Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objective of the trial is to determine the 24-hour FEV1-time profile of tiotropium + olodaterol FDC, administered once daily by the RESPIMAT Inhaler after 6 weeks of treatment.
Interventions
low dose + one dose only
DRUGtiotropium
low dose
DRUGolodaterol
one dose only
DRUGPlacebo
placebo matching tiotropium+olodaterol FDC
DEVICERespimat
Respimat inhaler
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 FEV1\< 80% of predicted normal and a post-bronchodilator FEV1/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 and from a metered dose inhaler (MDI)
Exclusion criteria
1. significant disease other than COPD 2. clinically relevant abnormal lab values 3. history of asthma 4. diagnosis of thyrotoxicosis 5. diagnosis of paroxysmal tachycardia 6. history of myocardial infarction 7. unstable or life-threatening cardiac arrhythmia 8. Hospitalization for heart failure within the past year 9. known active tuberculosis 10. malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years 11. history of life-threatening pulmonary obstruction 12. history of cystic fibrosis 13. clinically evident bronchiectasis 14. history of significant alcohol or drug abuse 15. history of thoracotomy with pulmonary resection 16. oral or patch ß-adrenergics 17. oral corticosteroid medication at unstable doses 18. regular use daytime oxygen therapy for more than one hour per day 19. Pulmonary rehabilitation program in the six weeks prior to the screening visit 20. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit 21. Known hypersensitivity to ß-adrenergic drugs, BAC, EDTA 22. Pregnant or nursing women 23. Women of childbearing potential not using a highly effective method of birth control 24. Patients who have previously been randomised in this study or are currently participating in another study 25. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 24 h post-dose, using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| Trough FEV1 Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Trough Forced Expiratory Volume in 1 second (FEV1) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and Response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Peak (0-3h) Forced Expiratory Volume in 1 second (FEV1) response. The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| FVC AUC0-24h Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 12 h post-dose, using the trapezoidal rule, divided by the duration (12h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| FVC AUC12-24h Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| Trough FVC Response [L] After 6 Weeks Treatment. | day1 and week 6 | Trough Forced Vital Capacity (FVC) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Peak (0-3h) Forced Vital Capacity (FVC) responses after 6 weeks treatment. Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
| FVC AUC0-12h Response [L] After 6 Weeks Treatment. | day 1 and week 6 | Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom. |
Countries
Belgium, Canada, Denmark, Germany, Hungary, Netherlands, United States
Participant flow
Pre-assignment details
This is a randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over design. Each patient was randomised to one of 30 treatment sequences. Each sequence consisted of four 6-week treatment periods separated by 3-week washout periods.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Randomised, double-blind, placebo-controlled, 6 treatment, 4 period, incomplete cross-over trial to characterise the 24-hour lung function profiles of tiotropium + olodaterol fixed dose combination (2.5/5 μg, 5/5 μg), tiotropium (2.5 μg, 5 μg) and olodaterol (5 μg) (oral inhalation, delivered by the Respimat® Inhaler) after 6 weeks once daily treatment in patients with Chronic Obstructive Pulmonary Disease (COPD) \[VIVACITOTM\]. | 219 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 10 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | other than stated above | 9 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 61.1 Years STANDARD_DEVIATION 7.7 |
| Sex: Female, Male Female | 90 Participants |
| Sex: Female, Male Male | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 138 | 21 / 138 | 30 / 137 | 29 / 138 | 23 / 136 | 25 / 139 |
| serious Total, serious adverse events | 4 / 138 | 8 / 138 | 5 / 137 | 3 / 138 | 4 / 136 | 1 / 139 |
Outcome results
Primary
Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment.
Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 24 h post-dose, using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS): This patient set included patients in the Treated Set (TS) who had any period baseline and any evaluable post-dose data for the primary efficacy endpoint at any Week 6 visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | -0.037 Litres (L) | Standard Error 0.014 |
| Olodaterol (5 µg) | Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | 0.129 Litres (L) | Standard Error 0.013 |
| Tiotropium (2.5 µg) | Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | 0.117 Litres (L) | Standard Error 0.013 |
| Tiotropium (5 µg) | Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | 0.133 Litres (L) | Standard Error 0.014 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | 0.241 Litres (L) | Standard Error 0.014 |
| Tiotropium+Olodaterol FDC (5/5 µg) | Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment. | 0.244 Litres (L) | Standard Error 0.013 |
p-value: <0.000195% CI: [0.252, 0.309]Mixed Models Analysis
p-value: <0.000195% CI: [0.087, 0.143]Mixed Models Analysis
p-value: <0.000195% CI: [0.082, 0.139]Mixed Models Analysis
p-value: <0.000195% CI: [0.249, 0.306]Mixed Models Analysis
p-value: <0.000195% CI: [0.083, 0.14]Mixed Models Analysis
p-value: <0.000195% CI: [0.096, 0.152]Mixed Models Analysis
p-value: <0.000195% CI: [0.079, 0.136]Mixed Models Analysis
Secondary
FEV1 AUC0-12h Response [L] After 6 Weeks Treatment.
Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 12 h post-dose, using the trapezoidal rule, divided by the duration (12h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | -0.013 Litres (L) | Standard Error 0.015 |
| Olodaterol (5 µg) | FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | 0.179 Litres (L) | Standard Error 0.015 |
| Tiotropium (2.5 µg) | FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | 0.171 Litres (L) | Standard Error 0.015 |
| Tiotropium (5 µg) | FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | 0.186 Litres (L) | Standard Error 0.015 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | 0.310 Litres (L) | Standard Error 0.015 |
| Tiotropium+Olodaterol FDC (5/5 µg) | FEV1 AUC0-12h Response [L] After 6 Weeks Treatment. | 0.305 Litres (L) | Standard Error 0.015 |
p-value: <0.000195% CI: [0.289, 0.349]Mixed Models Analysis
p-value: <0.000195% CI: [0.096, 0.156]Mixed Models Analysis
p-value: <0.000195% CI: [0.089, 0.149]Mixed Models Analysis
p-value: <0.000195% CI: [0.293, 0.354]Mixed Models Analysis
p-value: <0.000195% CI: [0.101, 0.161]Mixed Models Analysis
p-value: <0.000195% CI: [0.109, 0.169]Mixed Models Analysis
p-value: <0.000195% CI: [0.093, 0.154]Mixed Models Analysis
Secondary
FEV1 AUC12-24h Response [L] After 6 Weeks Treatment.
Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | -0.060 Litres (L) | Standard Error 0.014 |
| Olodaterol (5 µg) | FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | 0.079 Litres (L) | Standard Error 0.013 |
| Tiotropium (2.5 µg) | FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | 0.062 Litres (L) | Standard Error 0.013 |
| Tiotropium (5 µg) | FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | 0.081 Litres (L) | Standard Error 0.014 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | 0.172 Litres (L) | Standard Error 0.014 |
| Tiotropium+Olodaterol FDC (5/5 µg) | FEV1 AUC12-24h Response [L] After 6 Weeks Treatment. | 0.182 Litres (L) | Standard Error 0.013 |
p-value: <0.000195% CI: [0.212, 0.273]Mixed Models Analysis
p-value: <0.000195% CI: [0.074, 0.133]Mixed Models Analysis
p-value: <0.000195% CI: [0.072, 0.132]Mixed Models Analysis
p-value: <0.000195% CI: [0.201, 0.262]Mixed Models Analysis
p-value: <0.000195% CI: [0.063, 0.123]Mixed Models Analysis
p-value: <0.000195% CI: [0.08, 0.14]Mixed Models Analysis
p-value: <0.000195% CI: [0.061, 0.121]Mixed Models Analysis
Secondary
FVC AUC0-12h Response [L] After 6 Weeks Treatment.
Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC0-12h Response [L] After 6 Weeks Treatment. | -0.023 Litres (L) | Standard Error 0.024 |
| Olodaterol (5 µg) | FVC AUC0-12h Response [L] After 6 Weeks Treatment. | 0.240 Litres (L) | Standard Error 0.024 |
| Tiotropium (2.5 µg) | FVC AUC0-12h Response [L] After 6 Weeks Treatment. | 0.249 Litres (L) | Standard Error 0.024 |
| Tiotropium (5 µg) | FVC AUC0-12h Response [L] After 6 Weeks Treatment. | 0.261 Litres (L) | Standard Error 0.024 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | FVC AUC0-12h Response [L] After 6 Weeks Treatment. | 0.420 Litres (L) | Standard Error 0.024 |
| Tiotropium+Olodaterol FDC (5/5 µg) | FVC AUC0-12h Response [L] After 6 Weeks Treatment. | 0.440 Litres (L) | Standard Error 0.024 |
p-value: <0.000195% CI: [0.417, 0.509]Mixed Models Analysis
p-value: <0.000195% CI: [0.154, 0.246]Mixed Models Analysis
p-value: <0.000195% CI: [0.133, 0.225]Mixed Models Analysis
p-value: <0.000195% CI: [0.396, 0.49]Mixed Models Analysis
p-value: <0.000195% CI: [0.134, 0.227]Mixed Models Analysis
p-value: <0.000195% CI: [0.125, 0.218]Mixed Models Analysis
p-value: <0.000195% CI: [0.113, 0.206]Mixed Models Analysis
Secondary
FVC AUC0-24h Response [L] After 6 Weeks Treatment.
Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC0-24h Response [L] After 6 Weeks Treatment. | -0.065 Litres(L) | Standard Error 0.023 |
| Olodaterol (5 µg) | FVC AUC0-24h Response [L] After 6 Weeks Treatment. | 0.158 Litres(L) | Standard Error 0.022 |
| Tiotropium (2.5 µg) | FVC AUC0-24h Response [L] After 6 Weeks Treatment. | 0.172 Litres(L) | Standard Error 0.022 |
| Tiotropium (5 µg) | FVC AUC0-24h Response [L] After 6 Weeks Treatment. | 0.191 Litres(L) | Standard Error 0.022 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | FVC AUC0-24h Response [L] After 6 Weeks Treatment. | 0.331 Litres(L) | Standard Error 0.022 |
| Tiotropium+Olodaterol FDC (5/5 µg) | FVC AUC0-24h Response [L] After 6 Weeks Treatment. | 0.368 Litres(L) | Standard Error 0.022 |
p-value: <0.000195% CI: [0.389, 0.477]Mixed Models Analysis
p-value: <0.000195% CI: [0.166, 0.253]Mixed Models Analysis
p-value: <0.000195% CI: [0.133, 0.221]Mixed Models Analysis
p-value: <0.000195% CI: [0.352, 0.441]Mixed Models Analysis
p-value: <0.000195% CI: [0.129, 0.217]Mixed Models Analysis
p-value: <0.000195% CI: [0.115, 0.203]Mixed Models Analysis
p-value: <0.000195% CI: [0.096, 0.184]Mixed Models Analysis
Secondary
FVC AUC12-24h Response [L] After 6 Weeks Treatment.
Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC12-24h Response [L] After 6 Weeks Treatment. | -0.108 Litres (L) | Standard Error 0.023 |
| Olodaterol (5 µg) | FVC AUC12-24h Response [L] After 6 Weeks Treatment. | 0.077 Litres (L) | Standard Error 0.023 |
| Tiotropium (2.5 µg) | FVC AUC12-24h Response [L] After 6 Weeks Treatment. | 0.095 Litres (L) | Standard Error 0.023 |
| Tiotropium (5 µg) | FVC AUC12-24h Response [L] After 6 Weeks Treatment. | 0.122 Litres (L) | Standard Error 0.023 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | FVC AUC12-24h Response [L] After 6 Weeks Treatment. | 0.243 Litres (L) | Standard Error 0.023 |
| Tiotropium+Olodaterol FDC (5/5 µg) | FVC AUC12-24h Response [L] After 6 Weeks Treatment. | 0.296 Litres (L) | Standard Error 0.023 |
p-value: <0.000195% CI: [0.355, 0.453]Mixed Models Analysis
p-value: <0.000195% CI: [0.17, 0.267]Mixed Models Analysis
p-value: <0.000195% CI: [0.126, 0.223]Mixed Models Analysis
p-value: <0.000195% CI: [0.301, 0.4]Mixed Models Analysis
p-value: <0.000195% CI: [0.117, 0.214]Mixed Models Analysis
p-value: <0.000195% CI: [0.099, 0.197]Mixed Models Analysis
p-value: <0.000195% CI: [0.072, 0.17]Mixed Models Analysis
Secondary
Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment.
Peak (0-3h) Forced Expiratory Volume in 1 second (FEV1) response. The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | 0.072 Litres (L) | Standard Error 0.017 |
| Olodaterol (5 µg) | Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | 0.291 Litres (L) | Standard Error 0.016 |
| Tiotropium (2.5 µg) | Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | 0.290 Litres (L) | Standard Error 0.016 |
| Tiotropium (5 µg) | Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | 0.300 Litres (L) | Standard Error 0.016 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | 0.422 Litres (L) | Standard Error 0.016 |
| Tiotropium+Olodaterol FDC (5/5 µg) | Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment. | 0.411 Litres (L) | Standard Error 0.016 |
p-value: <0.000195% CI: [0.305, 0.371]Mixed Models Analysis
p-value: <0.000195% CI: [0.087, 0.153]Mixed Models Analysis
p-value: <0.000195% CI: [0.078, 0.143]Mixed Models Analysis
p-value: <0.000195% CI: [0.317, 0.383]Mixed Models Analysis
p-value: <0.000195% CI: [0.098, 0.164]Mixed Models Analysis
p-value: <0.000195% CI: [0.099, 0.165]Mixed Models Analysis
p-value: <0.000195% CI: [0.089, 0.155]Mixed Models Analysis
Secondary
Peak (0-3h) FVC Response [L] After 6 Weeks Treatment.
Peak (0-3h) Forced Vital Capacity (FVC) responses after 6 weeks treatment. Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | 0.159 Litres (L) | Standard Error 0.029 |
| Olodaterol (5 µg) | Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | 0.463 Litres (L) | Standard Error 0.029 |
| Tiotropium (2.5 µg) | Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | 0.450 Litres (L) | Standard Error 0.029 |
| Tiotropium (5 µg) | Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | 0.470 Litres (L) | Standard Error 0.029 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | 0.612 Litres (L) | Standard Error 0.029 |
| Tiotropium+Olodaterol FDC (5/5 µg) | Peak (0-3h) FVC Response [L] After 6 Weeks Treatment. | 0.621 Litres (L) | Standard Error 0.028 |
p-value: <0.000195% CI: [0.408, 0.516]Mixed Models Analysis
p-value: <0.000195% CI: [0.105, 0.212]Mixed Models Analysis
p-value: <0.000195% CI: [0.098, 0.205]Mixed Models Analysis
p-value: <0.000195% CI: [0.398, 0.507]Mixed Models Analysis
p-value: <0.000195% CI: [0.095, 0.203]Mixed Models Analysis
p-value: <0.000195% CI: [0.107, 0.216]Mixed Models Analysis
p-value: <0.000195% CI: [0.087, 0.196]Mixed Models Analysis
Secondary
Trough FEV1 Response [L] After 6 Weeks Treatment.
Trough Forced Expiratory Volume in 1 second (FEV1) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and Response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day 1 and week 6
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response [L] After 6 Weeks Treatment. | -0.006 Litres | Standard Error 0.015 |
| Olodaterol (5 µg) | Trough FEV1 Response [L] After 6 Weeks Treatment. | 0.109 Litres | Standard Error 0.015 |
| Tiotropium (2.5 µg) | Trough FEV1 Response [L] After 6 Weeks Treatment. | 0.095 Litres | Standard Error 0.015 |
| Tiotropium (5 µg) | Trough FEV1 Response [L] After 6 Weeks Treatment. | 0.122 Litres | Standard Error 0.015 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | Trough FEV1 Response [L] After 6 Weeks Treatment. | 0.196 Litres | Standard Error 0.015 |
| Tiotropium+Olodaterol FDC (5/5 µg) | Trough FEV1 Response [L] After 6 Weeks Treatment. | 0.201 Litres | Standard Error 0.015 |
p-value: <0.000195% CI: [0.173, 0.241]Mixed Models Analysis
p-value: <0.000195% CI: [0.059, 0.126]Mixed Models Analysis
p-value: <0.000195% CI: [0.045, 0.113]Mixed Models Analysis
p-value: <0.000195% CI: [0.167, 0.235]Mixed Models Analysis
p-value: <0.000195% CI: [0.052, 0.12]Mixed Models Analysis
p-value: <0.000195% CI: [0.067, 0.135]Mixed Models Analysis
p-value: <0.000195% CI: [0.039, 0.107]Mixed Models Analysis
Secondary
Trough FVC Response [L] After 6 Weeks Treatment.
Trough Forced Vital Capacity (FVC) response after 6 weeks treatment period. The trough was defined as the mean of the 23 h and 23 h50 min measurements and response was defined as the change from patient baseline. Mean is actually the Adjusted mean. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: day1 and week 6
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response [L] After 6 Weeks Treatment. | -0.025 Litres (L) | Standard Error 0.026 |
| Olodaterol (5 µg) | Trough FVC Response [L] After 6 Weeks Treatment. | 0.134 Litres (L) | Standard Error 0.026 |
| Tiotropium (2.5 µg) | Trough FVC Response [L] After 6 Weeks Treatment. | 0.115 Litres (L) | Standard Error 0.026 |
| Tiotropium (5 µg) | Trough FVC Response [L] After 6 Weeks Treatment. | 0.183 Litres (L) | Standard Error 0.026 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | Trough FVC Response [L] After 6 Weeks Treatment. | 0.282 Litres (L) | Standard Error 0.026 |
| Tiotropium+Olodaterol FDC (5/5 µg) | Trough FVC Response [L] After 6 Weeks Treatment. | 0.304 Litres (L) | Standard Error 0.026 |
p-value: <0.000195% CI: [0.274, 0.385]Mixed Models Analysis
p-value: <0.000195% CI: [0.115, 0.225]Mixed Models Analysis
p-value: <0.000195% CI: [0.066, 0.176]Mixed Models Analysis
p-value: <0.000195% CI: [0.251, 0.363]Mixed Models Analysis
p-value: <0.000195% CI: [0.092, 0.203]Mixed Models Analysis
p-value: <0.000195% CI: [0.111, 0.222]Mixed Models Analysis
p-value: <0.000195% CI: [0.043, 0.154]Mixed Models Analysis