Evaluation of Efficacy and Safety of Symbicort® as an add-on Treatment to Spiriva® in Patients With Severe COPD.

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00496470
• Collaborator: (none)
• Enrollment: 660
• Locations: 93
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the effect of combined treatment with Symbicort and Spiriva, in terms of improvement of lung function, symptoms and inflammatory markers, in patients with severe COPD.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease, COPD	Drug: Symbicort (budesonide/formoterol turbuhaler 320/9ug); Drug: Spiriva (tiotropium bromide 18ug)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 660 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 12-week, Double-blind, Randomised, Parallel Group, Multi-centre, Study to Evaluate Efficacy and Safety of Budesonide/Formoterol (Symbicort Turbuhaler®) 320/9 µg One Inhalation Twice Daily on Top of Tiotropium (Spiriva®) 18 µg One Inhalation Once Daily
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Symbicort+TIO Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Drug: Symbicort (budesonide/formoterol turbuhaler 320/9ug); Symbicort (budesonide/formoterol turbuhaler 320/9ug)
Active Comparator: Spiriva® + Placebo Turbuhaler Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily	Drug: Spiriva (tiotropium bromide 18ug); Spiriva (tiotropium bromide 18ug)

Outcome Measures

Primary Outcome Measures

1. Forced Expiratory Volume in 1 Second (FEV1) Pre-dose [Baseline to 12 weeks]

   Change in the pre-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)

Secondary Outcome Measures

1. Forced Expiratory Volume in 1 Second (FEV1) 5 Min Post-dose [Baseline to 12 weeks]

   Change in the 5 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)

2. Forced Expiratory Volume in 1 Second (FEV1) 60 Min Post-dose [Baseline to 12 weeks]

   Change in the 60 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)

3. Forced Vital Capacity (FVC) Pre-dose [Baseline to 12 weeks]

   Change in the pre-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)

4. Forced Vital Capacity (FVC) 5 Minutes Post-dose [Baseline to 12 weeks]

   Change in the 5 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)

5. Forced Vital Capacity (FVC) 60 Minutes Post-dose [Baseline to 12 weeks]

   Change in the 60 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12

6. Inspiratory Capacity (IC) Pre-dose [Baseline to 12 weeks]

   Change in the pre-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)

7. Inspiratory Capacity (IC) 60 Minutes Post-dose [Baseline to 12 weeks]

   Change in the 60 min post-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)

8. St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Score [Baseline and 12 weeks]

   Change in total score from baseline (Visit 3) to end of treatment (Visit 6, or last available visit). SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life.

9. Morning Peak Expiratory Flow (PEF) Pre-dose [Baseline to 12 weeks]

   Daily diary record. Change in average values from run-in to the full treatment period

10. Evening Peak Expiratory Flow (PEF) Pre-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period

11. Morning Peak Expiratory Flow (PEF) 5 Min Post-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period

12. Morning Peak Expiratory Flow (PEF) 15 Min Post-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period

13. Morning Diary FEV1 Pre-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period

14. Evening Diary FEV1, Pre-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period

15. Morning Diary FEV1, 5 Minutes Post-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period

16. Morning Diary FEV1, 15 Minutes Post-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period

17. Global Chest Symptoms Questionnaire (GCSQ) Score, Pre-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.

18. GCSQ Score, 5 Minutes Post-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.

19. GCSQ Score, 15 Minutes Post-dose [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.

20. Capacity of Day Living in the Morning (CDLM) Score [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. The CDLM questionnaire is as a questionnaire to report on patient's ability to carry out each of six different morning activities (score ranging from 0 "not performed" to 1"performed") and rank the difficulty of performing each of those activities (score ranging from 0 "so difficult that the activity could not be carried out by the patient on their own" to 5 "activity was not at all difficult to carry out". Total score for each morning activity range from 0-6. Total score for whole CDLM questionnaire range from 0-36.

21. Use of Rescue Medication, Night [Baseline to 12 weeks]

    Daily diary record - Night, after evening measurement till morning. Change in average values from run-in to the full treatment period

22. Use of Rescue Medication, Morning [Baseline to 12 weeks]

    Daily diary record - Morning, after morning measurement till midday. Change in average values from run-in to the full treatment period

23. Use of Rescue Medication, Day [Baseline to 12 weeks]

    Daily diary record - Day, after morning measurement till evening. Change in average values from run-in to the full treatment period

24. Use of Rescue Medication, Total [Baseline to 12 weeks]

    Daily diary record - Total, 24 hours, during the night, and during the day. Change in average values from run-in to the full treatment period

25. COPD Symptoms, Breathing Score [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe

26. COPD Symptoms, Sleeping Score [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe

27. COPD Symptoms, Chest Score [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe

28. COPD Symptoms, Cough Score [Baseline to 12 weeks]

    Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe

29. Severe COPD Exacerbations [12 weeks]

    Patients with worsening of COPD leading to treatment with systemic steroids (oral or parenteral), emergency room treatment or hospitalisation

30. Serum High-sensitivity C-reactive Protein (hsCRP) [Baseline to 12 weeks]

    Ratio of treatment period mean to run-in value

31. Serum Interleukin 6 (IL-6) [Baseline to 12 weeks]

    Ratio of treatment period mean to run-in value

32. Serum Interleukin 8 (IL-8) [Baseline to 12 weeks]

    Ratio of treatment period mean to run-in value

33. Serum Monocyte Chemoattractant Protein-1 (MCP-1) [Baseline to 12 weeks]

    Ratio of treatment period mean to run-in value

34. Serum Soluble Tumor Necrosis Factor-alpha (sTNF-alpha) [Baseline to 12 weeks]

    Ratio of treatment period mean to run-in value

35. Serum Tumor Necrosis Factor-alpha (TNF-alpha) [Baseline to 12 weeks]

    Ratio of treatment period mean to run-in value

36. Serum Vascular Cell Adhesion Molecule-1 (VCAM-1) [Baseline to 12 weeks]

    Ratio of treatment period mean to run-in value

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• =40 years of age, diagnosed COPD with symptoms >=2 years, pre-bronchodilatory FEV1 <=50% of PN

Exclusion Criteria:

• Current respiratory tract disorder other than COPD, history of asthma or rhinitis, significant or unstable cardiovascular disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Concord	New South Wales	Australia
2	Research Site	Sydney	New South Wales	Australia
3	Research Site	Auchenflower	Queensland	Australia
4	Research Site	Carina Heights	Queensland	Australia
5	Research Site	North Mackay	Queensland	Australia
6	Research Site	Adelaide	South Australia	Australia
7	Research Site	Daw Park	South Australia	Australia
8	Research Site	Clayton	Victoria	Australia
9	Research Site	Malvern	Victoria	Australia
10	Research Site	Nedlands	Western Australia	Australia
11	Research Site	Calgary	Alberta	Canada
12	Research Site	Vancouver	British Columbia	Canada
13	Research Site	Winnipeg	Manitoba	Canada
14	Research Site	St. John's	Newfoundland and Labrador	Canada
15	Research Site	Halifax	Nova Scotia	Canada
16	Research Site	Mississauga	Ontario	Canada
17	Research Site	Toronto	Ontario	Canada
18	Research Site	La Malbaie	Quebec	Canada
19	Research Site	Trois-rivires	Quebec	Canada
20	Research Site	Saskatoon	Saskatchewan	Canada
21	Research Site	Quebec		Canada
22	Research Site	Chamalieres		France
23	Research Site	Creil		France
24	Research Site	Ferolles Attilly		France
25	Research Site	Grasse		France
26	Research Site	Lille		France
27	Research Site	Marseille Cedex 06		France
28	Research Site	Metz		France
29	Research Site	Montpellier		France
30	Research Site	Perpignan		France
31	Research Site	Poitiers Cedex		France
32	Research Site	Selestat		France
33	Research Site	St Laurent Du Var		France
34	Research Site	Strasbourg Cedex		France
35	Research Site	Toulouse Cedex 9		France
36	Research Site	Berlin		Germany
37	Research Site	Gelsenkirchen		Germany
38	Research Site	Hagen		Germany
39	Research Site	Hannover		Germany
40	Research Site	Kassel		Germany
41	Research Site	Koblenz		Germany
42	Research Site	Leipzig		Germany
43	Research Site	Marburg		Germany
44	Research Site	Potsdam		Germany
45	Research Site	Aszod		Hungary
46	Research Site	Baja		Hungary
47	Research Site	Balassagyarmat		Hungary
48	Research Site	Budapest		Hungary
49	Research Site	Cegled		Hungary
50	Research Site	Debrecen		Hungary
51	Research Site	Fuzesabony		Hungary
52	Research Site	Jaszbereny		Hungary
53	Research Site	Komlo		Hungary
54	Research Site	Nyiregyhaza		Hungary
55	Research Site	Torokbalint		Hungary
56	Research Site	Vásárosnamény		Hungary
57	Research Site	Bydgoszcz		Poland
58	Research Site	Chrzanów		Poland
59	Research Site	Ilawa		Poland
60	Research Site	Krakow		Poland
61	Research Site	Lomza		Poland
62	Research Site	Piekary Slaskie		Poland
63	Research Site	Tarnow		Poland
64	Research Site	Turek		Poland
65	Research Site	Zawadzkie		Poland
66	Research Site	Kosice		Slovakia
67	Research Site	Liptovsky Hradok		Slovakia
68	Research Site	Lucenec		Slovakia
69	Research Site	Nove Mesto Nad Vahom		Slovakia
70	Research Site	Nove Zamky		Slovakia
71	Research Site	Piestany		Slovakia
72	Research Site	Poprad		Slovakia
73	Research Site	Povazska Bystrica		Slovakia
74	Research Site	Presov		Slovakia
75	Research Site	Prievidza		Slovakia
76	Research Site	Revuca		Slovakia
77	Research Site	Trnava		Slovakia
78	Research Site	Zilina		Slovakia
79	Research Site	Barcelona	Cataluna	Spain
80	Research Site	Reus (tarragona)	Cataluna	Spain
81	Research Site	Madrid	Comunidad de Madrid	Spain
82	Research Site	Requena (valencia)	Comunidad Valenciana	Spain
83	Research Site	Valencia	Comunidad Valenciana	Spain
84	Research Site	Pontevedra	Galicia	Spain
85	Research Site	Lindesberg	Orebro Lan	Sweden
86	Research Site	Atvidaberg		Sweden
87	Research Site	Hollviken		Sweden
88	Research Site	Limhamn		Sweden
89	Research Site	Lund		Sweden
90	Research Site	Malmo		Sweden
91	Research Site	Motala		Sweden
92	Research Site	Stockholm		Sweden
93	Research Site	Uppsala		Sweden

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Tomas Andersson, MD, AstraZeneca R&D Lund
• Principal Investigator: Tobias Welte, MD, Hannover Medical School

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00496470
• Other Study ID Numbers: D5892C00015; Eudract no:2006-006796-21
• First Posted: Jul 4, 2007
• Last Update Posted: Nov 9, 2012
• Last Verified: Oct 1, 2012

• Keywords provided by AstraZeneca: Chronic Obstructive Pulmonary Disease, COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Budesonide; Bromides; Formoterol Fumarate; Tiotropium Bromide; Budesonide, Formoterol Fumarate Drug Combination

Study Results

Participant Flow

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Period Title: Overall Study
STARTED	329	331
Received Study Medication	329	330
COMPLETED	303	302
NOT COMPLETED	26	29

Baseline Characteristics

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium	Total
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily	Total of all reporting groups
Overall Participants	329	331	660
Age (Years) [Mean (Full Range) ]
Mean (Full Range) [Years]	62.4	62.5	62.45
Sex: Female, Male (Count of Participants)
Female	78 23.7%	86 26%	164 24.8%
Male	251 76.3%	245 74%	496 75.2%

Outcome Measures

1. Primary Outcome

Title	Forced Expiratory Volume in 1 Second (FEV1) Pre-dose
Description	Change in the pre-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	323	327
Mean (Standard Deviation) [Liters]	0.064 (0.198)	-0.001 (0.168)

2. Secondary Outcome

Title	Forced Expiratory Volume in 1 Second (FEV1) 5 Min Post-dose
Description	Change in the 5 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Mean (Standard Deviation) [Liters]	0.165 (0.184)	0.042 (0.14)

3. Secondary Outcome

Title	Forced Expiratory Volume in 1 Second (FEV1) 60 Min Post-dose
Description	Change in the 60 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Mean (Standard Deviation) [Liters]	0.214 (0.209)	0.083 (0.157)

4. Secondary Outcome

Title	Forced Vital Capacity (FVC) Pre-dose
Description	Change in the pre-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	323	327
Mean (Standard Deviation) [Liters]	0.07 (0.341)	0.014 (0.348)

5. Secondary Outcome

Title	Forced Vital Capacity (FVC) 5 Minutes Post-dose
Description	Change in the 5 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Mean (Standard Deviation) [Liters]	0.266 (0.32)	0.106 (0.296)

6. Secondary Outcome

Title	Forced Vital Capacity (FVC) 60 Minutes Post-dose
Description	Change in the 60 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Mean (Standard Deviation) [Liters]	0.353 (0.357)	0.19 (0.319)

7. Secondary Outcome

Title	Inspiratory Capacity (IC) Pre-dose
Description	Change in the pre-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	314	309
Mean (Standard Deviation) [Liters]	0.078 (0.35)	0.014 (0.389)

8. Secondary Outcome

Title	Inspiratory Capacity (IC) 60 Minutes Post-dose
Description	Change in the 60 min post-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	318	310
Mean (Standard Deviation) [Liters]	0.26 (0.353)	0.149 (0.359)

9. Secondary Outcome

Title	St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Score
Description	Change in total score from baseline (Visit 3) to end of treatment (Visit 6, or last available visit). SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	315	320
Mean (Standard Deviation) [Score on a scale]	-4.12 (12.81)	-1.99 (12.77)

10. Secondary Outcome

Title	Morning Peak Expiratory Flow (PEF) Pre-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Mean (Standard Deviation) [Liters/minute]	5.12 (38.3)	-3.52 (24.7)

11. Secondary Outcome

Title	Evening Peak Expiratory Flow (PEF) Pre-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	329
Mean (Standard Deviation) [Liters/minute]	2.82 (37.6)	-5.54 (28.9)

12. Secondary Outcome

Title	Morning Peak Expiratory Flow (PEF) 5 Min Post-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	294	307
Mean (Standard Deviation) [Liters/minute]	16.71 (42.6)	1.1 (26.5)

13. Secondary Outcome

Title	Morning Peak Expiratory Flow (PEF) 15 Min Post-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	293	311
Mean (Standard Deviation) [Liters/minute]	20.4 (43.7)	5.2 (28.3)

14. Secondary Outcome

Title	Morning Diary FEV1 Pre-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	219	233
Mean (Standard Deviation) [Liters]	0.054 (0.201)	-0.046 (0.185)

15. Secondary Outcome

Title	Evening Diary FEV1, Pre-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	221	237
Mean (Standard Deviation) [Liters]	0.012 (0.223)	-0.065 (0.249)

16. Secondary Outcome

Title	Morning Diary FEV1, 5 Minutes Post-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	191	205
Mean (Standard Deviation) [Liters]	0.169 (0.224)	-0.018 (0.189)

17. Secondary Outcome

Title	Morning Diary FEV1, 15 Minutes Post-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	190	208
Mean (Standard Deviation) [Liters]	0.209 (0.236)	0.014 (0.201)

18. Secondary Outcome

Title	Global Chest Symptoms Questionnaire (GCSQ) Score, Pre-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	328
Mean (Standard Deviation) [Scores on a scale]	-0.143 (0.453)	-0.006 (0.438)

19. Secondary Outcome

Title	GCSQ Score, 5 Minutes Post-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	296	305
Mean (Standard Deviation) [Scores on a scale]	-0.325 (0.508)	-0.202 (0.46)

20. Secondary Outcome

Title	GCSQ Score, 15 Minutes Post-dose
Description	Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	293	309
Mean (Standard Deviation) [Scores on a scale]	-0.404 (-0.526)	-0.28 (-0.501)

21. Secondary Outcome

Title	Capacity of Day Living in the Morning (CDLM) Score
Description	Daily diary record. Change in average values from run-in to the full treatment period. The CDLM questionnaire is as a questionnaire to report on patient's ability to carry out each of six different morning activities (score ranging from 0 "not performed" to 1"performed") and rank the difficulty of performing each of those activities (score ranging from 0 "so difficult that the activity could not be carried out by the patient on their own" to 5 "activity was not at all difficult to carry out". Total score for each morning activity range from 0-6. Total score for whole CDLM questionnaire range from 0-36.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	281	294
Mean (Standard Deviation) [Scores on a scale]	0.202 (0.467)	0.07 (0.435)

22. Secondary Outcome

Title	Use of Rescue Medication, Night
Description	Daily diary record - Night, after evening measurement till morning. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Mean (Standard Deviation) [Inhalations]	-0.279 (0.7)	0.022 (0.743)

23. Secondary Outcome

Title	Use of Rescue Medication, Morning
Description	Daily diary record - Morning, after morning measurement till midday. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	281	294
Mean (Standard Deviation) [Inhalations]	-0.417 (0.758)	-0.124 (0.877)

24. Secondary Outcome

Title	Use of Rescue Medication, Day
Description	Daily diary record - Day, after morning measurement till evening. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	329
Mean (Standard Deviation) [Inhalations]	-0.745 (1.286)	-0.371 (1.622)

25. Secondary Outcome

Title	Use of Rescue Medication, Total
Description	Daily diary record - Total, 24 hours, during the night, and during the day. Change in average values from run-in to the full treatment period
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	329
Mean (Standard Deviation) [Inhalations]	-1.024 (1.704)	-0.347 (2.102)

26. Secondary Outcome

Title	COPD Symptoms, Breathing Score
Description	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	329
Mean (Standard Deviation) [Units on a Scale]	-0.177 (0.503)	-0.049 (0.5)

27. Secondary Outcome

Title	COPD Symptoms, Sleeping Score
Description	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Mean (Standard Deviation) [Units on a Scale]	-0.197 (0.45)	-0.045 (0.462)

28. Secondary Outcome

Title	COPD Symptoms, Chest Score
Description	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	329
Mean (Standard Deviation) [Units on a Scale]	-0.184 (0.5)	-0.061 (0.473)

29. Secondary Outcome

Title	COPD Symptoms, Cough Score
Description	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	329
Mean (Standard Deviation) [Units on a Scale]	-0.246 (0.567)	-0.079 (0.545)

30. Secondary Outcome

Title	Severe COPD Exacerbations
Description	Patients with worsening of COPD leading to treatment with systemic steroids (oral or parenteral), emergency room treatment or hospitalisation
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	329	330
Number [Participants]	25 7.6%	61 18.4%

31. Secondary Outcome

Title	Serum High-sensitivity C-reactive Protein (hsCRP)
Description	Ratio of treatment period mean to run-in value
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	304	309
Median (Inter-Quartile Range) [Ratio]	0.91	0.97

32. Secondary Outcome

Title	Serum Interleukin 6 (IL-6)
Description	Ratio of treatment period mean to run-in value
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	304	309
Median (Inter-Quartile Range) [Ratio]	1.0	1.0

33. Secondary Outcome

Title	Serum Interleukin 8 (IL-8)
Description	Ratio of treatment period mean to run-in value
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	304	309
Median (Inter-Quartile Range) [Ratio]	1.0	1.0

34. Secondary Outcome

Title	Serum Monocyte Chemoattractant Protein-1 (MCP-1)
Description	Ratio of treatment period mean to run-in value
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	304	309
Median (Inter-Quartile Range) [Ratio]	0.95	0.95

35. Secondary Outcome

Title	Serum Soluble Tumor Necrosis Factor-alpha (sTNF-alpha)
Description	Ratio of treatment period mean to run-in value
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	304	309
Median (Inter-Quartile Range) [Ratio]	0.97	0.98

36. Secondary Outcome

Title	Serum Tumor Necrosis Factor-alpha (TNF-alpha)
Description	Ratio of treatment period mean to run-in value
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	304	309
Median (Inter-Quartile Range) [Ratio]	1.0	1.0

37. Secondary Outcome

Title	Serum Vascular Cell Adhesion Molecule-1 (VCAM-1)
Description	Ratio of treatment period mean to run-in value
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) was performed and was based on data from all subjects who were randomized, took at least 1 dose of study medication, and contributed sufficient data for calculation of this outcome Measure.

Arm/Group Title	Symbicort+Tiotropium	Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Measure Participants	304	309
Median (Inter-Quartile Range) [Ratio]	0.96	0.99

Adverse Events

Arm/Group Title	Symbicort+Tiotropium		Placebo+Tiotropium
Arm/Group Description	Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily		Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
All Cause Mortality
	Symbicort+Tiotropium		Placebo+Tiotropium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Symbicort+Tiotropium		Placebo+Tiotropium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/329 (3%)		16/330 (4.8%)
Cardiac disorders
Acute Coronary Syndrome	1/329 (0.3%)		0/330 (0%)
Atrioventricular Block Second Degree	0/329 (0%)		1/330 (0.3%)
Infections and infestations
Infective Exacerbation of Chronic Obstructive Airways Disease	2/329 (0.6%)		2/330 (0.6%)
Pneomonia	1/329 (0.3%)		1/330 (0.3%)
Injury, poisoning and procedural complications
Pelvic Fracture	0/329 (0%)		1/330 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Pancreas	0/329 (0%)		1/330 (0.3%)
Lung Neoplasm	1/329 (0.3%)		0/330 (0%)
Lung Neoplasm Malignant	1/329 (0.3%)		0/330 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	3/329 (0.9%)		8/330 (2.4%)
Bronchospasm	0/329 (0%)		1/330 (0.3%)
Haemoptysis	0/329 (0%)		1/330 (0.3%)
Pleuritic Pain	1/329 (0.3%)		0/330 (0%)
Other (Not Including Serious) Adverse Events
	Symbicort+Tiotropium		Placebo+Tiotropium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/329 (0%)		0/330 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Prior to any publication or disclosure, the PI provides AstraZeneca with preliminary data and drafts and with the proposed final manuscript. AstraZeneca shall have a period of 30 days from receipt of the proposed final manuscript to review it and may within such time frame require that submission for publication or disclosure be delayed.