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 2]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01431287
• Other study ID #: 1237.6
• Secondary ID: 2009-010669-22
• Status: Completed
• Phase: Phase 3
• First received: September 8, 2011
• Last updated: June 19, 2015
• Start date: September 2011
• Est. completion date: November 2013

Study information

• Verified date: June 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Medicines and Medical Devices AgencyBelgium: Federal Agency for Medicinal and Health ProductsBrazil: National Health Surveillance AgencyCanada: Health CanadaChina: Food and Drug AdministrationColombia: Instituto Nacional de Vigilancia de Medicamentos y AlimentosCroatia: Agency for Medicinal Product and Medical DevicesGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyIndia: Drugs Controller General of IndiaIreland: Irish Medicines BoardJapan: Ministry of Health, Labor and WelfareMexico: Federal Commission for Protection Against Health RisksNorway: Norwegian Medicines AgencyRomania: National Medicines AgencyRussia: Pharmacological Committee, Ministry of HealthSerbia and Montenegro: Agency for Drugs and Medicinal DevicesSlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilSpain: Spanish Agency of MedicinesSweden: Medical Products AgencyTaiwan : Food and Drug AdministrationTurkey: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited 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 COPD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2539
• Est. completion date: November 2013
• Est. primary completion date: November 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 + olodaterol
fixed dose combination
• tiotropium
low dose or high dose
• tiotropium
low dose or high dose
• olodaterol
one dose only

Device:
• Respimat
Respimat inhaler

Locations

Country	Name	City	State
Austria	1237.6.43006 Boehringer Ingelheim Investigational Site	Feldbach
Austria	1237.6.43005 Boehringer Ingelheim Investigational Site	Gänserndorf
Austria	1237.6.43002 Boehringer Ingelheim Investigational Site	Innsbruck
Austria	1237.6.43004 Boehringer Ingelheim Investigational Site	Leoben
Austria	1237.6.43001 Boehringer Ingelheim Investigational Site	Linz
Austria	1237.6.43003 Boehringer Ingelheim Investigational Site	Salzburg
Belgium	1237.6.32007 Boehringer Ingelheim Investigational Site	Brussel
Belgium	1237.6.32005 Boehringer Ingelheim Investigational Site	Bruxelles
Belgium	1237.6.32004 Boehringer Ingelheim Investigational Site	Gent
Belgium	1237.6.32002 Boehringer Ingelheim Investigational Site	Jambes
Belgium	1237.6.32009 Boehringer Ingelheim Investigational Site	Lebbeke
Belgium	1237.6.32001 Boehringer Ingelheim Investigational Site	Leuven
Belgium	1237.6.32006 Boehringer Ingelheim Investigational Site	Liège
Belgium	1237.6.32008 Boehringer Ingelheim Investigational Site	Oostende
Belgium	1237.6.32010 Boehringer Ingelheim Investigational Site	Turnhout
Brazil	1237.6.55013 Boehringer Ingelheim Investigational Site	Botucatu
Brazil	1237.6.55010 Boehringer Ingelheim Investigational Site	Florianopolis
Brazil	1237.6.55012 Boehringer Ingelheim Investigational Site	Passo Fundo
Brazil	1237.6.55001 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1237.6.55002 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1237.6.55003 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1237.6.55005 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1237.6.55009 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	1237.6.55006 Boehringer Ingelheim Investigational Site	Sao Paulo
Brazil	1237.6.55007 Boehringer Ingelheim Investigational Site	Sao Paulo
Brazil	1237.6.55011 Boehringer Ingelheim Investigational Site	Sao Paulo
Canada	1237.6.02110 Boehringer Ingelheim Investigational Site	Courtice	Ontario
Canada	1237.6.02101 Boehringer Ingelheim Investigational Site	Downsview	Ontario
Canada	1237.6.02109 Boehringer Ingelheim Investigational Site	Edmonton	Alberta
Canada	1237.6.02106 Boehringer Ingelheim Investigational Site	Moncton	New Brunswick
Canada	1237.6.02104 Boehringer Ingelheim Investigational Site	Point Claire	Quebec
Canada	1237.6.02112 Boehringer Ingelheim Investigational Site	Sarnia	Ontario
Canada	1237.6.02105 Boehringer Ingelheim Investigational Site	Sherbrooke	Quebec
Canada	1237.6.02108 Boehringer Ingelheim Investigational Site	Ste-Foy	Quebec
Canada	1237.6.02103 Boehringer Ingelheim Investigational Site	Toronto	Ontario
Canada	1237.6.02111 Boehringer Ingelheim Investigational Site	Vancouver	British Columbia
Canada	1237.6.02102 Boehringer Ingelheim Investigational Site	Windsor	Ontario
China	1237.6.86117 Boehringer Ingelheim Investigational Site	Baotou
China	1237.6.86102 Boehringer Ingelheim Investigational Site	Beijing
China	1237.6.86104 Boehringer Ingelheim Investigational Site	Beijing
China	1237.6.86105 Boehringer Ingelheim Investigational Site	Beijing
China	1237.6.86115 Boehringer Ingelheim Investigational Site	Changsha
China	1237.6.86110 Boehringer Ingelheim Investigational Site	Chengdu
China	1237.6.86111 Boehringer Ingelheim Investigational Site	Chongqing
China	1237.6.86109 Boehringer Ingelheim Investigational Site	Haikou
China	1237.6.86108 Boehringer Ingelheim Investigational Site	Hangzhou
China	1237.6.86116 Boehringer Ingelheim Investigational Site	Hohhot
China	1237.6.86114 Boehringer Ingelheim Investigational Site	Jinan
China	1237.6.86106 Boehringer Ingelheim Investigational Site	Nanjing
China	1237.6.86101 Boehringer Ingelheim Investigational Site	Shanghai
China	1237.6.86113 Boehringer Ingelheim Investigational Site	Shenyang
China	1237.6.86107 Boehringer Ingelheim Investigational Site	Suzhou
China	1237.6.86112 Boehringer Ingelheim Investigational Site	Xi'An
Colombia	1237.6.57008 Boehringer Ingelheim Investigational Site	Bogota
Colombia	1237.6.57001 Boehringer Ingelheim Investigational Site	Bogota DC
Colombia	1237.6.57003 Boehringer Ingelheim Investigational Site	Bogota DC
Colombia	1237.6.57007 Boehringer Ingelheim Investigational Site	Bogota DC
Colombia	1237.6.57006 Boehringer Ingelheim Investigational Site	Cali
Colombia	1237.6.57004 Boehringer Ingelheim Investigational Site	Floridablanca
Croatia	1237.6.38503 Boehringer Ingelheim Investigational Site	Petrinja
Croatia	1237.6.38504 Boehringer Ingelheim Investigational Site	Rijeka
Croatia	1237.6.38502 Boehringer Ingelheim Investigational Site	Zadar
Croatia	1237.6.38501 Boehringer Ingelheim Investigational Site	Zagreb
Germany	1237.6.49022 Boehringer Ingelheim Investigational Site	Aschaffenburg
Germany	1237.6.49017 Boehringer Ingelheim Investigational Site	Berlin
Germany	1237.6.49026 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	1237.6.49027 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	1237.6.49025 Boehringer Ingelheim Investigational Site	Großhansdorf
Germany	1237.6.49016 Boehringer Ingelheim Investigational Site	Halle
Germany	1237.6.49024 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1237.6.49021 Boehringer Ingelheim Investigational Site	Hannover
Germany	1237.6.49019 Boehringer Ingelheim Investigational Site	Leipzig
Germany	1237.6.49028 Boehringer Ingelheim Investigational Site	Mainz
Germany	1237.6.49018 Boehringer Ingelheim Investigational Site	Rodgau/Dudenhofen
Germany	1237.6.49020 Boehringer Ingelheim Investigational Site	Schwerin
Germany	1237.6.49023 Boehringer Ingelheim Investigational Site	Teuchern
Hungary	1237.6.36001 Boehringer Ingelheim Investigational Site	Debrecen
Hungary	1237.6.36004 Boehringer Ingelheim Investigational Site	Gödöllö
Hungary	1237.6.36005 Boehringer Ingelheim Investigational Site	Pecs
Hungary	1237.6.36003 Boehringer Ingelheim Investigational Site	Sopron
Hungary	1237.6.36002 Boehringer Ingelheim Investigational Site	Szeged
India	1237.6.91003 Boehringer Ingelheim Investigational Site	Chennai
India	1237.6.91011 Boehringer Ingelheim Investigational Site	Coimbatore
India	1237.6.91004 Boehringer Ingelheim Investigational Site	Jaipur
India	1237.6.91002 Boehringer Ingelheim Investigational Site	Kolkatta
India	1237.6.91007 Boehringer Ingelheim Investigational Site	Maharastra
India	1237.6.91006 Boehringer Ingelheim Investigational Site	Mumbai
India	1237.6.91009 Boehringer Ingelheim Investigational Site	Nashik, Maharashtra
India	1237.6.91008 Boehringer Ingelheim Investigational Site	Pune
Ireland	1237.6.35304 Boehringer Ingelheim Investigational Site	County Limerick
Ireland	1237.6.35303 Boehringer Ingelheim Investigational Site	Dublin 24
Ireland	1237.6.35301 Boehringer Ingelheim Investigational Site	Dublin 4
Japan	1237.6.81127 Boehringer Ingelheim Investigational Site	Abeno-ku, Osaka, Osaka
Japan	1237.6.81123 Boehringer Ingelheim Investigational Site	Aoi-ku, Shizuoka, Shizuoka
Japan	1237.6.81132 Boehringer Ingelheim Investigational Site	Chuo-ku, Kobe, Hyogo
Japan	1237.6.81121 Boehringer Ingelheim Investigational Site	Fukui, Fukui
Japan	1237.6.81137 Boehringer Ingelheim Investigational Site	Fukuyama, Hiroshima
Japan	1237.6.81109 Boehringer Ingelheim Investigational Site	Hachioji, Tokyo
Japan	1237.6.81134 Boehringer Ingelheim Investigational Site	Himeji, Hyogo
Japan	1237.6.81106 Boehringer Ingelheim Investigational Site	Hitachi, Ibaraki
Japan	1237.6.81139 Boehringer Ingelheim Investigational Site	Iizuka, Fukuoka
Japan	1237.6.81102 Boehringer Ingelheim Investigational Site	Iwamizawa, Hokkaido
Japan	1237.6.81117 Boehringer Ingelheim Investigational Site	Kamakura, Kanagawa
Japan	1237.6.81120 Boehringer Ingelheim Investigational Site	Kanazawa, Ishikawa
Japan	1237.6.81113 Boehringer Ingelheim Investigational Site	Kanazawa, Yokohama, Kanagawa
Japan	1237.6.81108 Boehringer Ingelheim Investigational Site	Kashiwa, Chiba
Japan	1237.6.81114 Boehringer Ingelheim Investigational Site	Kawasaki-ku, Kawasaki, Kanagawa
Japan	1237.6.81135 Boehringer Ingelheim Investigational Site	Kita-ku, Okayama, Okayama
Japan	1237.6.81126 Boehringer Ingelheim Investigational Site	Kita-ku, Sakai, Osaka
Japan	1237.6.81101 Boehringer Ingelheim Investigational Site	Kita-ku, Sapporo, Hokkaido
Japan	1237.6.81136 Boehringer Ingelheim Investigational Site	Kurashiki, Okayama
Japan	1237.6.81116 Boehringer Ingelheim Investigational Site	Minami-ku, Yokohama, Kanagawa
Japan	1237.6.81118 Boehringer Ingelheim Investigational Site	Minami-ku, Yokohama, Kanagawa
Japan	1237.6.81112 Boehringer Ingelheim Investigational Site	Mitaka, Tokyo
Japan	1237.6.81105 Boehringer Ingelheim Investigational Site	Mito, Ibaraki
Japan	1237.6.81142 Boehringer Ingelheim Investigational Site	Naha, Okinawa
Japan	1237.6.81131 Boehringer Ingelheim Investigational Site	Nishi-ku, Kobe, Hyogo
Japan	1237.6.81104 Boehringer Ingelheim Investigational Site	Obihiro, Hokkaido
Japan	1237.6.81141 Boehringer Ingelheim Investigational Site	Okinawa, Okinawa
Japan	1237.6.81110 Boehringer Ingelheim Investigational Site	Ota-ku, Tokyo
Japan	1237.6.81138 Boehringer Ingelheim Investigational Site	Sakaide, Kagawa
Japan	1237.6.81103 Boehringer Ingelheim Investigational Site	Sapporo, Hokkaido
Japan	1237.6.81140 Boehringer Ingelheim Investigational Site	Shimajiri-gun, Okinawa
Japan	1237.6.81144 Boehringer Ingelheim Investigational Site	Shimajiri-gun, Okinawa
Japan	1237.6.81111 Boehringer Ingelheim Investigational Site	Shinjuku-ku, Tokyo
Japan	1237.6.81145 Boehringer Ingelheim Investigational Site	Shinjuku-ku, Tokyo
Japan	1237.6.81107 Boehringer Ingelheim Investigational Site	Soka, Saitama
Japan	1237.6.81133 Boehringer Ingelheim Investigational Site	Takarazuka, Hyogo
Japan	1237.6.81122 Boehringer Ingelheim Investigational Site	Takayama, Gifu
Japan	1237.6.81143 Boehringer Ingelheim Investigational Site	Tomigusuku, Okinawa
Japan	1237.6.81128 Boehringer Ingelheim Investigational Site	Toyonaka, Osaka
Japan	1237.6.81124 Boehringer Ingelheim Investigational Site	Uji, Kyoto
Japan	1237.6.81130 Boehringer Ingelheim Investigational Site	Yabu, Hyogo
Japan	1237.6.81129 Boehringer Ingelheim Investigational Site	Yao, Osaka
Japan	1237.6.81119 Boehringer Ingelheim Investigational Site	Yokosuka, Kanagawa
Norway	1237.6.47005 Boehringer Ingelheim Investigational Site	Elverum
Norway	1237.6.47001 Boehringer Ingelheim Investigational Site	Hønefoss
Norway	1237.6.47002 Boehringer Ingelheim Investigational Site	Kløfta
Norway	1237.6.47004 Boehringer Ingelheim Investigational Site	Lierskogen
Norway	1237.6.47003 Boehringer Ingelheim Investigational Site	Oslo
Norway	1237.6.47007 Boehringer Ingelheim Investigational Site	SKI
Norway	1237.6.47008 Boehringer Ingelheim Investigational Site	Svelvik
Romania	1237.6.40004 Boehringer Ingelheim Investigational Site	Arad
Romania	1237.6.40005 Boehringer Ingelheim Investigational Site	Arad
Romania	1237.6.40001 Boehringer Ingelheim Investigational Site	Bucharest
Romania	1237.6.40002 Boehringer Ingelheim Investigational Site	Bucuresti
Romania	1237.6.40003 Boehringer Ingelheim Investigational Site	Cluj
Russian Federation	1237.6.07004 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	1237.6.07005 Boehringer Ingelheim Investigational Site	Moscow
Russian Federation	1237.6.07002 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	1237.6.07003 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	1237.6.07001 Boehringer Ingelheim Investigational Site	Yaroslavl
Serbia	1237.6.38103 Boehringer Ingelheim Investigational Site	Belgrade
Serbia	1237.6.38104 Boehringer Ingelheim Investigational Site	Belgrade
Serbia	1237.6.38105 Boehringer Ingelheim Investigational Site	Belgrade
Serbia	1237.6.38102 Boehringer Ingelheim Investigational Site	Kragujevac
Serbia	1237.6.38101 Boehringer Ingelheim Investigational Site	Nis
Slovakia	1237.6.42101 Boehringer Ingelheim Investigational Site	Bardejov
Slovakia	1237.6.42102 Boehringer Ingelheim Investigational Site	Bojnice
Slovakia	1237.6.42104 Boehringer Ingelheim Investigational Site	Kosice
Slovakia	1237.6.42107 Boehringer Ingelheim Investigational Site	Nitra
Slovakia	1237.6.42103 Boehringer Ingelheim Investigational Site	Spisska Nova Ves
Slovakia	1237.6.42106 Boehringer Ingelheim Investigational Site	Zilina
South Africa	1237.6.27002 Boehringer Ingelheim Investigational Site	Bellville
South Africa	1237.6.27001 Boehringer Ingelheim Investigational Site	Cape Town
South Africa	1237.6.27003 Boehringer Ingelheim Investigational Site	Cape Town
South Africa	1237.6.27004 Boehringer Ingelheim Investigational Site	Cape Town
South Africa	1237.6.27005 Boehringer Ingelheim Investigational Site	Pretoria
Spain	1237.6.34008 Boehringer Ingelheim Investigational Site	Badalona (Barcelona)
Spain	1237.6.34003 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1237.6.34009 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1237.6.34001 Boehringer Ingelheim Investigational Site	Hospitalet de Llobregat
Spain	1237.6.34002 Boehringer Ingelheim Investigational Site	Mérida
Spain	1237.6.34005 Boehringer Ingelheim Investigational Site	Pozuelo de Alarcón
Spain	1237.6.34004 Boehringer Ingelheim Investigational Site	San Juan de Alicante
Spain	1237.6.34006 Boehringer Ingelheim Investigational Site	Vic (Barcelona)
Sweden	1237.6.46003 Boehringer Ingelheim Investigational Site	Boden
Sweden	1237.6.46002 Boehringer Ingelheim Investigational Site	Göteborg
Sweden	1237.6.46006 Boehringer Ingelheim Investigational Site	Härnösand
Sweden	1237.6.46005 Boehringer Ingelheim Investigational Site	Höllviken
Sweden	1237.6.46001 Boehringer Ingelheim Investigational Site	Lund
Sweden	1237.6.46004 Boehringer Ingelheim Investigational Site	Stockholm
Sweden	1237.6.46007 Boehringer Ingelheim Investigational Site	Uddevalla
Taiwan	1237.6.88608 Boehringer Ingelheim Investigational Site	Kaohsiung
Taiwan	1237.6.88607 Boehringer Ingelheim Investigational Site	Kaohsiung City
Taiwan	1237.6.88602 Boehringer Ingelheim Investigational Site	New Taipei City
Taiwan	1237.6.88604 Boehringer Ingelheim Investigational Site	Taichung
Taiwan	1237.6.88605 Boehringer Ingelheim Investigational Site	Tainan
Taiwan	1237.6.88601 Boehringer Ingelheim Investigational Site	Taipei
Taiwan	1237.6.88603 Boehringer Ingelheim Investigational Site	Taoyuan County
Turkey	1237.6.90105 Boehringer Ingelheim Investigational Site	Ankara
Turkey	1237.6.90103 Boehringer Ingelheim Investigational Site	Denizli
Turkey	1237.6.90104 Boehringer Ingelheim Investigational Site	Istanbul
Turkey	1237.6.90101 Boehringer Ingelheim Investigational Site	Izmir
Turkey	1237.6.90102 Boehringer Ingelheim Investigational Site	Izmir
United Kingdom	1237.6.44002 Boehringer Ingelheim Investigational Site	Blackpool
United Kingdom	1237.6.44009 Boehringer Ingelheim Investigational Site	Blackpool
United Kingdom	1237.6.44007 Boehringer Ingelheim Investigational Site	Bristol
United Kingdom	1237.6.44010 Boehringer Ingelheim Investigational Site	Chertsey
United Kingdom	1237.6.44011 Boehringer Ingelheim Investigational Site	Fleetwood
United Kingdom	1237.6.44001 Boehringer Ingelheim Investigational Site	Manchester
United Kingdom	1237.6.44008 Boehringer Ingelheim Investigational Site	Midsomer Norton
United States	1237.6.01108 Boehringer Ingelheim Investigational Site	Albuquerque	New Mexico
United States	1237.6.01134 Boehringer Ingelheim Investigational Site	Atlanta	Georgia
United States	1237.6.01128 Boehringer Ingelheim Investigational Site	Baltimore	Maryland
United States	1237.6.01127 Boehringer Ingelheim Investigational Site	Bayside	New York
United States	1237.6.01122 Boehringer Ingelheim Investigational Site	Charleston	South Carolina
United States	1237.6.01135 Boehringer Ingelheim Investigational Site	Charlotte	North Carolina
United States	1237.6.01114 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio
United States	1237.6.01102 Boehringer Ingelheim Investigational Site	Columbus	Ohio
United States	1237.6.01107 Boehringer Ingelheim Investigational Site	Couer d'Alene	Idaho
United States	1237.6.01131 Boehringer Ingelheim Investigational Site	Danbury	Connecticut
United States	1237.6.01118 Boehringer Ingelheim Investigational Site	Deland	Florida
United States	1237.6.01113 Boehringer Ingelheim Investigational Site	East Providence	Rhode Island
United States	1237.6.01120 Boehringer Ingelheim Investigational Site	Fort Collins	Colorado
United States	1237.6.01139 Boehringer Ingelheim Investigational Site	Great Neck	New York
United States	1237.6.01132 Boehringer Ingelheim Investigational Site	Greenville	South Carolina
United States	1237.6.01137 Boehringer Ingelheim Investigational Site	Greenville	South Carolina
United States	1237.6.01106 Boehringer Ingelheim Investigational Site	Greer	California
United States	1237.6.01129 Boehringer Ingelheim Investigational Site	Henderson	Nevada
United States	1237.6.01138 Boehringer Ingelheim Investigational Site	Killeen	Texas
United States	1237.6.01110 Boehringer Ingelheim Investigational Site	Lafayette	Louisiana
United States	1237.6.01136 Boehringer Ingelheim Investigational Site	Marlton	New Jersey
United States	1237.6.01124 Boehringer Ingelheim Investigational Site	McKinney	Texas
United States	1237.6.01104 Boehringer Ingelheim Investigational Site	Minneapolis	Minnesota
United States	1237.6.01130 Boehringer Ingelheim Investigational Site	North Dartmouth	Massachusetts
United States	1237.6.01115 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma
United States	1237.6.01101 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1237.6.01116 Boehringer Ingelheim Investigational Site	Plymouth	Minnesota
United States	1237.6.01112 Boehringer Ingelheim Investigational Site	Richmond	Virginia
United States	1237.6.01133 Boehringer Ingelheim Investigational Site	Richmond	Virginia
United States	1237.6.01111 Boehringer Ingelheim Investigational Site	Spartanburg	South Carolina
United States	1237.6.01125 Boehringer Ingelheim Investigational Site	Spokane	Washington
United States	1237.6.01121 Boehringer Ingelheim Investigational Site	St. Louis	Missouri
United States	1237.6.01123 Boehringer Ingelheim Investigational Site	St. Louis	Missouri
United States	1237.6.01103 Boehringer Ingelheim Investigational Site	Tacoma	Washington
United States	1237.6.01126 Boehringer Ingelheim Investigational Site	Tampa	Florida
United States	1237.6.01105 Boehringer Ingelheim Investigational Site	Union	South Carolina
United States	1237.6.01117 Boehringer Ingelheim Investigational Site	Waterbury	Connecticut
United States	1237.6.01109 Boehringer Ingelheim Investigational Site	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Brazil,  Canada,  China,  Colombia,  Croatia,  Germany,  Hungary,  India,  Ireland,  Japan,  Norway,  Romania,  Russian Federation,  Serbia,  Slovakia,  South Africa,  Spain,  Sweden,  Taiwan,  Turkey,  United Kingdom, 

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 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	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 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) 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 1hr 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 1hr 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	Forced Vital Capacity (FVC) 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	Forced Vital Capacity (FVC) 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	Forced Vital Capacity (FVC) 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	Forced Vital Capacity (FVC) 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 23h and at 23h 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 Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	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 Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	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 Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	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 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	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 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	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 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	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 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Mahler TDI focal score on Day 43 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).; 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 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Mahler TDI focal score on Day 85 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).; 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 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	Mahler TDI focal score on Day 365 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).; 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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