Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The objective of this study is to assess the efficacy and safety of 12 weeks once daily treatment with orally inhaled tiotropium + olodaterol FDC (delivered by the Respimat inhaler) compared with tiotropium and placebo in patients with COPD.
Interventions
DRUGtiotropium
fixed dose combination
DRUGplacebo
DRUGolodaterol
fixed dose combination
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis chronic obstructive pulmonary disease * Relatively stable airway obstruction with post FEV1 \>=30 and \< 80% predicted normal and post FEV1/ FVC \< 70% * Male or female patients, 40 years of age or more * Smoking history more than 10 pack years
Exclusion criteria
* Significant diseases other than COPD * History of asthma * COPD exacerbation in previous 3 months * Completion of pulmonary rehabilitation program within previous 6 weeks or current participation in pulmonary rehabilitation program. * Pregnant or nursing women * Patients unable to comply with pulmonary medication restrictions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC0-3h Response | baseline and 12 weeks | Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. |
| Trough FEV1 Response (Change From Baseline) | baseline and 12 weeks | Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. |
| St. George's Respiratory Questionnaire (SGRQ) Total Score | 12 weeks treatment | This endpoint was evaluated based on the data from this individual trial and also based on the data from the combined dataset from this trial and the replicate study NCT02006732. The results for the combined dataset are included in the disclosure for NCT02006732 as specified in the analysis plan. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life). The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Vital Capacity (FVC) Response (Change From Baseline) | baseline and 12 weeks | Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. |
| TDI Focal Score | 12 weeks | This endpoint was evaluated based on the data from this individual trial and also based on the data from the combined dataset from this trial and the replicate study NCT02006732. The results for the combined dataset are included in the disclosure for NCT02006732 as specified in the analysis plan. Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9). The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. |
| FVC AUC0-3h Response (Change From Baseline) | baseline and 12 weeks | The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. |
Countries
Belgium, Canada, Czechia, Denmark, Finland, Germany, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
814 were entered and randomized. One patient randomized to Tiotropium 5 μg was not treated. One patient entered the study with 2 different patient numbers. This patient was counted twice in the randomized set but only once in the treated set. Thus a total of 812 unique patients were treated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Once daily 2 puffs solution of placebo for inhalation with Respimat | 204 |
| Tiotropium 5 μg Once daily 2 puffs solution of 2.5 μg tiotropium for inhalation with Respimat | 203 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg Once daily 2 puffs solution of 1.25 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat. | 202 |
| Tiotropium 5 μg + Olodaterol 5 μg Once daily 2 puffs solution of 2.5 μg tiotropium / 2.5 μg olodaterol for inhalation with Respimat. | 203 |
| Total | 812 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 3 | 4 | 3 |
| Overall Study | Lack of Efficacy | 6 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 1 |
| Overall Study | Other than stated above | 0 | 2 | 1 | 2 |
| Overall Study | Protocol Violation | 2 | 4 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Tiotropium 5 μg | Tiotropium 2.5 μg+ Olodaterol 5 μg | Tiotropium 5 μg + Olodaterol 5 μg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65.1 years STANDARD_DEVIATION 8.3 | 64.9 years STANDARD_DEVIATION 8.2 | 64.7 years STANDARD_DEVIATION 8.2 | 64.7 years STANDARD_DEVIATION 8.9 | 64.9 years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 77 Participants | 79 Participants | 86 Participants | 89 Participants | 331 Participants |
| Sex: Female, Male Male | 127 Participants | 124 Participants | 116 Participants | 114 Participants | 481 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 | 32 / 204 | 28 / 203 | 25 / 202 | 16 / 203 |
| serious Total, serious adverse events | 11 / 204 | 6 / 203 | 4 / 202 | 10 / 203 |
Outcome results
Primary
FEV1 AUC0-3h Response
Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: baseline and 12 weeks
Population: Patients from the Full Analysis Set (FAS): This patient set included all randomized and treated patients who had a baseline and at least one postbaseline measurement for any of the primary efficacy endpoints. The patient that entered the study with two different patient numbers was excluded from the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 AUC0-3h Response | -0.014 L | Standard Error 0.014 |
| Tiotropium 5 μg | FEV1 AUC0-3h Response | 0.205 L | Standard Error 0.013 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | FEV1 AUC0-3h Response | 0.285 L | Standard Error 0.013 |
| Tiotropium 5 μg + Olodaterol 5 μg | FEV1 AUC0-3h Response | 0.316 L | Standard Error 0.013 |
p-value: <0.000195% CI: [0.293, 0.369]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.075, 0.148]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.262, 0.337]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.044, 0.116]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.181, 0.258]Mixed Effects Model for Repeated Measure
p-value: 0.087295% CI: [-0.005, 0.067]Mixed Effects Model for Repeated Measure
Primary
St. George's Respiratory Questionnaire (SGRQ) Total Score
This endpoint was evaluated based on the data from this individual trial and also based on the data from the combined dataset from this trial and the replicate study NCT02006732. The results for the combined dataset are included in the disclosure for NCT02006732 as specified in the analysis plan. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life). The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: 12 weeks treatment
Population: Patients from FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | St. George's Respiratory Questionnaire (SGRQ) Total Score | 42.038 units on a scale | Standard Error 0.738 |
| Tiotropium 5 μg | St. George's Respiratory Questionnaire (SGRQ) Total Score | 39.637 units on a scale | Standard Error 0.717 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | St. George's Respiratory Questionnaire (SGRQ) Total Score | 37.916 units on a scale | Standard Error 0.708 |
| Tiotropium 5 μg + Olodaterol 5 μg | St. George's Respiratory Questionnaire (SGRQ) Total Score | 37.144 units on a scale | Standard Error 0.71 |
p-value: <0.000195% CI: [-6.904, -2.884]Mixed Effects Model for Repeated Measure
p-value: 0.013695% CI: [-4.473, -0.513]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [-6.129, -2.114]Mixed Effects Model for Repeated Measure
p-value: 0.08895% CI: [-3.698, 0.256]Mixed Effects Model for Repeated Measure
p-value: 0.019895% CI: [-4.419, -0.382]Mixed Effects Model for Repeated Measure
p-value: 0.441595% CI: [-2.741, 1.196]Mixed Effects Model for Repeated Measure
Primary
Trough FEV1 Response (Change From Baseline)
Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: baseline and 12 weeks
Population: Patients from FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response (Change From Baseline) | 0.001 L | Standard Error 0.014 |
| Tiotropium 5 μg | Trough FEV1 Response (Change From Baseline) | 0.135 L | Standard Error 0.014 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | Trough FEV1 Response (Change From Baseline) | 0.151 L | Standard Error 0.013 |
| Tiotropium 5 μg + Olodaterol 5 μg | Trough FEV1 Response (Change From Baseline) | 0.163 L | Standard Error 0.013 |
p-value: <0.000195% CI: [0.0124, 0.2]Mixed Effects Model for Repeated Measure
p-value: 0.138195% CI: [-0.009, 0.066]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.113, 0.188]Mixed Effects Model for Repeated Measure
p-value: 0.387295% CI: [-0.021, 0.054]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.096, 0.172]Mixed Effects Model for Repeated Measure
p-value: 0.533395% CI: [-0.025, 0.049]Mixed Effects Model for Repeated Measure
Secondary
FVC AUC0-3h Response (Change From Baseline)
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: baseline and 12 weeks
Population: Patients from FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC0-3h Response (Change From Baseline) | -0.011 L | Standard Error 0.025 |
| Tiotropium 5 μg | FVC AUC0-3h Response (Change From Baseline) | 0.286 L | Standard Error 0.024 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | FVC AUC0-3h Response (Change From Baseline) | 0.387 L | Standard Error 0.023 |
| Tiotropium 5 μg + Olodaterol 5 μg | FVC AUC0-3h Response (Change From Baseline) | 0.446 L | Standard Error 0.023 |
p-value: <0.000195% CI: [0.39, 0.524]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.095, 0.225]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.331, 0.465]Mixed Effects Model for Repeated Measure
p-value: 0.002395% CI: [0.036, 0.165]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.229, 0.365]Mixed Effects Model for Repeated Measure
p-value: 0.070195% CI: [-0.005, 0.123]Mixed Effects Model for Repeated Measure
Secondary
TDI Focal Score
This endpoint was evaluated based on the data from this individual trial and also based on the data from the combined dataset from this trial and the replicate study NCT02006732. The results for the combined dataset are included in the disclosure for NCT02006732 as specified in the analysis plan. Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9). The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: 12 weeks
Population: Patients from FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | TDI Focal Score | -0.113 Units on a scale | Standard Error 0.196 |
| Tiotropium 5 μg | TDI Focal Score | 1.332 Units on a scale | Standard Error 0.192 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | TDI Focal Score | 1.839 Units on a scale | Standard Error 0.189 |
| Tiotropium 5 μg + Olodaterol 5 μg | TDI Focal Score | 1.939 Units on a scale | Standard Error 0.19 |
p-value: <0.000195% CI: [1.516, 2.588]Mixed Effects Model for Repeated Measure
p-value: 0.024695% CI: [0.078, 1.137]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [1.417, 2.487]Mixed Effects Model for Repeated Measure
p-value: 0.059995% CI: [-0.021, 1.035]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.907, 1.983]Mixed Effects Model for Repeated Measure
p-value: 0.708195% CI: [-0.425, 0.626]Mixed Effects Model for Repeated Measure
Secondary
Trough Forced Vital Capacity (FVC) Response (Change From Baseline)
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom.
Time frame: baseline and 12 weeks
Population: Patients from FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough Forced Vital Capacity (FVC) Response (Change From Baseline) | 0.025 L | Standard Error 0.023 |
| Tiotropium 5 μg | Trough Forced Vital Capacity (FVC) Response (Change From Baseline) | 0.223 L | Standard Error 0.023 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | Trough Forced Vital Capacity (FVC) Response (Change From Baseline) | 0.233 L | Standard Error 0.022 |
| Tiotropium 5 μg + Olodaterol 5 μg | Trough Forced Vital Capacity (FVC) Response (Change From Baseline) | 0.244 L | Standard Error 0.022 |
p-value: <0.000195% CI: [0.157, 0.282]Mixed Effects Model for Repeated Measure
p-value: 0.505295% CI: [-0.041, 0.084]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.146, 0.271]Mixed Effects Model for Repeated Measure
p-value: 0.756695% CI: [-0.052, 0.072]Mixed Effects Model for Repeated Measure
p-value: <0.000195% CI: [0.136, 0.261]Mixed Effects Model for Repeated Measure
p-value: 0.719995% CI: [-0.051, 0.073]Mixed Effects Model for Repeated Measure