Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL inhalation solution delivered by the Respimat inhaler once daily for 4 weeks in Japanese patients with chronic obstructive pulmonary disease (COPD). The selection of the optimum dose(s) will be based on bronchodilator efficacy, safety evaluations and pharmacokinetic evaluations.
Interventions
DRUGBI 1744 CL 2 µg
2 puffs of 1 µg/actuation delivered by the Respimat® inhaler
DRUGBI 1744 CL 5 µg
2 puffs of 2.5 µg/actuation delivered by the Respimat® inhaler
DRUGBI 1744 CL 10 µg
2 puffs of 5 µg/actuation delivered by Respimat®
DRUGPlacebo
2 puffs delivered by the Respimat® inhaler
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
1. All patients must sign an informed consent consistent with GCP guidelines prior to participation in the trial. 2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have relatively stable, moderate to severe airway obstruction with a post-bronchodilator FEV1 \>=30% of predicted normal and \<80% of predicted normal and a post-bronchodilator FEV1/FVC \<70% at Visit 1 3. Male or female patients, 40 years of age or older 4. Patients must be current or ex-smokers with a smoking history of more than 10 pack-years. Pack-Years = \[Number of cigarettes/day/20\] - years of smoking Patients who have never smoked cigarettes must be excluded. 5. Patients must be able to perform technically acceptable pulmonary function tests (both supervised and unsupervised) and PEFR measurements, and must be able to record a patient diary during the study period as required in the protocol. 6. Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a MDI.
Exclusion criteria
1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may i) put the patient at risk because of participation in the study ii) influence the results of the study, or iii) cause concern regarding the patient's ability to participate in the study 2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an AST \>80 IU/L, ALT \>80 IU/L, bilirubin \>1.5 x ULN or creatinine \>1.5 x ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients) 3. Patients with a history of asthma or a total blood eosinophil count \>=600/mm3. A repeat eosinophil count will not be conducted in these patients 4. Patients with any of the following conditions: * a diagnosis of thyrotoxicosis * a diagnosis of paroxysmal tachycardia (\>100 beats per minute) * a marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval \>450 ms) as recommended by ICH E14. For patients who have a QTc interval between 450 ms and 500 ms, as judged by site personnel, there will be a confirmatory reading by centralized evaluation institute. If the confirmatory reading is still greater than 450 ms, patient will be excluded. Patients with a QTc interval \>=500 ms will immediately be excluded from the study. * a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of Long QT Syndrome) as recommended by ICH E14. 5. Patients with any of the following conditions: * a history of myocardial infarction within 1 year * a diagnosis of clinically relevant cardiac arrhythmia * known active tuberculosis * a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last 5 years (patients with treated basal cell carcinoma are allowed) * a history of life-threatening pulmonary obstruction * a history of cystic fibrosis * clinically evident bronchiectasis * a history of significant alcohol or drug abuse 6. Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1) 7. Patients being treated with any of the following concomitant medications: * medications that prolong the QT/QTc interval * oral beta-adrenergics and beta-adrenergics patchs * beta-blockers (topical beta-blockers for ocular conditions are allowed) * oral corticosteroid medication at unstable doses (i.e. less than 6 weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day. 8. Patients who regularly use daytime oxygen therapy for more than 1 hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits 9. Patients who have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program 10. Patients who have taken an investigational drug within 1 month or 6 half lives (whichever is greater) prior to screening visit 11. Patients with known hypersensitivity to beta-adrenergics drugs, BAC, EDTA or any other component of the Respimat inhalation solution delivery system 12. Pregnant or suspect of pregnant or women who are willing to become pregnant during the study period or nursing women 13. Patients who have previously been participated in this study or are currently participating in another study 14. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation 15. The randomization of patients with any respiratory infection or COPD exacerbation in the 6 weeks prior to the screening visit or during the screening period should be postponed. Patients may be randomised 6 weeks following recovery from the infection or exacerbation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough FEV1 Response at Week 4 | baseline and after 4 weeks treatment | The change from baseline in trough FEV1 after 4 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline . Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC(0-3) Response at 4 Weeks | baseline and after 4 weeks treatment | The change from baseline in FEV1 AUC(0-3) after 4 weeks of treatment. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in liters. Due to normalization the unit is liters. |
| FEV1 Peak(0-3) Response at 4 Weeks | baseline and after 4 weeks treatment | The change from baseline in FEV1 peak(0-3) after 4 weeks of treatment. |
| Trough FVC Response at Week 4 | baseline and after 4 weeks treatment | The change from baseline in Trough FVC after 4 weeks of treatment |
| FVC AUC(0-3) Response | baseline and after 4 weeks treatment | The change from baseline in FVC AUC(0-3) response after 4 weeks of treatment. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in liters. Due to normalization the unit is liters. |
| FVC Peak(0-3) Response | baseline and after 4 weeks treatment | The change from baseline in FVC peak(0-3) response after 4 weeks of treatment. |
| Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks | baseline and after 4weeks treatment | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters. |
| Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks | Baseline and after 4weeks treatment | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters. |
| Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks | Week 4 | PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs, Morning measurements were performed immediately upon arising before administration of trial and/or rescue medication.The highest of three readings for each measurement were recorded. |
| Trough FEV1 Response at Week 2 | baseline and after 2 weeks treatment | Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication |
| Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks | Week 4 | Weekly mean number of occasions of rescue therapy used per day (PRN salbutamol ) |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | 4 weeks | Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical examination. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations). |
| Difference From Baseline in Potassium | Baseline, Week 4 | Difference from baseline in Potassium (normalized values). Normalization means that the values from different laboratories are transformed in such a way that they are directly comparable. |
| Cmax (Maximum Measured Concentration of the Analyte in Plasma) | after first inhalated administration | Cmax only calculated if \>1/3 of the patients have available pharmacokinetic parameters,thus not applicable for the Olodaterol 2 mcg |
| Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State) | visit at week 4 | Cmax,ss only calculated if \>1/3 of the patients have available pharmacokinetic parameters, thus not applicable for the Olodaterol 2 mcg |
| AUC0-1 | after first inhalated administration | Area under the concentration curve from 0 to 1 hour using trapezoid rule, only calculated if \>1/3 of the patients have available pharmacokinetic parameters,thus not applicable for Olodaterol 2mcg group |
| AUC0-1,ss | visit at week 4 | Area under the concentration curve from 0 to 1 hour at steady state using trapezoid rule, only calculated if \>1/3 of the patients have available pharmacokinetic parameters, thus not applicable for Olodaterol 2mcg group |
| Weekly Mean Evening PEFR After 4 Weeks | Week 4 | PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs, Evening measurements were performed at bedtime.The highest of three readings for each measurement were recorded. |
Countries
Japan
Participant flow
Recruitment details
The first patient was enrolled in the trial on 13 January 2009 and the last patient made the last visit on 31 March 2010. A total of 515 patients were enrolled in the trial at 48 trial sites. Of the 515 patients, 328 patients were entered in the trial and were randomly assigned to receive either one of the four treatments for 4 weeks.
Pre-assignment details
Informed consent was obtained prior to patient participation in the trial, which included medication washout procedures or restrictions. Upon obtaining consent, the patients were instructed on the medication washout and other restrictions for the screening PFT (Visit 1).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo | 79 |
| Olodaterol 2mcg Olodaterol 2mcg inhalation solution via Respimat | 84 |
| Olodaterol 5mcg Olodaterol 5mcg inhalation solution via Respimat | 79 |
| Olodaterol 10mcg Olodaterol 10mcg inhalation solution via Respimat | 86 |
| Total | 328 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 | 1 | 4 |
| Overall Study | Investigator's decision | 0 | 1 | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Olodaterol 2mcg | Olodaterol 5mcg | Olodaterol 10mcg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 68.9 years STANDARD_DEVIATION 6.5 | 68.9 years STANDARD_DEVIATION 7.6 | 70.1 years STANDARD_DEVIATION 6.7 | 69.3 years STANDARD_DEVIATION 7.4 | 69.3 years STANDARD_DEVIATION 7.1 |
| Percent predicted normal FEV1 < 30% | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Percent predicted normal FEV1 30 to < 50% | 35 Participants | 40 Participants | 38 Participants | 41 Participants | 154 Participants |
| Percent predicted normal FEV1 50% to 80% | 43 Participants | 43 Participants | 41 Participants | 45 Participants | 172 Participants |
| Percent predicted normal FEV1 | 50.64 percent STANDARD_DEVIATION 12.32 | 51.36 percent STANDARD_DEVIATION 14.15 | 52.07 percent STANDARD_DEVIATION 12.82 | 51.73 percent STANDARD_DEVIATION 11.81 | 51.45 percent STANDARD_DEVIATION 12.76 |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 3 Participants | 6 Participants | 18 Participants |
| Sex: Female, Male Male | 75 Participants | 79 Participants | 76 Participants | 80 Participants | 310 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 | 7 / 79 | 9 / 84 | 3 / 79 | 5 / 86 |
| serious Total, serious adverse events | 2 / 79 | 3 / 84 | 1 / 79 | 3 / 86 |
Outcome results
Primary
Trough FEV1 Response at Week 4
The change from baseline in trough FEV1 after 4 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline . Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication.
Time frame: baseline and after 4 weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response at Week 4 | -0.032 Liter | Standard Error 0.015 |
| Olodaterol 2mcg | Trough FEV1 Response at Week 4 | 0.059 Liter | Standard Error 0.015 |
| Olodaterol 5mcg | Trough FEV1 Response at Week 4 | 0.100 Liter | Standard Error 0.015 |
| Olodaterol 10mcg | Trough FEV1 Response at Week 4 | 0.100 Liter | Standard Error 0.015 |
Comparison: Olodaterol 2mcg - Placebop-value: <0.000195% CI: [0.051, 0.131]ANCOVA
Comparison: Olodaterol 5mcg - Placebop-value: <0.000195% CI: [0.091, 0.172]ANCOVA
Comparison: Olodaterol 10mcg - Placebop-value: <0.000195% CI: [0.092, 0.172]ANCOVA
Secondary
AUC0-1
Area under the concentration curve from 0 to 1 hour using trapezoid rule, only calculated if \>1/3 of the patients have available pharmacokinetic parameters,thus not applicable for Olodaterol 2mcg group
Time frame: after first inhalated administration
Population: Treated set which is however restricted to patients with evaluable data for this endpoint (Patients in which all plasma concentration values were below limit of quantification (BLQ), were excluded from the analysis and were not included into the total number of participants affected for this outcome measure)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC0-1 | 3.67 pg*h/mL | Geometric Coefficient of Variation 35.6 |
| Olodaterol 2mcg | AUC0-1 | 6.08 pg*h/mL | Geometric Coefficient of Variation 50.8 |
Secondary
AUC0-1,ss
Area under the concentration curve from 0 to 1 hour at steady state using trapezoid rule, only calculated if \>1/3 of the patients have available pharmacokinetic parameters, thus not applicable for Olodaterol 2mcg group
Time frame: visit at week 4
Population: Treated set which is however restricted to patients with evaluable data for this endpoint (Patients in which all plasma concentration values were below limit of quantification (BLQ), were excluded from the analysis and were not included into the total number of participants affected for this outcome measure)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC0-1,ss | 4.85 pg*h/mL | Geometric Coefficient of Variation 54.6 |
| Olodaterol 2mcg | AUC0-1,ss | 10.8 pg*h/mL | Geometric Coefficient of Variation 54 |
Secondary
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination
Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical examination. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations).
Time frame: 4 weeks
Population: Treated set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Atrioventricular block second degree | 0.0 percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood lactate dehydrogenase increased | 0.0 percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood glucose increased | 0.0 percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | White blood cell count decreased | 0.0 percentage of participants |
| Olodaterol 2mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood lactate dehydrogenase increased | 0.0 percentage of participants |
| Olodaterol 2mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood glucose increased | 0.0 percentage of participants |
| Olodaterol 2mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | White blood cell count decreased | 0.0 percentage of participants |
| Olodaterol 2mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Atrioventricular block second degree | 0.0 percentage of participants |
| Olodaterol 5mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood glucose increased | 0.0 percentage of participants |
| Olodaterol 5mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood lactate dehydrogenase increased | 1.3 percentage of participants |
| Olodaterol 5mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | White blood cell count decreased | 0.0 percentage of participants |
| Olodaterol 5mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Atrioventricular block second degree | 0.0 percentage of participants |
| Olodaterol 10mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | White blood cell count decreased | 1.2 percentage of participants |
| Olodaterol 10mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood lactate dehydrogenase increased | 0.0 percentage of participants |
| Olodaterol 10mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Atrioventricular block second degree | 1.2 percentage of participants |
| Olodaterol 10mcg | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Blood glucose increased | 1.2 percentage of participants |
Secondary
Cmax (Maximum Measured Concentration of the Analyte in Plasma)
Cmax only calculated if \>1/3 of the patients have available pharmacokinetic parameters,thus not applicable for the Olodaterol 2 mcg
Time frame: after first inhalated administration
Population: Treated set which is however restricted to patients with evaluable data for this endpoint (Patients in which all plasma concentration values were below limit of quantification (BLQ), were excluded from the analysis and were not included into the total number of participants affected for this outcome measure)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 4.17 pg/mL | Geometric Coefficient of Variation 46.7 |
| Olodaterol 2mcg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 8.22 pg/mL | Geometric Coefficient of Variation 58.3 |
Secondary
Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State)
Cmax,ss only calculated if \>1/3 of the patients have available pharmacokinetic parameters, thus not applicable for the Olodaterol 2 mcg
Time frame: visit at week 4
Population: Treated set which is however restricted to patients with evaluable data for this endpoint (Patients in which all plasma concentration values were below limit of quantification (BLQ), were excluded from the analysis and were not included into the total number of participants affected for this outcome measure)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State) | 5.92 pg/mL | Geometric Coefficient of Variation 57.4 |
| Olodaterol 2mcg | Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State) | 13.1 pg/mL | Geometric Coefficient of Variation 58.6 |
Secondary
Difference From Baseline in Potassium
Difference from baseline in Potassium (normalized values). Normalization means that the values from different laboratories are transformed in such a way that they are directly comparable.
Time frame: Baseline, Week 4
Population: Treated set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Difference From Baseline in Potassium | 0.0 mmol/L | Standard Deviation 0.5 |
| Olodaterol 2mcg | Difference From Baseline in Potassium | 0.1 mmol/L | Standard Deviation 0.6 |
| Olodaterol 5mcg | Difference From Baseline in Potassium | -0.0 mmol/L | Standard Deviation 0.5 |
| Olodaterol 10mcg | Difference From Baseline in Potassium | 0.1 mmol/L | Standard Deviation 1.1 |
Secondary
FEV1 AUC(0-3) Response at 4 Weeks
The change from baseline in FEV1 AUC(0-3) after 4 weeks of treatment. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in liters. Due to normalization the unit is liters.
Time frame: baseline and after 4 weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 AUC(0-3) Response at 4 Weeks | -0.020 Liter | Standard Error 0.017 |
| Olodaterol 2mcg | FEV1 AUC(0-3) Response at 4 Weeks | 0.118 Liter | Standard Error 0.016 |
| Olodaterol 5mcg | FEV1 AUC(0-3) Response at 4 Weeks | 0.177 Liter | Standard Error 0.017 |
| Olodaterol 10mcg | FEV1 AUC(0-3) Response at 4 Weeks | 0.173 Liter | Standard Error 0.016 |
Comparison: Olodaterol 2mcg - Placebop-value: <0.000195% CI: [0.095, 0.182]ANCOVA
Comparison: Olodaterol 5mcg - Placebop-value: <0.000195% CI: [0.154, 0.241]ANCOVA
Comparison: Olodaterol 10mcg - Placebop-value: <0.000195% CI: [0.15, 0.236]ANCOVA
Secondary
FEV1 Peak(0-3) Response at 4 Weeks
The change from baseline in FEV1 peak(0-3) after 4 weeks of treatment.
Time frame: baseline and after 4 weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Peak(0-3) Response at 4 Weeks | 0.025 Liter | Standard Error 0.017 |
| Olodaterol 2mcg | FEV1 Peak(0-3) Response at 4 Weeks | 0.170 Liter | Standard Error 0.017 |
| Olodaterol 5mcg | FEV1 Peak(0-3) Response at 4 Weeks | 0.227 Liter | Standard Error 0.017 |
| Olodaterol 10mcg | FEV1 Peak(0-3) Response at 4 Weeks | 0.220 Liter | Standard Error 0.017 |
Comparison: Olodaterol 2mcg - Placebop-value: <0.000195% CI: [0.101, 0.191]ANCOVA
Comparison: Olodaterol 5mcg - Placebop-value: <0.000195% CI: [0.157, 0.247]ANCOVA
Comparison: Olodaterol 10mcg - Placebop-value: <0.000195% CI: [0.151, 0.24]ANCOVA
Secondary
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters.
Time frame: baseline and after 4weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period which is however restricted to patients with evaluable data for this endpoint - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks | -0.022 Liter | Standard Error 0.028 |
| Olodaterol 2mcg | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks | 0.090 Liter | Standard Error 0.027 |
| Olodaterol 5mcg | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks | 0.195 Liter | Standard Error 0.027 |
| Olodaterol 10mcg | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks | 0.195 Liter | Standard Error 0.026 |
p-value: 0.004595% CI: [0.035, 0.188]ANCOVA
p-value: <0.000195% CI: [0.14, 0.293]ANCOVA
p-value: <0.000195% CI: [0.142, 0.292]ANCOVA
Secondary
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters.
Time frame: Baseline and after 4weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period which is however restricted to patients with evaluable data for this endpoint - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks | -0.005 Liter | Standard Error 0.028 |
| Olodaterol 2mcg | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks | 0.078 Liter | Standard Error 0.027 |
| Olodaterol 5mcg | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks | 0.171 Liter | Standard Error 0.027 |
| Olodaterol 10mcg | Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks | 0.186 Liter | Standard Error 0.026 |
p-value: 0.034895% CI: [0.006, 0.159]ANCOVA
p-value: <0.000195% CI: [0.1, 0.252]ANCOVA
p-value: <0.000195% CI: [0.115, 0.265]ANCOVA
Secondary
FVC AUC(0-3) Response
The change from baseline in FVC AUC(0-3) response after 4 weeks of treatment. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in liters. Due to normalization the unit is liters.
Time frame: baseline and after 4 weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC(0-3) Response | 0.004 Liter | Standard Error 0.036 |
| Olodaterol 2mcg | FVC AUC(0-3) Response | 0.257 Liter | Standard Error 0.035 |
| Olodaterol 5mcg | FVC AUC(0-3) Response | 0.254 Liter | Standard Error 0.036 |
| Olodaterol 10mcg | FVC AUC(0-3) Response | 0.237 Liter | Standard Error 0.035 |
Comparison: Olodaterol 2mcg - Placebop-value: <0.000195% CI: [0.16, 0.345]ANCOVA
Comparison: Olodaterol 5mcg - Placebop-value: <0.000195% CI: [0.156, 0.343]ANCOVA
Comparison: Olodaterol 10mcg - Placebop-value: <0.000195% CI: [0.141, 0.325]ANCOVA
Secondary
FVC Peak(0-3) Response
The change from baseline in FVC peak(0-3) response after 4 weeks of treatment.
Time frame: baseline and after 4 weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Peak(0-3) Response | 0.109 Liter | Standard Error 0.038 |
| Olodaterol 2mcg | FVC Peak(0-3) Response | 0.362 Liter | Standard Error 0.037 |
| Olodaterol 5mcg | FVC Peak(0-3) Response | 0.351 Liter | Standard Error 0.038 |
| Olodaterol 10mcg | FVC Peak(0-3) Response | 0.335 Liter | Standard Error 0.036 |
Comparison: Olodaterol 2mcg - Placebop-value: <0.000195% CI: [0.155, 0.351]ANCOVA
Comparison: Olodaterol 5mcg - Placebop-value: <0.000195% CI: [0.142, 0.341]ANCOVA
Comparison: Olodaterol 10mcg - Placebop-value: <0.000195% CI: [0.129, 0.324]ANCOVA
Secondary
Trough FEV1 Response at Week 2
Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication
Time frame: baseline and after 2 weeks treatment
Population: The full analysis set (FAS) - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response at Week 2 | -0.020 Liter | Standard Error 0.016 |
| Olodaterol 2mcg | Trough FEV1 Response at Week 2 | 0.061 Liter | Standard Error 0.015 |
| Olodaterol 5mcg | Trough FEV1 Response at Week 2 | 0.120 Liter | Standard Error 0.016 |
| Olodaterol 10mcg | Trough FEV1 Response at Week 2 | 0.136 Liter | Standard Error 0.015 |
p-value: 0.000295% CI: [0.039, 0.124]ANCOVA
p-value: <0.000195% CI: [0.098, 0.184]ANCOVA
p-value: <0.000195% CI: [0.115, 0.199]ANCOVA
Secondary
Trough FVC Response at Week 4
The change from baseline in Trough FVC after 4 weeks of treatment
Time frame: baseline and after 4 weeks treatment
Population: The full analysis set (FAS) for 4 weeks treatment period - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response at Week 4 | -0.037 Liter | Standard Error 0.033 |
| Olodaterol 2mcg | Trough FVC Response at Week 4 | 0.154 Liter | Standard Error 0.032 |
| Olodaterol 5mcg | Trough FVC Response at Week 4 | 0.154 Liter | Standard Error 0.033 |
| Olodaterol 10mcg | Trough FVC Response at Week 4 | 0.150 Liter | Standard Error 0.032 |
Comparison: Olodaterol 2mcg - Placebop-value: <0.000195% CI: [0.107, 0.275]ANCOVA
Comparison: Olodaterol 5mcg - Placebop-value: <0.000195% CI: [0.106, 0.276]ANCOVA
Comparison: Olodaterol 10mcg - Placebop-value: <0.000195% CI: [0.103, 0.27]ANCOVA
Secondary
Weekly Mean Evening PEFR After 4 Weeks
PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs, Evening measurements were performed at bedtime.The highest of three readings for each measurement were recorded.
Time frame: Week 4
Population: The full analysis set (FAS) for 4 weeks treatment period which is however restricted to patients with evaluable data for this endpoint - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Weekly Mean Evening PEFR After 4 Weeks | 227.39 Liter/minute | Standard Error 4.085 |
| Olodaterol 2mcg | Weekly Mean Evening PEFR After 4 Weeks | 256.44 Liter/minute | Standard Error 3.955 |
| Olodaterol 5mcg | Weekly Mean Evening PEFR After 4 Weeks | 258.34 Liter/minute | Standard Error 4.083 |
| Olodaterol 10mcg | Weekly Mean Evening PEFR After 4 Weeks | 264.58 Liter/minute | Standard Error 3.89 |
p-value: <0.000195% CI: [18.159, 39.946]ANCOVA
p-value: <0.000195% CI: [19.861, 42.049]ANCOVA
p-value: <0.000195% CI: [26.386, 47.996]ANCOVA
Secondary
Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks
Weekly mean number of occasions of rescue therapy used per day (PRN salbutamol )
Time frame: Week 4
Population: The full analysis set (FAS) for 4 weeks treatment period which is however restricted to patients with evaluable data for this endpoint - analysis with imputation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks | 0.778 Number of puffs | Standard Error 0.11 |
| Olodaterol 2mcg | Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks | 0.587 Number of puffs | Standard Error 0.107 |
| Olodaterol 5mcg | Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks | 0.324 Number of puffs | Standard Error 0.109 |
| Olodaterol 10mcg | Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks | 0.392 Number of puffs | Standard Error 0.105 |
p-value: 0.201695% CI: [-0.485, 0.103]ANCOVA
p-value: 0.002995% CI: [-0.752, -0.156]ANCOVA
p-value: 0.009595% CI: [-0.678, -0.095]ANCOVA
Secondary
Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks
PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs, Morning measurements were performed immediately upon arising before administration of trial and/or rescue medication.The highest of three readings for each measurement were recorded.
Time frame: Week 4
Population: The full analysis set (FAS) for 4 weeks treatment period which is however restricted to patients with evaluable data for this endpoint - analysis with imputation
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks | 217.54 Liter/minute | Standard Error 4.059 |
| Olodaterol 2mcg | Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks | 244.80 Liter/minute | Standard Error 3.933 |
| Olodaterol 5mcg | Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks | 246.93 Liter/minute | Standard Error 4.059 |
| Olodaterol 10mcg | Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks | 254.22 Liter/minute | Standard Error 3.869 |
p-value: <0.000195% CI: [16.477, 38.036]ANCOVA
p-value: <0.000195% CI: [18.41, 40.357]ANCOVA
p-value: <0.000195% CI: [25.987, 47.369]ANCOVA