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Inhaled Corticosteroid Withdrawal in Patients With Chronic Obstructive Pulmonary Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00975195
Recruitment Status : Completed
First Posted : September 11, 2009
Results First Posted : February 10, 2015
Last Update Posted : February 10, 2015
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: tiotropium inhalation
Drug: salmeterol xinafoate
Drug: fluticasone propionate
Drug: placebo matched for fluticasone propionate
Enrollment 2488
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description 18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period). 18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Period Title: Overall Study
Started 1244 1244
Completed 1016 [1] 1011 [1]
Not Completed 228 233
Reason Not Completed
Adverse Event             108             101
Lack of Efficacy             6             6
Protocol Violation             27             23
Lost to Follow-up             9             7
Withdrawal by Subject             48             61
Other reason not defined above             29             33
Not treated             1             2
[1]
Includes open-label treatment if appropriate
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal Total
Hide Arm/Group Description 18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period). 18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period). Total of all reporting groups
Overall Number of Baseline Participants 1243 1242 2485
Hide Baseline Analysis Population Description
Treated Set (TS) which included all patients who were dispensed study medication and were documented to have taken ≥1 dose of randomised treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1243 participants 1242 participants 2485 participants
63.6  (8.6) 64.0  (8.4) 63.8  (8.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1243 participants 1242 participants 2485 participants
Female
230
  18.5%
206
  16.6%
436
  17.5%
Male
1013
  81.5%
1036
  83.4%
2049
  82.5%
1.Primary Outcome
Title Time to First Moderate or Severe On-treatment COPD Exacerbation
Hide Description A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as an increase or new onset of ≥2 lower respiratory symptoms related to COPD, with ≥1 symptom lasting ≥3 days, requiring a change in treatment. Lower respiratory symptoms included shortness of breath, sputum production (volume), sputum purulence, cough, wheezing and chest tightness. A change in treatment included: hospitalisation/treatment in an urgent care unit, prescription of antibiotics and/or systemic steroids or a significant change of prescribed respiratory medication such as theophyllines, long-acting beta-agonists or inhaled corticosteroids. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.The "measure type" displays the 25th percentile and its 95% confidence interval.
Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: days
107.0
(94.0 to 124.0)
110.0
(99.0 to 120.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Upper limit of 95% confidence interval (CI) <1.2 indicates non-inferiority of Fluticasone withdrawal compared with Fluticasone maintenance
Statistical Test of Hypothesis P-Value 0.3497
Comments Two-sided p-value to test superiority of fluticasone maintenance over fluticasone withdrawal if non-inferiority shown.
Method Chi-squared
Comments Wald's chi-square test
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.058
Confidence Interval (2-Sided) 95%
0.941 to 1.189
Estimation Comments Ratio calculated as fluticasone withdrawal divided by fluticasone maintenance
2.Secondary Outcome
Title Number of Moderate or Severe On-treatment COPD Exacerbations
Hide Description

Number of moderate or severe on-treatment COPD exacerbations, based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined and counted as moderate or severe if ≥1 of the contributing exacerbation events was moderate or severe. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. Exacerbations were considered moderate if they required prescription of antibiotics and/or systemic steroids.

Measured values show adjusted mean event rate.

Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Mean (95% Confidence Interval)
Unit of Measure: exacerbations per patient-year
0.91
(0.83 to 0.99)
0.95
(0.87 to 1.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4441
Comments [Not Specified]
Method Regression, Negative Binomial
Comments Adjusted for log time at risk using log link function
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.93 to 1.18
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.06
Estimation Comments Ratio calculated as fluticasone withdrawal divided by fluticasone maintenance
3.Secondary Outcome
Title Proportion of Patients With ≥1 Moderate or Severe On-treatment COPD Exacerbation
Hide Description Presence (yes vs no) of at least one moderate or severe on-treatment COPD exacerbation, displayed as a percentage. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. Exacerbations were considered moderate if they required prescription of antibiotics and/or systemic steroids.
Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Measure Type: Number
Unit of Measure: percentage of participants
44.2 46.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2269
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title Time to First Severe On-treatment COPD Exacerbation
Hide Description

Time to first severe on-treatment COPD exacerbation. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.

The "measure type" displays the 25th percentile and its 95% confidence interval.

Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
419.0 [1] 
(379.0 to NA)
[1]
Not estimable as not enough events during the timeframe.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0849
Comments [Not Specified]
Method Chi-squared
Comments Wald's chi-square test
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.202
Confidence Interval (2-Sided) 95%
0.975 to 1.481
Estimation Comments Ratio calculated as fluticasone withdrawal divided by fluticasone maintenance
5.Secondary Outcome
Title Number of Severe On-treatment COPD Exacerbations
Hide Description

Number of severe on-treatment COPD exacerbations based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined and counted as severe if ≥1 of the contributing exacerbation events was severe. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.

Measured values show adjusted event rate.

Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Mean (95% Confidence Interval)
Unit of Measure: exacerbations per patient-year
0.20
(0.17 to 0.23)
0.23
(0.19 to 0.27)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2291
Comments [Not Specified]
Method Regression, Negative Binomial
Comments Adjusted for log time at risk using log link function
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 1.15
Confidence Interval (2-Sided) 95%
0.92 to 1.45
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.13
Estimation Comments Ratio calculated as fluticasone withdrawal divided by fluticasone maintenance
6.Secondary Outcome
Title Proportion of Patients With at Least One Severe On-treatment COPD Exacerbation.
Hide Description Presence (yes vs no) of at least one severe on-treatment COPD exacerbation, displayed as a percentage. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.
Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Measure Type: Number
Unit of Measure: percentage of participants
13.4 15.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2083
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
7.Secondary Outcome
Title Time to First On-treatment COPD Exacerbation
Hide Description Time to first on-treatment COPD exacerbation of any severity. The "measure type" displays the 25th percentile and its 95% confidence interval.
Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: days
365.0 [1] 
(309.0 to NA)
346.0 [1] 
(302.0 to NA)
[1]
Not estimable as not enough events during the timeframe.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5562
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.035
Confidence Interval (2-Sided) 95%
0.923 to 1.160
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Number of On-treatment COPD Exacerbations
Hide Description

Number of on-treatment COPD exacerbations of any severity, based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined.

Measured values show adjusted event rate.

Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Mean (95% Confidence Interval)
Unit of Measure: exacerbations per patient-year
1.03
(0.95 to 1.12)
1.08
(0.99 to 1.17)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4342
Comments [Not Specified]
Method Regression, Negative binomial
Comments Adjusted for log time at risk using log link function
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.93 to 1.18
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.06
Estimation Comments Ratio calculated as fluticasone withdrawal divided by fluticasone maintenance
9.Secondary Outcome
Title Proportion of Patients With at Least One On-treatment COPD Exacerbation
Hide Description Presence (yes vs no) of at least one on-treatment COPD exacerbation of any severity, displayed as a percentage.
Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Measure Type: Number
Unit of Measure: percentage of participants
46.9 49.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3155
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
10.Secondary Outcome
Title Severity of On-treatment COPD Exacerbations
Hide Description Severity of on-treatment COPD exacerbations: for each patient, the worst applicable category was taken (i.e. none, mild, moderate or severe)
Time Frame During randomised treatment, up to 488 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Measure Type: Number
Unit of Measure: percentage of participants
None and patient completed randomised treatment 42.9 41.2
None and patient discontinued randomised treatment 10.2 9.8
Mild 2.7 2.3
Moderate 30.8 31.5
Severe 13.4 15.2
11.Secondary Outcome
Title Change in On-treatment Lung Function as Measured by Trough FEV1
Hide Description Change from baseline in on-treatment lung function as measured by trough forced expiratory volume in one second (FEV1); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.
Time Frame Baseline and week 6, 12, 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: Litres
Week 6 visit (N=1135, 1135) -0.009  (0.0062) -0.011  (0.0062)
Week 12 visit (N=1114, 1092) -0.011  (0.0062) -0.018  (0.0063)
Week 18 visit (N=1077, 1058) -0.011  (0.0064) -0.050  (0.0064)
Week 52 visit (N=970, 935) -0.016  (0.0094) -0.059  (0.0096)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.043
Confidence Interval (2-Sided) 95%
-0.069 to -0.017
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0134
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
12.Secondary Outcome
Title Changes in On-treatment Dyspnoea as Measured by the Modified Medical Research Council (MMRC) Dyspnoea Scale
Hide Description

Change from baseline in on-treatment dyspnoea as measured by the Modified Medical Research Council (MMRC) dyspnoea scale; change was calculated as week score minus baseline score. Negative changes from baseline indicate an improvement in health.

Scale from 0 to 4:

  • 0 = not troubled by breathlessness, except during strenuous exercise
  • 1 = short of breath when hurrying or walking up a slight hill
  • 2 = walks slower than contemporaries on the same level because of breathlessness, or has to stop for breath when walking at own pace
  • 3 = stops for breath after approximately 100 yards, or after a few minutes on the level
  • 4 = too breathless to leave the house, or breathless when dressing or undressing

"No breathlessness" was given a score of -1

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 18 visit (N=1140, 1143) -0.030  (0.022) -0.001  (0.022)
Week 52 visit (N=1043, 1019) -0.028  (0.024) 0.035  (0.024)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0632
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.064
Confidence Interval (2-Sided) 95%
-0.004 to 0.131
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.034
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
13.Secondary Outcome
Title Change in On-treatment Physical Health Status as Determined by Body Mass Index (BMI)
Hide Description Change from baseline in on-treatment physical health status as determined by body mass index (BMI); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.
Time Frame Baseline and week 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: kg/m2
Week 18 visit (N=1143, 1146) 0.030  (0.028) 0.040  (0.028)
Week 52 visit (N=1047, 1021) 0.004  (0.039) -0.009  (0.039)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8137
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.013
Confidence Interval (2-Sided) 95%
-0.122 to 0.096
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.055
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
14.Secondary Outcome
Title Change in On-treatment Exercise Capacity Measured by Six-minute Walk Test (6-MWT)
Hide Description Change from baseline in on-treatment exercise capacity measured by six-minute walk test (6-MWT); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.
Time Frame Baseline and week 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: meters
Week 18 visit (N=1111, 1110) 3.89  (1.993) 1.94  (1.993)
Week 52 visit (N=1013, 987) 3.94  (2.231) 0.42  (2.252)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2663
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -3.53
Confidence Interval (2-Sided) 95%
-9.74 to 2.69
Parameter Dispersion
Type: Standard Error of the mean
Value: 3.170
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
15.Secondary Outcome
Title Change in On-treatment BODE Index
Hide Description Change from baseline in on-treatment BODE index (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity index), a composite score ranging from 0 (best) to 10 (worst); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.
Time Frame Baseline and week 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 18 visit (N=1038, 1024) -0.06  (0.03) 0.06  (0.03)
Week 52 visit (N=931, 907) -0.03  (0.04) 0.14  (0.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0033
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.16
Confidence Interval (2-Sided) 95%
0.05 to 0.27
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.06
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
16.Secondary Outcome
Title Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Cough Impact Domain
Hide Description

Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Cough impact domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from "not at all/never" to "extremely/always" on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less impact due to cough.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 12, 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set who completed CASA-Q
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 364 361
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 12 visit (N=307, 319) -1.65  (0.986) -1.24  (0.968)
Week 18 visit (N=302, 312) -2.87  (1.035) -3.71  (1.018)
Week 52 visit (N=268, 269) -4.51  (1.063) -5.54  (1.057)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4914
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.03
Confidence Interval (2-Sided) 95%
-3.98 to 1.91
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.499
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
17.Secondary Outcome
Title Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Cough Symptoms Domain
Hide Description

Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Cough symptoms domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from "not at all/never" to "a lot/always" on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less symptoms due to cough.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 12, 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set who completed CASA-Q
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 364 361
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 12 visit (N=309, 318) -0.32  (1.062) -0.85  (1.048)
Week 18 visit (N=305, 312) -1.47  (1.103) -3.34  (1.091)
Week 52 visit (N=270, 268) -1.69  (1.180) -3.26  (1.180)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3490
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.56
Confidence Interval (2-Sided) 95%
-4.84 to 1.71
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.669
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
18.Secondary Outcome
Title Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Sputum Impact Domain
Hide Description

Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Sputum impact domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from "not at all/never" to "a lot/always" on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less impact due to sputum.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 12, 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set who completed CASA-Q
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 364 361
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 12 visit (N=308, 317) -2.26  (0.996) -1.63  (0.983)
Week 18 visit (N=303, 310) -2.38  (0.977) -3.31  (0.967)
Week 52 visit (N=267, 267) -4.29  (1.047) -4.15  (1.045)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9262
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.14
Confidence Interval (2-Sided) 95%
-2.77 to 3.04
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.480
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
19.Secondary Outcome
Title Change in On-treatment Cough and Expectoration as Measured by the CASA-Q: Sputum Symptoms Domain
Hide Description

Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Sputum symptoms domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from "not at all/never" to "extremely/always" on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less symptoms due to sputum.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 12, 18 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set who completed CASA-Q
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 364 361
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 12 visit (N=308, 317) -1.36  (1.154) -1.24  (1.139)
Week 18 visit (N=302, 311) -2.71  (1.119) -1.93  (1.105)
Week 52 visit (N=269, 268) -5.10  (1.212) -2.45  (1.211)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1241
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 2.64
Confidence Interval (2-Sided) 95%
-0.73 to 6.01
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.716
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
20.Secondary Outcome
Title Change in On-treatment FEV1 as Measured by Home Based Spirometry
Hide Description Change from baseline in on-treatment Forced Expiratory Volume in One Second (FEV1) as measured by home based spirometry. Change was calculated as week score minus baseline score. The weekly mean was defined as the mean of the measurements taken during the last 7 days prior to the visit date, and was calculated if ≥4 of the 7 days had non-missing measurements. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.
Time Frame Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: Litres
Week 6 visit (N=893, 939) -0.049  (0.0066) -0.053  (0.0065)
Week 12 visit (N=910, 930) -0.050  (0.0068) -0.056  (0.0067)
Week 18 visit (N=913, 901) -0.051  (0.0068) -0.093  (0.0068)
Week 27 visit (N=863, 843) -0.056  (0.0071) -0.092  (0.0072)
Week 36 visit (N=854, 845) -0.059  (0.0074) -0.099  (0.0074)
Week 45 visit (N=830, 815) -0.061  (0.0080) -0.103  (0.0080)
Week 52 visit (N=785, 788) -0.067  (0.0087) -0.115  (0.0087)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.048
Confidence Interval (2-Sided) 95%
-0.073 to -0.024
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0123
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
21.Secondary Outcome
Title Change in On-treatment FVC as Measured by Home Based Spirometry
Hide Description Change from baseline in on-treatment forced vital capacity (FVC) as measured by home based spirometry. Change was calculated as week score minus baseline score. The weekly mean was defined as the mean of the measurements taken during the last 7 days prior to the visit date, and was calculated if ≥4 of the 7 days had non-missing measurements. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.
Time Frame Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: Litres
Week 6 visit (N=893, 939) -0.116  (0.0179) -0.089  (0.0177)
Week 12 visit (N=910, 930) -0.113  (0.0168) -0.105  (0.0167)
Week 18 visit (N=913, 901) -0.122  (0.0177) -0.124  (0.0177)
Week 27 visit (N=863, 843) -0.123  (0.0167) -0.147  (0.0167)
Week 36 visit (N=854, 845) -0.135  (0.0170) -0.158  (0.0171)
Week 45 visit (N=830, 815) -0.141  (0.0174) -0.168  (0.0175)
Week 52 visit (N=785, 788) -0.157  (0.0180) -0.201  (0.0180)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0855
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.044
Confidence Interval (2-Sided) 95%
-0.094 to 0.006
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0255
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
22.Secondary Outcome
Title Change in On-treatment PEFR as Measured by Home Based Spirometry
Hide Description Change from baseline in on-treatment peak expiratory flow rate (PEFR) as measured by home based spirometry; change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.
Time Frame Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: Litres/sec
Week 6 visit (N=893, 939) -0.228  (0.0249) -0.230  (0.0246)
Week 12 visit (N=910, 930) -0.266  (0.0253) -0.290  (0.0252)
Week 18 visit (N=913, 901) -0.295  (0.0253) -0.435  (0.0254)
Week 27 visit (N=863, 843) -0.319  (0.0273) -0.430  (0.0274)
Week 36 visit (N=854, 845) -0.352  (0.0278) -0.473  (0.0278)
Week 45 visit (N=830, 815) -0.368  (0.0297) -0.490  (0.0298)
Week 52 visit (N=785, 788) -0.377  (0.0318) -0.538  (0.0318)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.161
Confidence Interval (2-Sided) 95%
-0.249 to -0.073
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0450
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
23.Secondary Outcome
Title Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Activity Domain
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Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Activity domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 27 and 52 visits
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Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 27 visit (N=1002, 988) 0.09  (0.492) 0.85  (0.496)
Week 52 visit (N=942, 916) -0.19  (0.512) 0.78  (0.518)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1838
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
-0.46 to 2.40
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.728
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
24.Secondary Outcome
Title Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Impact Domain
Hide Description

Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Impact Domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 27 and 52 visits
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Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 27 visit (N=1004, 998) -0.78  (0.456) 0.35  (0.457)
Week 52 visit (N=946, 921) -0.08  (0.494) 1.27  (0.499)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0551
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 1.35
Confidence Interval (2-Sided) 95%
-0.03 to 2.72
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.702
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
25.Secondary Outcome
Title Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Symptoms Domain
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Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Symptoms domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 27 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 27 visit (N=1010, 998) 0.12  (0.583) 0.62  (0.586)
Week 52 visit (N=955, 921) 0.51  (0.593) 1.11  (0.602)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4804
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
-1.06 to 2.25
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.845
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
26.Secondary Outcome
Title Change in On-treatment St Georges Respiratory Questionnaire (SGRQ) Scores: Total Score
Hide Description

Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Total score. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 27 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 27 visit (N=996, 986) -0.42  (0.398) 0.55  (0.401)
Week 52 visit (N=939, 913) -0.07  (0.432) 1.15  (0.437)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0467
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 1.22
Confidence Interval (2-Sided) 95%
0.02 to 2.43
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.614
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
27.Secondary Outcome
Title Change in On-treatment Physician Global Evaluation
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Change from baseline in on-treatment physician global evaluation. The evaluation reflected the physician's opinion of the patient's overall condition and was based on the need for concomitant medication, the number and severity of exacerbations, the severity of cough, the ability to exercise, the amount of wheezing and any other relevant clinical observations. Patients were graded on a scale of 1 (poor) to 8 (excellent). Change was calculated as week score minus baseline score.

Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest.

Time Frame Baseline and week 27 and 52 visits
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description:
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period).
18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
Overall Number of Participants Analyzed 1243 1242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 27 visit (N=1113, 1093) 0.10  (0.03) 0.04  (0.03)
Week 52 visit (N=1041, 1014) 0.19  (0.03) 0.08  (0.03)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fluticasone Maintenance, Fluticasone Withdrawal
Comments Week 52 visit
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0223
Comments [Not Specified]
Method Restricted maximum likelihood
Comments Repeated measures restricted maximum likelihood
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.11
Confidence Interval (2-Sided) 95%
-0.21 to -0.02
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.05
Estimation Comments Difference calculated as fluticasone withdrawal minus fluticasone maintenance
Time Frame Randomised treatment plus 30 days post-treatment for patients not switching to open-label, up to 518 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Fluticasone Maintenance Fluticasone Withdrawal
Hide Arm/Group Description 18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d., 50 μg salmeterol b.i.d.,and 500 μg fluticasone b.i.d. for 52 weeks (randomised treatment period). 18μg tiotropium administered by oral inhalation once daily (q.d.), 50μg salmeterol and 500μg fluticasone, each administered by oral inhalation twice daily (b.i.d) for 6 weeks (open-label run in period), followed by 18 μg tiotropium q.d.and 50 μg salmeterol b.i.d. for 52 weeks, in combination with a stepwise withdrawal of fluticasone, consisting of 250μg fluticasone b.i.d for 6 weeks, followed by 100μg fluticasone b.i.d for 6 weeks, followed by placebo for 40 weeks (randomised treatment period).
All-Cause Mortality
Fluticasone Maintenance Fluticasone Withdrawal
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Fluticasone Maintenance Fluticasone Withdrawal
Affected / at Risk (%) Affected / at Risk (%)
Total   292/1243 (23.49%)   300/1242 (24.15%) 
Blood and lymphatic system disorders     
Anaemia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Anaemia macrocytic  1  0/1243 (0.00%)  1/1242 (0.08%) 
Febrile neutropenia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Cardiac disorders     
Acute coronary syndrome  1  1/1243 (0.08%)  2/1242 (0.16%) 
Acute myocardial infarction  1  5/1243 (0.40%)  1/1242 (0.08%) 
Angina pectoris  1  2/1243 (0.16%)  1/1242 (0.08%) 
Angina unstable  1  4/1243 (0.32%)  0/1242 (0.00%) 
Aortic valve disease  1  1/1243 (0.08%)  0/1242 (0.00%) 
Arrhythmia  1  3/1243 (0.24%)  1/1242 (0.08%) 
Arteriosclerosis coronary artery  1  1/1243 (0.08%)  0/1242 (0.00%) 
Atrial fibrillation  1  9/1243 (0.72%)  5/1242 (0.40%) 
Atrial flutter  1  3/1243 (0.24%)  1/1242 (0.08%) 
Bradycardia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Bundle branch block right  1  1/1243 (0.08%)  0/1242 (0.00%) 
Cardiac arrest  1  3/1243 (0.24%)  4/1242 (0.32%) 
Cardiac asthma  1  1/1243 (0.08%)  0/1242 (0.00%) 
Cardiac disorder  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cardiac failure  1  1/1243 (0.08%)  3/1242 (0.24%) 
Cardiac failure acute  1  1/1243 (0.08%)  2/1242 (0.16%) 
Cardiac failure chronic  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cardiac failure congestive  1  2/1243 (0.16%)  2/1242 (0.16%) 
Cardiopulmonary failure  1  1/1243 (0.08%)  0/1242 (0.00%) 
Congestive cardiomyopathy  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cor pulmonale  1  2/1243 (0.16%)  2/1242 (0.16%) 
Cor pulmonale chronic  1  0/1243 (0.00%)  1/1242 (0.08%) 
Coronary artery disease  1  3/1243 (0.24%)  0/1242 (0.00%) 
Coronary artery stenosis  1  1/1243 (0.08%)  1/1242 (0.08%) 
Hypertensive heart disease  1  1/1243 (0.08%)  2/1242 (0.16%) 
Left ventricular failure  1  0/1243 (0.00%)  1/1242 (0.08%) 
Myocardial infarction  1  3/1243 (0.24%)  2/1242 (0.16%) 
Myocardial ischaemia  1  4/1243 (0.32%)  0/1242 (0.00%) 
Right ventricular failure  1  2/1243 (0.16%)  0/1242 (0.00%) 
Sinus bradycardia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Stress cardiomyopathy  1  0/1243 (0.00%)  1/1242 (0.08%) 
Tachyarrhythmia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Tachycardia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Ventricular tachycardia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Ear and labyrinth disorders     
Deafness unilateral  1  0/1243 (0.00%)  1/1242 (0.08%) 
Vertigo  1  1/1243 (0.08%)  1/1242 (0.08%) 
Eye disorders     
Angle closure glaucoma  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cataract  1  3/1243 (0.24%)  4/1242 (0.32%) 
Pterygium  1  0/1243 (0.00%)  1/1242 (0.08%) 
Visual impairment  1  0/1243 (0.00%)  1/1242 (0.08%) 
Gastrointestinal disorders     
Abdominal pain upper  1  1/1243 (0.08%)  0/1242 (0.00%) 
Colonic stenosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Constipation  1  1/1243 (0.08%)  2/1242 (0.16%) 
Dental caries  1  0/1243 (0.00%)  1/1242 (0.08%) 
Dyspepsia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Gastric ulcer perforation  1  0/1243 (0.00%)  1/1242 (0.08%) 
Gastritis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Gastroduodenitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Gastrointestinal haemorrhage  1  1/1243 (0.08%)  0/1242 (0.00%) 
Inguinal hernia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Intestinal obstruction  1  3/1243 (0.24%)  0/1242 (0.00%) 
Large intestine polyp  1  1/1243 (0.08%)  0/1242 (0.00%) 
Melaena  1  1/1243 (0.08%)  0/1242 (0.00%) 
Oesophageal food impaction  1  0/1243 (0.00%)  1/1242 (0.08%) 
Oesophagitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Pancreatitis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Rectal haemorrhage  1  1/1243 (0.08%)  0/1242 (0.00%) 
Salivary gland calculus  1  0/1243 (0.00%)  1/1242 (0.08%) 
Stomatitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
General disorders     
Chest pain  1  0/1243 (0.00%)  3/1242 (0.24%) 
Death  1  0/1243 (0.00%)  2/1242 (0.16%) 
Impaired healing  1  1/1243 (0.08%)  0/1242 (0.00%) 
Inflammation  1  1/1243 (0.08%)  0/1242 (0.00%) 
Oedema  1  1/1243 (0.08%)  0/1242 (0.00%) 
Oedema peripheral  1  1/1243 (0.08%)  0/1242 (0.00%) 
Sudden cardiac death  1  1/1243 (0.08%)  3/1242 (0.24%) 
Sudden death  1  1/1243 (0.08%)  3/1242 (0.24%) 
Hepatobiliary disorders     
Bile duct obstruction  1  1/1243 (0.08%)  0/1242 (0.00%) 
Cholangitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cholecystitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cholelithiasis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Infections and infestations     
Appendicitis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Arthritis bacterial  1  1/1243 (0.08%)  0/1242 (0.00%) 
Aspergillosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Bacterial infection  1  0/1243 (0.00%)  1/1242 (0.08%) 
Bronchitis  1  3/1243 (0.24%)  3/1242 (0.24%) 
Bronchitis bacterial  1  0/1243 (0.00%)  2/1242 (0.16%) 
Bronchopneumonia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Chronic sinusitis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Device related infection  1  0/1243 (0.00%)  1/1242 (0.08%) 
Ear infection  1  1/1243 (0.08%)  0/1242 (0.00%) 
Erysipelas  1  1/1243 (0.08%)  1/1242 (0.08%) 
Escherichia infection  1  1/1243 (0.08%)  0/1242 (0.00%) 
Extradural abscess  1  1/1243 (0.08%)  0/1242 (0.00%) 
Gastroenteritis  1  2/1243 (0.16%)  0/1242 (0.00%) 
Gastroenteritis norovirus  1  1/1243 (0.08%)  0/1242 (0.00%) 
Gastrointestinal infection  1  1/1243 (0.08%)  0/1242 (0.00%) 
Infective exacerbation of chronic obstructive airways disease  1  7/1243 (0.56%)  5/1242 (0.40%) 
Klebsiella infection  1  1/1243 (0.08%)  0/1242 (0.00%) 
Liver abscess  1  1/1243 (0.08%)  0/1242 (0.00%) 
Lobar pneumonia  1  12/1243 (0.97%)  3/1242 (0.24%) 
Lower respiratory tract infection  1  1/1243 (0.08%)  1/1242 (0.08%) 
Lung infection  1  1/1243 (0.08%)  2/1242 (0.16%) 
Meningitis viral  1  1/1243 (0.08%)  0/1242 (0.00%) 
Peritonsillar abscess  1  0/1243 (0.00%)  1/1242 (0.08%) 
Pneumonia  1  34/1243 (2.74%)  38/1242 (3.06%) 
Pneumonia klebsiella  1  0/1243 (0.00%)  1/1242 (0.08%) 
Pneumonia pneumococcal  1  1/1243 (0.08%)  0/1242 (0.00%) 
Post procedural infection  1  0/1243 (0.00%)  1/1242 (0.08%) 
Postoperative wound infection  1  0/1243 (0.00%)  1/1242 (0.08%) 
Pseudomonal sepsis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Pulmonary tuberculosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Pyelonephritis acute  1  1/1243 (0.08%)  0/1242 (0.00%) 
Pyelonephritis chronic  1  1/1243 (0.08%)  0/1242 (0.00%) 
Respiratory syncytial virus infection  1  0/1243 (0.00%)  1/1242 (0.08%) 
Respiratory tract infection  1  3/1243 (0.24%)  3/1242 (0.24%) 
Respiratory tract infection viral  1  0/1243 (0.00%)  1/1242 (0.08%) 
Sepsis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Septic shock  1  1/1243 (0.08%)  2/1242 (0.16%) 
Tracheobronchitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Tuberculosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Urinary tract infection  1  2/1243 (0.16%)  0/1242 (0.00%) 
Vestibular neuronitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Wound infection  1  1/1243 (0.08%)  0/1242 (0.00%) 
Injury, poisoning and procedural complications     
Accidental overdose  1  1/1243 (0.08%)  0/1242 (0.00%) 
Acetabulum fracture  1  1/1243 (0.08%)  0/1242 (0.00%) 
Avulsion fracture  1  0/1243 (0.00%)  1/1242 (0.08%) 
Back injury  1  1/1243 (0.08%)  0/1242 (0.00%) 
Bronchitis chemical  1  1/1243 (0.08%)  0/1242 (0.00%) 
Burns second degree  1  1/1243 (0.08%)  0/1242 (0.00%) 
Burns third degree  1  1/1243 (0.08%)  0/1242 (0.00%) 
Carbon monoxide poisoning  1  1/1243 (0.08%)  0/1242 (0.00%) 
Fall  1  0/1243 (0.00%)  2/1242 (0.16%) 
Femoral neck fracture  1  0/1243 (0.00%)  2/1242 (0.16%) 
Fibula fracture  1  0/1243 (0.00%)  1/1242 (0.08%) 
Foot fracture  1  1/1243 (0.08%)  0/1242 (0.00%) 
Forearm fracture  1  1/1243 (0.08%)  0/1242 (0.00%) 
Fracture  1  1/1243 (0.08%)  0/1242 (0.00%) 
Graft thrombosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Hand fracture  1  1/1243 (0.08%)  0/1242 (0.00%) 
Humerus fracture  1  1/1243 (0.08%)  0/1242 (0.00%) 
Injury  1  1/1243 (0.08%)  0/1242 (0.00%) 
Joint injury  1  0/1243 (0.00%)  1/1242 (0.08%) 
Laceration  1  1/1243 (0.08%)  0/1242 (0.00%) 
Lower limb fracture  1  0/1243 (0.00%)  1/1242 (0.08%) 
Pneumothorax traumatic  1  0/1243 (0.00%)  1/1242 (0.08%) 
Radiation pneumonitis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Rib fracture  1  0/1243 (0.00%)  1/1242 (0.08%) 
Scrotal haematoma  1  0/1243 (0.00%)  1/1242 (0.08%) 
Tendon rupture  1  1/1243 (0.08%)  2/1242 (0.16%) 
Tibia fracture  1  0/1243 (0.00%)  2/1242 (0.16%) 
Traumatic intracranial haemorrhage  1  1/1243 (0.08%)  0/1242 (0.00%) 
Urethral injury  1  1/1243 (0.08%)  0/1242 (0.00%) 
Vascular graft thrombosis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Wound  1  1/1243 (0.08%)  0/1242 (0.00%) 
Investigations     
Angiogram  1  0/1243 (0.00%)  1/1242 (0.08%) 
Blood pressure decreased  1  1/1243 (0.08%)  0/1242 (0.00%) 
Hepatic enzyme increased  1  1/1243 (0.08%)  0/1242 (0.00%) 
Pulmonary function test decreased  1  1/1243 (0.08%)  0/1242 (0.00%) 
Weight decreased  1  1/1243 (0.08%)  0/1242 (0.00%) 
Metabolism and nutrition disorders     
Diabetes mellitus  1  2/1243 (0.16%)  0/1242 (0.00%) 
Diabetes mellitus inadequate control  1  2/1243 (0.16%)  0/1242 (0.00%) 
Dyslipidaemia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Back pain  1  1/1243 (0.08%)  1/1242 (0.08%) 
Exostosis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Musculoskeletal chest pain  1  1/1243 (0.08%)  0/1242 (0.00%) 
Osteoarthritis  1  3/1243 (0.24%)  0/1242 (0.00%) 
Pain in extremity  1  0/1243 (0.00%)  2/1242 (0.16%) 
Spinal column stenosis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acute myeloid leukaemia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Adenocarcinoma of colon  1  0/1243 (0.00%)  1/1242 (0.08%) 
Basal cell carcinoma  1  1/1243 (0.08%)  1/1242 (0.08%) 
Bladder cancer  1  0/1243 (0.00%)  2/1242 (0.16%) 
Breast cancer  1  1/1243 (0.08%)  1/1242 (0.08%) 
Bronchial carcinoma  1  1/1243 (0.08%)  0/1242 (0.00%) 
Colon cancer  1  1/1243 (0.08%)  0/1242 (0.00%) 
Colon neoplasm  1  1/1243 (0.08%)  0/1242 (0.00%) 
Hepatocellular carcinoma  1  1/1243 (0.08%)  0/1242 (0.00%) 
Hodgkin's disease  1  0/1243 (0.00%)  1/1242 (0.08%) 
Hypergammaglobulinaemia benign monoclonal  1  1/1243 (0.08%)  0/1242 (0.00%) 
Leukaemia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Lung adenocarcinoma  1  0/1243 (0.00%)  1/1242 (0.08%) 
Lung adenocarcinoma stage III  1  0/1243 (0.00%)  1/1242 (0.08%) 
Lung cancer metastatic  1  0/1243 (0.00%)  1/1242 (0.08%) 
Lung neoplasm  1  2/1243 (0.16%)  0/1242 (0.00%) 
Lung neoplasm malignant  1  5/1243 (0.40%)  3/1242 (0.24%) 
Malignant neoplasm of unknown primary site  1  0/1243 (0.00%)  1/1242 (0.08%) 
Maxillofacial sinus neoplasm  1  1/1243 (0.08%)  0/1242 (0.00%) 
Metastases to bone  1  0/1243 (0.00%)  1/1242 (0.08%) 
Metastases to spine  1  0/1243 (0.00%)  1/1242 (0.08%) 
Myelodysplastic syndrome  1  0/1243 (0.00%)  1/1242 (0.08%) 
Non-small cell lung cancer  1  0/1243 (0.00%)  2/1242 (0.16%) 
Oropharyngeal cancer  1  1/1243 (0.08%)  0/1242 (0.00%) 
Pancreatic carcinoma  1  1/1243 (0.08%)  0/1242 (0.00%) 
Prostate cancer  1  0/1243 (0.00%)  2/1242 (0.16%) 
Prostatic adenoma  1  0/1243 (0.00%)  2/1242 (0.16%) 
Renal cancer  1  0/1243 (0.00%)  1/1242 (0.08%) 
Renal cell carcinoma  1  0/1243 (0.00%)  1/1242 (0.08%) 
Renal neoplasm  1  1/1243 (0.08%)  1/1242 (0.08%) 
Small cell lung cancer metastatic  1  1/1243 (0.08%)  0/1242 (0.00%) 
Squamous cell carcinoma  1  1/1243 (0.08%)  0/1242 (0.00%) 
Squamous cell carcinoma of lung  1  0/1243 (0.00%)  1/1242 (0.08%) 
Squamous cell carcinoma of skin  1  1/1243 (0.08%)  0/1242 (0.00%) 
Tongue neoplasm malignant stage unspecified  1  0/1243 (0.00%)  1/1242 (0.08%) 
Tonsil cancer  1  0/1243 (0.00%)  1/1242 (0.08%) 
Vocal cord neoplasm  1  0/1243 (0.00%)  1/1242 (0.08%) 
Nervous system disorders     
Carotid artery stenosis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cerebellar infarction  1  1/1243 (0.08%)  0/1242 (0.00%) 
Cerebral arteriosclerosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Cerebral infarction  1  1/1243 (0.08%)  2/1242 (0.16%) 
Cerebral microangiopathy  1  0/1243 (0.00%)  1/1242 (0.08%) 
Cerebrovascular accident  1  3/1243 (0.24%)  1/1242 (0.08%) 
Cervicobrachial syndrome  1  0/1243 (0.00%)  1/1242 (0.08%) 
Convulsion  1  0/1243 (0.00%)  1/1242 (0.08%) 
Embolic cerebral infarction  1  1/1243 (0.08%)  0/1242 (0.00%) 
Hypoxic-ischaemic encephalopathy  1  0/1243 (0.00%)  2/1242 (0.16%) 
Intercostal neuralgia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Ischaemic cerebral infarction  1  1/1243 (0.08%)  0/1242 (0.00%) 
Ischaemic stroke  1  1/1243 (0.08%)  1/1242 (0.08%) 
Meningorrhagia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Radiculitis cervical  1  0/1243 (0.00%)  1/1242 (0.08%) 
Sciatica  1  1/1243 (0.08%)  0/1242 (0.00%) 
Transient ischaemic attack  1  0/1243 (0.00%)  1/1242 (0.08%) 
Psychiatric disorders     
Bipolar I disorder  1  1/1243 (0.08%)  0/1242 (0.00%) 
Depression  1  1/1243 (0.08%)  0/1242 (0.00%) 
Panic attack  1  1/1243 (0.08%)  0/1242 (0.00%) 
Renal and urinary disorders     
Calculus ureteric  1  1/1243 (0.08%)  0/1242 (0.00%) 
Focal segmental glomerulosclerosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Haematuria  1  0/1243 (0.00%)  1/1242 (0.08%) 
Mesangioproliferative glomerulonephritis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Proteinuria  1  1/1243 (0.08%)  0/1242 (0.00%) 
Renal colic  1  0/1243 (0.00%)  1/1242 (0.08%) 
Renal failure  1  2/1243 (0.16%)  0/1242 (0.00%) 
Renal failure acute  1  0/1243 (0.00%)  1/1242 (0.08%) 
Renal failure chronic  1  4/1243 (0.32%)  0/1242 (0.00%) 
Renal impairment  1  1/1243 (0.08%)  0/1242 (0.00%) 
Urethral haemorrhage  1  1/1243 (0.08%)  0/1242 (0.00%) 
Urinary retention  1  1/1243 (0.08%)  0/1242 (0.00%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  2/1243 (0.16%)  2/1242 (0.16%) 
Cervical dysplasia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  2/1243 (0.16%)  5/1242 (0.40%) 
Asphyxia  1  1/1243 (0.08%)  0/1242 (0.00%) 
Atelectasis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Bronchospasm  1  1/1243 (0.08%)  0/1242 (0.00%) 
Bullous lung disease  1  0/1243 (0.00%)  1/1242 (0.08%) 
Chronic obstructive pulmonary disease  1  154/1243 (12.39%)  180/1242 (14.49%) 
Chronic respiratory failure  1  2/1243 (0.16%)  4/1242 (0.32%) 
Dysphonia  1  1/1243 (0.08%)  1/1242 (0.08%) 
Dyspnoea  1  3/1243 (0.24%)  2/1242 (0.16%) 
Emphysema  1  0/1243 (0.00%)  1/1242 (0.08%) 
Hypercapnia  1  1/1243 (0.08%)  1/1242 (0.08%) 
Hypoxia  1  1/1243 (0.08%)  3/1242 (0.24%) 
Laryngeal leukoplakia  1  0/1243 (0.00%)  1/1242 (0.08%) 
Lung disorder  1  2/1243 (0.16%)  1/1242 (0.08%) 
Nasal polyps  1  1/1243 (0.08%)  0/1242 (0.00%) 
Pleural effusion  1  1/1243 (0.08%)  1/1242 (0.08%) 
Pneumonia aspiration  1  0/1243 (0.00%)  2/1242 (0.16%) 
Pneumothorax  1  1/1243 (0.08%)  2/1242 (0.16%) 
Pulmonary embolism  1  1/1243 (0.08%)  3/1242 (0.24%) 
Pulmonary fibrosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Pulmonary hypertension  1  0/1243 (0.00%)  1/1242 (0.08%) 
Respiratory arrest  1  0/1243 (0.00%)  1/1242 (0.08%) 
Respiratory distress  1  1/1243 (0.08%)  0/1242 (0.00%) 
Respiratory failure  1  9/1243 (0.72%)  10/1242 (0.81%) 
Sleep apnoea syndrome  1  0/1243 (0.00%)  1/1242 (0.08%) 
Skin and subcutaneous tissue disorders     
Skin ulcer  1  0/1243 (0.00%)  1/1242 (0.08%) 
Surgical and medical procedures     
Alcohol detoxification  1  1/1243 (0.08%)  0/1242 (0.00%) 
Angioplasty  1  1/1243 (0.08%)  0/1242 (0.00%) 
Hip arthroplasty  1  1/1243 (0.08%)  0/1242 (0.00%) 
Oxygen supplementation  1  1/1243 (0.08%)  0/1242 (0.00%) 
Transurethral prostatectomy  1  1/1243 (0.08%)  0/1242 (0.00%) 
Vascular disorders     
Aortic aneurysm  1  2/1243 (0.16%)  1/1242 (0.08%) 
Aortic arteriosclerosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Aortic thrombosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Arterial occlusive disease  1  1/1243 (0.08%)  2/1242 (0.16%) 
Arteriosclerosis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Hypertension  1  1/1243 (0.08%)  3/1242 (0.24%) 
Hypertensive crisis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Hypertensive emergency  1  1/1243 (0.08%)  0/1242 (0.00%) 
Intermittent claudication  1  1/1243 (0.08%)  0/1242 (0.00%) 
Peripheral ischaemia  1  2/1243 (0.16%)  0/1242 (0.00%) 
Phlebitis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Subclavian artery stenosis  1  0/1243 (0.00%)  1/1242 (0.08%) 
Thrombosis  1  1/1243 (0.08%)  0/1242 (0.00%) 
Venous thrombosis limb  1  1/1243 (0.08%)  0/1242 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Fluticasone Maintenance Fluticasone Withdrawal
Affected / at Risk (%) Affected / at Risk (%)
Total   464/1243 (37.33%)   458/1242 (36.88%) 
Infections and infestations     
Nasopharyngitis  1  93/1243 (7.48%)  80/1242 (6.44%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  410/1243 (32.98%)  413/1242 (33.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.0
Additional secondary endpoints were listed in the original protocol. Those endpoints are of exploratory nature only and were not considered relevant for trial conclusions. For more information see tab "Full Text Review", section "More Information".
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00975195    
Other Study ID Numbers: 352.2046
2007-002522-29 ( EudraCT Number: EudraCT )
First Submitted: September 10, 2009
First Posted: September 11, 2009
Results First Submitted: December 23, 2014
Results First Posted: February 10, 2015
Last Update Posted: February 10, 2015