Trial Outcomes & Findings for Evaluation of Efficacy and Safety of Symbicort® as an add-on Treatment to Spiriva® in Patients With Severe COPD. (NCT NCT00496470)

NCT ID: NCT00496470

Last Updated: 2012-11-09

Results Overview

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)

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 660 participants
• Primary outcome timeframe: Baseline to 12 weeks
• Results posted on: 2012-11-09

Participant Flow

Participant milestones

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

Reasons for withdrawal

Measure	Symbicort+Tiotropium Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Overall Study Adverse Event	8	10
Overall Study Withdrawal by Subject	5	12
Overall Study Incorrectly enrolled	13	5
Overall Study Other reason	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=331 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily	Total n=660 Participants Total of all reporting groups
Age Continuous	62.4 Years n=5 Participants	62.5 Years n=7 Participants	62.45 Years n=5 Participants
Sex: Female, Male Female	78 Participants n=5 Participants	86 Participants n=7 Participants	164 Participants n=5 Participants
Sex: Female, Male Male	251 Participants n=5 Participants	245 Participants n=7 Participants	496 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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)

Outcome measures

Measure	Symbicort+Tiotropium n=323 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=327 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Forced Expiratory Volume in 1 Second (FEV1) Pre-dose	0.064 Liters Standard Deviation 0.198	-0.001 Liters Standard Deviation 0.168

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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)

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Forced Expiratory Volume in 1 Second (FEV1) 5 Min Post-dose	0.165 Liters Standard Deviation 0.184	0.042 Liters Standard Deviation 0.14

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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)

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Forced Expiratory Volume in 1 Second (FEV1) 60 Min Post-dose	0.214 Liters Standard Deviation 0.209	0.083 Liters Standard Deviation 0.157

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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)

Outcome measures

Measure	Symbicort+Tiotropium n=323 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=327 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Forced Vital Capacity (FVC) Pre-dose	0.07 Liters Standard Deviation 0.341	0.014 Liters Standard Deviation 0.348

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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)

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Forced Vital Capacity (FVC) 5 Minutes Post-dose	0.266 Liters Standard Deviation 0.32	0.106 Liters Standard Deviation 0.296

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Forced Vital Capacity (FVC) 60 Minutes Post-dose	0.353 Liters Standard Deviation 0.357	0.19 Liters Standard Deviation 0.319

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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)

Outcome measures

Measure	Symbicort+Tiotropium n=314 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Inspiratory Capacity (IC) Pre-dose	0.078 Liters Standard Deviation 0.35	0.014 Liters Standard Deviation 0.389

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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)

Outcome measures

Measure	Symbicort+Tiotropium n=318 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=310 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Inspiratory Capacity (IC) 60 Minutes Post-dose	0.26 Liters Standard Deviation 0.353	0.149 Liters Standard Deviation 0.359

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: 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.

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.

Outcome measures

Measure	Symbicort+Tiotropium n=315 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=320 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Score	-4.12 Score on a scale Standard Deviation 12.81	-1.99 Score on a scale Standard Deviation 12.77

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Morning Peak Expiratory Flow (PEF) Pre-dose	5.12 Liters/minute Standard Deviation 38.3	-3.52 Liters/minute Standard Deviation 24.7

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=329 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Evening Peak Expiratory Flow (PEF) Pre-dose	2.82 Liters/minute Standard Deviation 37.6	-5.54 Liters/minute Standard Deviation 28.9

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=294 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=307 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Morning Peak Expiratory Flow (PEF) 5 Min Post-dose	16.71 Liters/minute Standard Deviation 42.6	1.1 Liters/minute Standard Deviation 26.5

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=293 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=311 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Morning Peak Expiratory Flow (PEF) 15 Min Post-dose	20.4 Liters/minute Standard Deviation 43.7	5.2 Liters/minute Standard Deviation 28.3

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=219 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=233 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Morning Diary FEV1 Pre-dose	0.054 Liters Standard Deviation 0.201	-0.046 Liters Standard Deviation 0.185

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=221 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=237 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Evening Diary FEV1, Pre-dose	0.012 Liters Standard Deviation 0.223	-0.065 Liters Standard Deviation 0.249

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=191 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=205 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Morning Diary FEV1, 5 Minutes Post-dose	0.169 Liters Standard Deviation 0.224	-0.018 Liters Standard Deviation 0.189

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=190 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=208 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Morning Diary FEV1, 15 Minutes Post-dose	0.209 Liters Standard Deviation 0.236	0.014 Liters Standard Deviation 0.201

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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.

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=328 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Global Chest Symptoms Questionnaire (GCSQ) Score, Pre-dose	-0.143 Scores on a scale Standard Deviation 0.453	-0.006 Scores on a scale Standard Deviation 0.438

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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.

Outcome measures

Measure	Symbicort+Tiotropium n=296 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=305 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
GCSQ Score, 5 Minutes Post-dose	-0.325 Scores on a scale Standard Deviation 0.508	-0.202 Scores on a scale Standard Deviation 0.46

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Symbicort+Tiotropium n=293 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
GCSQ Score, 15 Minutes Post-dose	-0.404 Scores on a scale Standard Deviation -0.526	-0.28 Scores on a scale Standard Deviation -0.501

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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.

Outcome measures

Measure	Symbicort+Tiotropium n=281 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=294 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Capacity of Day Living in the Morning (CDLM) Score	0.202 Scores on a scale Standard Deviation 0.467	0.07 Scores on a scale Standard Deviation 0.435

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Use of Rescue Medication, Night	-0.279 Inhalations Standard Deviation 0.7	0.022 Inhalations Standard Deviation 0.743

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=281 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=294 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Use of Rescue Medication, Morning	-0.417 Inhalations Standard Deviation 0.758	-0.124 Inhalations Standard Deviation 0.877

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=329 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Use of Rescue Medication, Day	-0.745 Inhalations Standard Deviation 1.286	-0.371 Inhalations Standard Deviation 1.622

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=329 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Use of Rescue Medication, Total	-1.024 Inhalations Standard Deviation 1.704	-0.347 Inhalations Standard Deviation 2.102

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=329 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
COPD Symptoms, Breathing Score	-0.177 Units on a Scale Standard Deviation 0.503	-0.049 Units on a Scale Standard Deviation 0.5

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
COPD Symptoms, Sleeping Score	-0.197 Units on a Scale Standard Deviation 0.45	-0.045 Units on a Scale Standard Deviation 0.462

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=329 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
COPD Symptoms, Chest Score	-0.184 Units on a Scale Standard Deviation 0.5	-0.061 Units on a Scale Standard Deviation 0.473

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=329 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
COPD Symptoms, Cough Score	-0.246 Units on a Scale Standard Deviation 0.567	-0.079 Units on a Scale Standard Deviation 0.545

SECONDARY outcome

Timeframe: 12 weeks

Population: 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.

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

Outcome measures

Measure	Symbicort+Tiotropium n=329 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Severe COPD Exacerbations	25 Participants	61 Participants

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

Ratio of treatment period mean to run-in value

Outcome measures

Measure	Symbicort+Tiotropium n=304 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Serum High-sensitivity C-reactive Protein (hsCRP)	0.91 Ratio Interval 0.5 to 1.76	0.97 Ratio Interval 0.6 to 1.54

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

Ratio of treatment period mean to run-in value

Outcome measures

Measure	Symbicort+Tiotropium n=304 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Serum Interleukin 6 (IL-6)	1.0 Ratio Interval 0.72 to 1.56	1.0 Ratio Interval 0.67 to 1.56

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

Ratio of treatment period mean to run-in value

Outcome measures

Measure	Symbicort+Tiotropium n=304 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Serum Interleukin 8 (IL-8)	1.0 Ratio Interval 1.0 to 1.0	1.0 Ratio Interval 1.0 to 1.0

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

Ratio of treatment period mean to run-in value

Outcome measures

Measure	Symbicort+Tiotropium n=304 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Serum Monocyte Chemoattractant Protein-1 (MCP-1)	0.95 Ratio Interval 0.78 to 1.15	0.95 Ratio Interval 0.79 to 1.11

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

Ratio of treatment period mean to run-in value

Outcome measures

Measure	Symbicort+Tiotropium n=304 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Serum Soluble Tumor Necrosis Factor-alpha (sTNF-alpha)	0.97 Ratio Interval 0.85 to 1.08	0.98 Ratio Interval 0.88 to 1.1

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

Ratio of treatment period mean to run-in value

Outcome measures

Measure	Symbicort+Tiotropium n=304 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Serum Tumor Necrosis Factor-alpha (TNF-alpha)	1.0 Ratio Interval 0.69 to 1.28	1.0 Ratio Interval 0.67 to 1.2

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: 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.

Ratio of treatment period mean to run-in value

Outcome measures

Measure	Symbicort+Tiotropium n=304 Participants Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=309 Participants Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Serum Vascular Cell Adhesion Molecule-1 (VCAM-1)	0.96 Ratio Interval 0.87 to 1.06	0.99 Ratio Interval 0.91 to 1.09

Adverse Events

Symbicort+Tiotropium

Serious events: 10 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo+Tiotropium

Serious events: 16 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Symbicort+Tiotropium n=329 participants at risk Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Placebo+Tiotropium n=330 participants at risk Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily
Cardiac disorders Acute Coronary Syndrome	0.30% 1/329	0.00% 0/330
Cardiac disorders Atrioventricular Block Second Degree	0.00% 0/329	0.30% 1/330
Infections and infestations Infective Exacerbation of Chronic Obstructive Airways Disease	0.61% 2/329	0.61% 2/330
Infections and infestations Pneomonia	0.30% 1/329	0.30% 1/330
Injury, poisoning and procedural complications Pelvic Fracture	0.00% 0/329	0.30% 1/330
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma Pancreas	0.00% 0/329	0.30% 1/330
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Neoplasm	0.30% 1/329	0.00% 0/330
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Neoplasm Malignant	0.30% 1/329	0.00% 0/330
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.91% 3/329	2.4% 8/330
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.00% 0/329	0.30% 1/330
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/329	0.30% 1/330
Respiratory, thoracic and mediastinal disorders Pleuritic Pain	0.30% 1/329	0.00% 0/330

Other adverse events

Adverse event data not reported

Additional Information

Gerard Lynch

AstraZeneca

Email: ClinicalTrialTransparency@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER