, Tokyo
Japan	1237.5.81025 Boehringer Ingelheim Investigational Site	Kuki, Saitama
Japan	1237.5.81038 Boehringer Ingelheim Investigational Site	Kure, Hiroshima
Japan	1237.5.81015 Boehringer Ingelheim Investigational Site	Kurume, Fukuoka
Japan	1237.5.81029 Boehringer Ingelheim Investigational Site	Matsumoto, Nagano
Japan	1237.5.81030 Boehringer Ingelheim Investigational Site	Matsumoto, Nagano
Japan	1237.5.81010 Boehringer Ingelheim Investigational Site	Matsusaka, Mie
Japan	1237.5.81041 Boehringer Ingelheim Investigational Site	Minami-ku. Fukuoka, Fukuoka
Japan	1237.5.81002 Boehringer Ingelheim Investigational Site	Morioka, Iwate
Japan	1237.5.81034 Boehringer Ingelheim Investigational Site	Nagoya, Aichi
Japan	1237.5.81036 Boehringer Ingelheim Investigational Site	Nagoya, Aichi
Japan	1237.5.81004 Boehringer Ingelheim Investigational Site	Naka-gun, Ibaraki
Japan	1237.5.81022 Boehringer Ingelheim Investigational Site	Okinawa, Urasoe
Japan	1237.5.81023 Boehringer Ingelheim Investigational Site	Okinawa, Urasoe
Japan	1237.5.81012 Boehringer Ingelheim Investigational Site	Sayama, Osaka
Japan	1237.5.81045 Boehringer Ingelheim Investigational Site	Sendai, Miyagi
Japan	1237.5.81009 Boehringer Ingelheim Investigational Site	Seto, Aichi
Japan	1237.5.81026 Boehringer Ingelheim Investigational Site	Shinagawa, Tokyo
Japan	1237.5.81007 Boehringer Ingelheim Investigational Site	Shinjyuku-ku, Tokyo
Japan	1237.5.81039 Boehringer Ingelheim Investigational Site	Takamatsu, Kagawa
Japan	1237.5.81040 Boehringer Ingelheim Investigational Site	Takamatsu, Kagawa
Japan	1237.5.81013 Boehringer Ingelheim Investigational Site	Wakayama, Wakayama
Japan	1237.5.81043 Boehringer Ingelheim Investigational Site	Yanagawa-shi, Fukuoka,
Japan	1237.5.81028 Boehringer Ingelheim Investigational Site	Yokohama, Kanagawa
Korea, Republic of	1237.5.82004 Boehringer Ingelheim Investigational Site	Bucheon
Korea, Republic of	1237.5.82008 Boehringer Ingelheim Investigational Site	Daegu
Korea, Republic of	1237.5.82001 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1237.5.82002 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1237.5.82003 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1237.5.82007 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1237.5.82005 Boehringer Ingelheim Investigational Site	Suwon
Korea, Republic of	1237.5.82006 Boehringer Ingelheim Investigational Site	Wonju
Mexico	1237.5.52002 Boehringer Ingelheim Investigational Site	Hermosillo
Mexico	1237.5.52003 Boehringer Ingelheim Investigational Site	Mexico
Mexico	1237.5.52007 Boehringer Ingelheim Investigational Site	Monterrey
Mexico	1237.5.52001 Boehringer Ingelheim Investigational Site	Tijuana
Netherlands	1237.5.31004 Boehringer Ingelheim Investigational Site	Almelo
Netherlands	1237.5.31006 Boehringer Ingelheim Investigational Site	Breda
Netherlands	1237.5.31001 Boehringer Ingelheim Investigational Site	Eindhoven
Netherlands	1237.5.31008 Boehringer Ingelheim Investigational Site	Harderwijk
Netherlands	1237.5.31007 Boehringer Ingelheim Investigational Site	Heerlen
Netherlands	1237.5.31010 Boehringer Ingelheim Investigational Site	Hengelo
Netherlands	1237.5.31009 Boehringer Ingelheim Investigational Site	Hoorn
Netherlands	1237.5.31005 Boehringer Ingelheim Investigational Site	Nieuwegein
Netherlands	1237.5.31002 Boehringer Ingelheim Investigational Site	Veldhoven
Netherlands	1237.5.31003 Boehringer Ingelheim Investigational Site	Zutphen
New Zealand	1237.5.64002 Boehringer Ingelheim Investigational Site	Dunedin
New Zealand	1237.5.64001 Boehringer Ingelheim Investigational Site	Greenlane East Auckland NZ
Portugal	1237.5.35105 Boehringer Ingelheim Investigational Site	Amadora
Portugal	1237.5.35101 Boehringer Ingelheim Investigational Site	Coimbra
Portugal	1237.5.35102 Boehringer Ingelheim Investigational Site	Lisboa
Portugal	1237.5.35104 Boehringer Ingelheim Investigational Site	Lisboa
Portugal	1237.5.35103 Boehringer Ingelheim Investigational Site	Porto
Portugal	1237.5.35106 Boehringer Ingelheim Investigational Site	Vila Nova de Gaia
Portugal	1237.5.35107 Boehringer Ingelheim Investigational Site	Viseu
Russian Federation	1237.5.07001 Boehringer Ingelheim Investigational Site	Gatchina (Leningradskaya oblast)
Russian Federation	1237.5.07003 Boehringer Ingelheim Investigational Site	Kazan
Russian Federation	1237.5.07004 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	1237.5.07005 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	1237.5.07002 Boehringer Ingelheim Investigational Site	St. Petersburg
Slovenia	1237.5.38601 Boehringer Ingelheim Investigational Site	Golnik
Slovenia	1237.5.38602 Boehringer Ingelheim Investigational Site	Golnik
Turkey	1237.5.90003 Boehringer Ingelheim Investigational Site	Istanbul
Turkey	1237.5.90004 Boehringer Ingelheim Investigational Site	Istanbul
Turkey	1237.5.90002 Boehringer Ingelheim Investigational Site	Izmir
Turkey	1237.5.90005 Boehringer Ingelheim Investigational Site	Izmit
Turkey	1237.5.90001 Boehringer Ingelheim Investigational Site	Mersin
United States	1237.5.01017 Boehringer Ingelheim Investigational Site	Biddeford	Maine
United States	1237.5.01015 Boehringer Ingelheim Investigational Site	Boulder	Colorado
United States	1237.5.01032 Boehringer Ingelheim Investigational Site	Charleston	Pennsylvania
United States	1237.5.01006 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio
United States	1237.5.01003 Boehringer Ingelheim Investigational Site	Clearwater	Florida
United States	1237.5.01010 Boehringer Ingelheim Investigational Site	Clearwater	Florida
United States	1237.5.01028 Boehringer Ingelheim Investigational Site	Columbia	Maryland
United States	1237.5.01040 Boehringer Ingelheim Investigational Site	Columbus	Ohio
United States	1237.5.01039 Boehringer Ingelheim Investigational Site	Dayton	Ohio
United States	1237.5.01021 Boehringer Ingelheim Investigational Site	Easley	South Carolina
United States	1237.5.01029 Boehringer Ingelheim Investigational Site	Ft. Worth	Texas
United States	1237.5.01012 Boehringer Ingelheim Investigational Site	Gaffney	South Carolina
United States	1237.5.01038 Boehringer Ingelheim Investigational Site	Jasper	Alabama
United States	1237.5.01005 Boehringer Ingelheim Investigational Site	Johnston	Rhode Island
United States	1237.5.01025 Boehringer Ingelheim Investigational Site	Larchmont	New York
United States	1237.5.01013 Boehringer Ingelheim Investigational Site	Livonia	Michigan
United States	1237.5.01026 Boehringer Ingelheim Investigational Site	Lynchburg	Virginia
United States	1237.5.01036 Boehringer Ingelheim Investigational Site	Mobile	Alabama
United States	1237.5.01001 Boehringer Ingelheim Investigational Site	Morgantown	West Virginia
United States	1237.5.01031 Boehringer Ingelheim Investigational Site	O'Fallon	Illinois
United States	1237.5.01009 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma
United States	1237.5.01019 Boehringer Ingelheim Investigational Site	Omaha	Nebraska
United States	1237.5.01035 Boehringer Ingelheim Investigational Site	Opelousas	Louisiana
United States	1237.5.01027 Boehringer Ingelheim Investigational Site	Panama City	Florida
United States	1237.5.01023 Boehringer Ingelheim Investigational Site	Raleigh	North Carolina
United States	1237.5.01008 Boehringer Ingelheim Investigational Site	Rochester	New York
United States	1237.5.01002 Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	1237.5.01004 Boehringer Ingelheim Investigational Site	Shreveport	Louisiana
United States	1237.5.01014 Boehringer Ingelheim Investigational Site	Spartanburg	South Carolina
United States	1237.5.01007 Boehringer Ingelheim Investigational Site	Spokane	Washington
United States	1237.5.01034 Boehringer Ingelheim Investigational Site	Stamford	Connecticut
United States	1237.5.01016 Boehringer Ingelheim Investigational Site	Tabor City	North Carolina
United States	1237.5.01033 Boehringer Ingelheim Investigational Site	Tacoma	Washington
United States	1237.5.01037 Boehringer Ingelheim Investigational Site	Toledo	Ohio
United States	1237.5.01024 Boehringer Ingelheim Investigational Site	Wheat Ridge	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Bulgaria,  Canada,  China,  Czech Republic,  Denmark,  Estonia,  Finland,  France,  Germany,  Guatemala,  Hungary,  India,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Portugal,  Russian Federation,  Slovenia,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169.	No
Primary	Trough FEV1 Response on Day 170.	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FEV1 measurements performed at 23 h and at 23 h 50 min after inhalation of study medication at the clinic visit on the previous day.; Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170	No
Primary	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.	Day 169	No
Secondary	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) is the key secondary endpoint.; The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.	Day 169	No
Secondary	FEV1 AUC(0-3h) Response on Day 1	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.; FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment.	No
Secondary	FEV1 AUC(0-3h) Response on Day 85	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85.	No
Secondary	FEV1 AUC(0-3h) Response on Day 365	FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365.	No
Secondary	Trough FEV1 Response on Day 15.	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed; 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15	No
Secondary	Trough FEV1 Response on Day 43	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed; 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43.	No
Secondary	Trough FEV1 Response on Day 85	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed; 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 85.	No
Secondary	Trough FEV1 Response on Day 169	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed; 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on Day 169	No
Secondary	Trough FEV1 Response on Day 365	Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed; 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365	No
Secondary	FVC (Forced Vital Capacity) AUC(0-3h) Response on Day 1	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.; FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment.	No
Secondary	FVC (Forced Vital Capacity) AUC(0-3h) Response on Day 85	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.; FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85.	No
Secondary	FVC (Forced Vital Capacity) AUC(0-3h) Response on Day 169	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.; FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169.	No
Secondary	FVC (Forced Vital Capacity) AUC(0-3h) Response on Day 365	FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.; FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365.	No
Secondary	Trough FVC Response on Day 15.	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15	No
Secondary	Trough FVC Response on Day 43.	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43	No
Secondary	Trough FVC Response on Day 85.	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85	No
Secondary	Trough FVC Response on Day 170.	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FVC measurements performed at 23h and at 23h 50 min after inhalation of study medication at the clinic visit on the previous day.; Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170	No
Secondary	Trough FVC Response on Day 365.	Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.; Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.; The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.	1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on Day 365.	No
Secondary	FEV1 AUC(0-12h) Response in the Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.; FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.; Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169.	No
Secondary	FEV1 AUC(0-24h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.; Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169.	No
Secondary	FVC AUC(0-12h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.; FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169.	No
Secondary	FVC AUC(0-24h) Response in Sub-set of Patients With 24-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres.; FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).; The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.; Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.	1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169.	No
Secondary	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.	Day 85	No
Secondary	Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.	Day 365	No
Secondary	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 43 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287).; The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.	Day 43	No
Secondary	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 85 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287).; The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.; Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.	Day 85	No
Secondary	Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 365 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287).; The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.	Day 365	No

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