Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The objective of the trial is to compare the lung function profile of once daily treatment with tiotropium+olodaterol FDC \[2.5/ 5µg and 5/ 5µg\] delivered by the RESPIMAT with the lung function profile of twice daily treatment with fluticasone propionate+salmeterol FDC \[250/50µg and 500/50µg\] delivered by the Accuhaler® after 6 weeks of treatment.
Interventions
DRUGfluticasone propionate
low dose
DRUGsalmeterol
DRUGplacebo
placebo/dummy for blinding purposes
DRUGtiotropium
tiotropium high dose
DRUGolodaterol
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of chronic obstructive pulmonary disease 2. Relatively stable airway obstruction with a post-bronchodilator 30% \</= Forced Expiratory Volume in 1 second (FEV1)\<80% of predicted normal and a post-bronchodilator FEV1/(Forced Vital Capacity)FVC \<70% 3. Male or female patients, 40 years of age or older 4. Smoking history of more than 10 pack years 5. Ability to perform technically acceptable pulmonary function tests and maintain records 6. Ability to inhale medication in a competent manner from the RESPIMAT Inhaler, Accuhaler and from a metered dose inhaler (MDI)
Exclusion criteria
1. Significant disease other than COPD 2. COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or iv) or hospitalization in the last 3 months. 3. Clinically relevant abnormal lab values 4. History of asthma 5. Diagnosis of thyrotoxicosis 6. Diagnosis of paroxysmal tachycardia 7. History of myocardial infarction 8. Unstable or life-threatening cardiac arrhythmia 9. Hospitalization for heart failure within the past year 10. Known active tuberculosis 11. malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years 12. History of life-threatening pulmonary obstruction 13. History of cystic fibrosis 14. Clinically evident bronchiectasis 15. History of significant alcohol or drug abuse 16. History of thoracotomy with pulmonary resection 17. oral or patch ß-adrenergics 18. Oral corticosteroid medication within 6 weeks prior to Visit 1 19. Regular use daytime oxygen therapy for more than one hour per day 20. Pulmonary rehabilitation program in the six weeks prior to the screening visit 21. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit 22. Known hypersensitivity to ß-adrenergic drugs, BAC, EDTA 23. Pregnant or nursing women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment | Baseline and 6 weeks. | Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 12hours post-dose (AUC 0-12h) \[L\] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment | Baseline and 6 weeks. | Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 24 hours post-dose (AUC 0-24h) \[L\] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient. |
| Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment | Baseline and 6 weeks. | Change from patient baseline in Trough Forced Expiratory Volume in one second (FEV1) after 6 weeks of treatment. Trough FEV1 was defined as the mean of the 23h and 23h 50min (minutes) post-dose FEV1 measurements. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient. |
| FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment | Baseline and 6 weeks. | Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 12 to 24 hours post-dose (AUC 12-24h) \[L\] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient. |
| FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment | Baseline and 6 weeks. | Change from patient baseline in Forced Expiratory Volume in one second (FEV1) peak (0-3 hours) after 6 weeks of treatment. FEV1 peak (0-3 hours) was defined as the maximum FEV1 value measured within the first three hours post dosing. Measured values presented are actually adjusted means. |
Countries
Belgium, Czechia, Denmark, Germany, Hungary, Netherlands, Spain, Sweden
Participant flow
Recruitment details
This was a randomized, double-blind, double-dummy, active-controlled, 4-treatment, 4-period, complete cross-over design.
Pre-assignment details
After signing informed consent, patients entered a 4-week screening period to ensure clinical stability (i.e. no exacerbations).
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Patients received a total of four treatments. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days. The treatments were orally inhaled.
* Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo.
* Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg plus Fluticasone propionate+Salmeterol placebo.
* Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo.
* Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg plus Tiotropium+Olodaterol placebo.
Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily, Fluticasone propionate+Salmeterol FDC inhalation powders were administered orally twice daily via Accuhaler®. | 229 |
| Total | 229 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 8 | 3 | 2 |
| Overall Study | Discontinued during washout periods. | 0 | 1 | 1 | 2 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 0 |
| Overall Study | Non compliant with protocol | 1 | 1 | 0 | 2 |
| Overall Study | Other not defined above | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 7.6 |
| Sex: Female, Male Female | 81 Participants |
| Sex: Female, Male Male | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 215 | 28 / 221 | 19 / 212 | 24 / 219 |
| serious Total, serious adverse events | 6 / 215 | 7 / 221 | 4 / 212 | 9 / 219 |
Outcome results
Primary
FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment
Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 12hours post-dose (AUC 0-12h) \[L\] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time frame: Baseline and 6 weeks.
Population: FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T+O 2.5/5 / F+S Placebo | FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment | 0.295 Litres | Standard Error 0.014 |
| T+O 5/5 / F+S Placebo | FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment | 0.317 Litres | Standard Error 0.014 |
| F+S 250/50 / T+O Placebo | FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment | 0.192 Litres | Standard Error 0.015 |
| F+S 500/50 / T+O Placebo | FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment | 0.188 Litres | Standard Error 0.014 |
Comparison: Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 µg).~Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.103, 0.147]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 µg).~Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.107, 0.15]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 2.5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 µg).~Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.081, 0.124]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 0-12h change from patient baseline (Tiotropium + Olodaterol 2.5/5 µg) = Mean FEV1 AUC 0-12h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 µg).~Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.085, 0.128]Mixed Models Analysis
Secondary
FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment
Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 24 hours post-dose (AUC 0-24h) \[L\] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time frame: Baseline and 6 weeks.
Population: FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T+O 2.5/5 / F+S Placebo | FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.228 Litres | Standard Error 0.014 |
| T+O 5/5 / F+S Placebo | FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.244 Litres | Standard Error 0.014 |
| F+S 250/50 / T+O Placebo | FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.162 Litres | Standard Error 0.014 |
| F+S 500/50 / T+O Placebo | FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.159 Litres | Standard Error 0.014 |
Comparison: Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.061, 0.103]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.065, 0.107]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.045, 0.086]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 0-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 0-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.048, 0.09]Mixed Models Analysis
Secondary
FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment
Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 12 to 24 hours post-dose (AUC 12-24h) \[L\] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time frame: Baseline and 6 weeks.
Population: FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T+O 2.5/5 / F+S Placebo | FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.160 Litres | Standard Error 0.014 |
| T+O 5/5 / F+S Placebo | FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.172 Litres | Standard Error 0.014 |
| F+S 250/50 / T+O Placebo | FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.132 Litres | Standard Error 0.014 |
| F+S 500/50 / T+O Placebo | FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment | 0.129 Litres | Standard Error 0.014 |
Comparison: Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: 0.000795% CI: [0.017, 0.062]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: 0.000295% CI: [0.021, 0.065]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: 0.014695% CI: [0.006, 0.051]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 AUC 12-24h change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 AUC 12-24h change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: 0.005595% CI: [0.009, 0.054]Mixed Models Analysis
Secondary
FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment
Change from patient baseline in Forced Expiratory Volume in one second (FEV1) peak (0-3 hours) after 6 weeks of treatment. FEV1 peak (0-3 hours) was defined as the maximum FEV1 value measured within the first three hours post dosing. Measured values presented are actually adjusted means.
Time frame: Baseline and 6 weeks.
Population: FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T+O 2.5/5 / F+S Placebo | FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment | 0.401 Litres | Standard Error 0.016 |
| T+O 5/5 / F+S Placebo | FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment | 0.432 Litres | Standard Error 0.016 |
| F+S 250/50 / T+O Placebo | FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment | 0.291 Litres | Standard Error 0.016 |
| F+S 500/50 / T+O Placebo | FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment | 0.285 Litres | Standard Error 0.015 |
Comparison: Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.118, 0.166]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.123, 0.171]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.087, 0.135]Mixed Models Analysis
Comparison: Null hypothesis: Mean FEV1 peak (0-3h) change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean FEV1 peak (0-3h) change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.092, 0.14]Mixed Models Analysis
Secondary
Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment
Change from patient baseline in Trough Forced Expiratory Volume in one second (FEV1) after 6 weeks of treatment. Trough FEV1 was defined as the mean of the 23h and 23h 50min (minutes) post-dose FEV1 measurements. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
Time frame: Baseline and 6 weeks.
Population: FAS (Full Analysis Set): Included all randomised patients who were documented to have had received any dose of trial medication and who had both baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| T+O 2.5/5 / F+S Placebo | Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment | 0.192 Litres | Standard Error 0.014 |
| T+O 5/5 / F+S Placebo | Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment | 0.197 Litres | Standard Error 0.014 |
| F+S 250/50 / T+O Placebo | Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment | 0.150 Litres | Standard Error 0.014 |
| F+S 500/50 / T+O Placebo | Trough FEV1 Change From Patient Baseline After 6 Weeks of Treatment | 0.139 Litres | Standard Error 0.014 |
Comparison: Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: 0.000295% CI: [0.022, 0.071]Mixed Models Analysis
Comparison: Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.034, 0.082]Mixed Models Analysis
Comparison: Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 250/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: 0.000795% CI: [0.018, 0.067]Mixed Models Analysis
Comparison: Null hypothesis: Mean trough FEV1 change from patient baseline (Tiotropium + Olodaterol 2.5/5 μg) = Mean trough FEV1 change from patient baseline (Fluticasone propionate + Salmeterol 500/50 μg). Hypothesis was analysed using a restricted maximum likelihood-based mixed effect repeated measures model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect.p-value: <0.000195% CI: [0.029, 0.078]Mixed Models Analysis