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The purpose of this study is to compare the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the fixed dose combination (FDC) of 10 μg BI 1744 CL plus 5 μg tiotropium bromide with the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the single agents, i.e., 10 μg BI 1744 CL and 5 μg tiotropium bromide, when administered once-daily via the Respimat® Inhaler for 21 days.
The secondary objectives were to compare the safety and tolerability (adverse events, 12-lead electrocardiogram recordings, pulmonary function testing) of BI 1744 CL and tiotropium bromide when administered as fixed dose combination or as single-agent therapy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| BI 1744 CL/Tiotropium FDC | Experimental |
| |
| BI 1744 CL | Active Comparator |
| |
| Tiotropium | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BI 1744 CL | Drug |
| ||
| BI 1744 CL/Tiotropium FDC |
| Measure | Description | Time Frame |
|---|---|---|
| AUC(0-1h,ss) of Olodaterol | Area under the concentration time curve of Olodaterol in plasma over the time interval t1=0 to t2=1 hour at steady state (AUC(0-1h,ss)). As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Olodaterol. Based on the given definition AUC(0-1h,ss) was selected as primary endpoint. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Cmax,ss of Olodaterol | Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Ae(0-24h,ss) of Tiotropium | Amount of Tiotropium that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period. |
| Measure | Description | Time Frame |
|---|---|---|
| Ae(0-24h,ss) of Olodaterol | Amount of Olodaterol that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period. |
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Inclusion Criteria:
Exclusion Criteria:
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
Patients with clinically relevant abnormal baseline haematology, blood chemistry or urinalysis; all patients with a serum glutamic oxaloacetic transaminase (SGOT) > 2.5 x ULN, serum glutamic pyruvic transaminase (SGPT) > 2.5 x ULN, bilirubin >2x upper limit of normal (ULN), creatinine >2 x ULN or creatinine clearance < 50 mL/min (Estimation of Glomerular Filtration Rate (GFR) by using the Cockcroft-Gault Formula) will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients)
Patients with a history of asthma or a total blood eosinophil count ≥600/mm3
Patients with any of the following conditions:
Patients with any of the following conditions:
Patients who have undergone thoracotomy with pulmonary resection
Patients being treated with any of the following concomitant medications:
Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits
Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the Screening Visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program
Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening Visit (Visit 1)
Patients with known hypersensitivity to β-adrenergics and/or anticholinergic drugs, benzalkonium chloride, ethylenediaminetetraacetic acid or any other component of the Respimat® inhalation solution delivery system
Pregnant or nursing women
Women of childbearing potential not using two highly effective methods of birth control (one barrier and one non-barrier). Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years
Patients who have previously been randomized in this study or are currently participating in another study
Patients who are unable to comply with pulmonary medication restrictions prior to randomization
According to Inclusion Criterion No. 2, patients with a post-bronchodilator FEV1 of < 30% of predicted normal will always be excluded. Patients with a post-bronchodilator FEV1 between 30 and 50% of predicted normal will be excluded from the study, if they display additional symptoms of chronic respiratory insufficiency or right ventricular insufficiency
Patients with narrow angle glaucoma, prostate hyperplasia, or bladder neck obstruction
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A randomised, double-blind, 3-way crossover study, each patient received each of the three treatments for 21 days according to randomisation.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tio+Olo 5/10 μg, Olo 10 μg, Tio 5 μg | Patients received a total of three treatments, the treatments which were administered by oral inhalation, from the Respimat inhaler once daily, in the morning for 21 days, were:
|
| FG001 | Tio+Olo 5/10 μg, Tio 5 μg, Olo 10 μg | Patients received a total of three treatments, the treatments which were administered by oral inhalation, from the Respimat inhaler once daily, in the morning for 21 days, were:
|
| FG002 | Olo 10 μg, Tio+Olo 5/10 μg, Tio 5 μg | Patients received a total of three treatments, the treatments which were administered by oral inhalation, from the Respimat inhaler once daily, in the morning for 21 days, were:
|
| FG003 | Olo 10 μg, Tio 5 μg, Tio+Olo 5/10 μg | Patients received a total of three treatments, the treatments which were administered by oral inhalation, from the Respimat inhaler once daily, in the morning for 21 days, were:
|
| FG004 | Tio 5 μg, Tio+Olo 5/10 μg, Olo 10 μg | Patients received a total of three treatments, the treatments which were administered by oral inhalation, from the Respimat inhaler once daily, in the morning for 21 days, were:
|
| FG005 | Tio 5 μg, Olo 10 μg, Tio+Olo 5/10 μg | Patients received a total of three treatments, the treatments which were administered by oral inhalation, from the Respimat inhaler once daily, in the morning for 21 days, were:
|
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 (21 Days) |
| |||||||||||||
| Treatment Period 2 (21 Days) |
| |||||||||||||
| Treatment Period 3 (21 Days) |
|
Treated Set. All randomised patients who received at least one dose of trial medication were included in the treated set.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Subjects | A randomised, active-controlled, double-blind, 3-way crossover study in patients with COPD (chronic obstructive pulmonary disease). All participants received each of the three treatment arms in a randomly assigned order, the three treatments, which were administered by oral inhalation, from the Respimat inhaler once daily, in the morning for 21 days, were:
|
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | AUC(0-1h,ss) of Olodaterol | Area under the concentration time curve of Olodaterol in plasma over the time interval t1=0 to t2=1 hour at steady state (AUC(0-1h,ss)). As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Olodaterol. Based on the given definition AUC(0-1h,ss) was selected as primary endpoint. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic (PK) set which included all patients in the treated set who provided at least one of the PK parameters in at least one treatment period and completed the trial without any important protocol violations, it is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
From drug administration until 14 days following the last drug administration were assigned to the last study treatment administered, upto 37 days.
At each visit, all adverse events, regardless of causality, were recorded on the adverse event case report form page after discussion with the patient.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tiotropium+Olodaterol 5/10 μg | Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning, for 21 days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | MedDRA 11.1 | Systematic Assessment |
Additional secondary endpoints were listed in the original protocol, but according to internal rules, descriptive statistics would not be calculated unless data from at least 2/3rds of all subjects were available.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim Call Center | Boehringer Ingelheim | 1-800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| ID | Term |
|---|---|
| C549647 | olodaterol |
| D000069447 | Tiotropium Bromide |
| ID | Term |
|---|---|
| D012602 | Scopolamine Derivatives |
| D014326 | Tropanes |
| D053961 | Azabicyclo Compounds |
| D001372 | Aza Compounds |
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|
| Tiotropium | Drug |
|
| AUC(0-6h,ss) of Tiotropium | Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=6 h at steady state (AUC(0-6h,ss)). As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Tiotropium. Based on the given definition AUC(0-6h,ss) was selected as secondary endpoint. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Cmax,ss of Tiotropium | Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| AUC(0-2h,ss) of Olodaterol | Area under the concentration time curve of Olodaterol in plasma over the time interval 0 to 2 hours at steady state (AUC(0-2h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| AUC(0-4h,ss) of Tiotropium | Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=4 h at steady state (AUC(0-4h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| AUC(0-tz,ss) of Olodaterol | Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Olodaterol. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| AUC(0-tz,ss) of Tiotropium | Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Tiotropium. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Tmax,ss of Olodaterol | Time from dosing to the maximum concentration of Olodaterol in plasma at steady state (tmax,ss). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Tmax,ss of Tiotropium | Time from dosing to the maximum concentration of Tiotropium in plasma at steady state (tmax,ss). | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| fe(0-24,ss) of Olodaterol | Fraction of Olodaterol eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| fe(0-24,ss) of Tiotropium | Fraction of Tiotropium eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Cmin,ss of Olodaterol | Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Cmin,ss of Tiotropium | Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Tmin,ss of Olodaterol | Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss) | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Tmin,ss of Tiotropium | Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss) | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Concentration of Olodaterol in Plasma | Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21. The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| Concentration of Tiotropium in Plasma | Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21. The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
| FVC Change From Baseline | Mean change from baseline in forced vital capacity (FVC). Pulmonary function test. The baseline value was measured pre-dose on day 1 of the first treatment period. | 0:30 and 1:00 h after drug administration on the first day of each treatment period |
| FEV1 Change From Baseline | Mean change from baseline in forced expiratory volume in one second (FEV1). Pulmonary function test. The baseline value was measured pre-dose on day 1 of the first treatment period. | 0:30 and 1:00 h after drug administration on the first day of each treatment period |
| Clinical Relevant Abnormalities in Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG | Clinically relevant abnormalities in vital signs (blood pressure and pulse rate), physical examination, blood chemistry, haematology, urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Any adverse events which occurred within 14 days following the last drug administration were assigned to the last study treatment administered. | From drug administration until 14 days following the last drug administration |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | Tiotropium+Olodaterol 5/10 μg | Oral inhalation of fixed dose combination (FDC) of Tiotropium 5 µg and Olodaterol 10 µg (Tiotropium: 2.5 µg per actuation and Olodaterol: 5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning, for 21 days. |
| OG001 | Olodaterol 10 µg | Oral inhalation of Olodaterol 10 µg (5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning, for 21 days. |
|
|
|
| Primary | Cmax,ss of Olodaterol | Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Primary | Ae(0-24h,ss) of Tiotropium | Amount of Tiotropium that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng | Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period. |
|
|
|
|
| Secondary | Ae(0-24h,ss) of Olodaterol | Amount of Olodaterol that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng | Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period. |
|
|
|
|
| Secondary | AUC(0-6h,ss) of Tiotropium | Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=6 h at steady state (AUC(0-6h,ss)). As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Tiotropium. Based on the given definition AUC(0-6h,ss) was selected as secondary endpoint. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
|
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|
| Secondary | Cmax,ss of Tiotropium | Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | AUC(0-2h,ss) of Olodaterol | Area under the concentration time curve of Olodaterol in plasma over the time interval 0 to 2 hours at steady state (AUC(0-2h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
|
|
|
|
| Secondary | AUC(0-4h,ss) of Tiotropium | Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=4 h at steady state (AUC(0-4h,ss)). The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | AUC(0-tz,ss) of Olodaterol | Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Olodaterol. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | AUC(0-tz,ss) of Tiotropium | Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Tiotropium. The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Tmax,ss of Olodaterol | Time from dosing to the maximum concentration of Olodaterol in plasma at steady state (tmax,ss). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Median | Full Range | h | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Tmax,ss of Tiotropium | Time from dosing to the maximum concentration of Tiotropium in plasma at steady state (tmax,ss). | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Median | Full Range | h | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | fe(0-24,ss) of Olodaterol | Fraction of Olodaterol eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | percentage of olodaterol dose | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | fe(0-24,ss) of Tiotropium | Fraction of Tiotropium eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | percentage of tiotropium dose | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Cmin,ss of Olodaterol | Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Cmin,ss of Tiotropium | Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss). The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Tmin,ss of Olodaterol | Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss) | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Median | Full Range | h | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Tmin,ss of Tiotropium | Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss) | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Median | Full Range | h | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Concentration of Olodaterol in Plasma | Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21. The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | Concentration of Tiotropium in Plasma | Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21. The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics. | Pharmacokinetic set which is however restricted to patients with evaluable data for this endpoint. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period. |
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| Secondary | FVC Change From Baseline | Mean change from baseline in forced vital capacity (FVC). Pulmonary function test. The baseline value was measured pre-dose on day 1 of the first treatment period. | Treated Set. | Posted | Mean | Standard Deviation | L | 0:30 and 1:00 h after drug administration on the first day of each treatment period |
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| Secondary | FEV1 Change From Baseline | Mean change from baseline in forced expiratory volume in one second (FEV1). Pulmonary function test. The baseline value was measured pre-dose on day 1 of the first treatment period. | Treated Set. | Posted | Mean | Standard Deviation | L | 0:30 and 1:00 h after drug administration on the first day of each treatment period |
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| Secondary | Clinical Relevant Abnormalities in Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG | Clinically relevant abnormalities in vital signs (blood pressure and pulse rate), physical examination, blood chemistry, haematology, urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Any adverse events which occurred within 14 days following the last drug administration were assigned to the last study treatment administered. | Treated Set. All randomised patients who received at least one dose of trial medication were included in the treated set. | Posted | Number | participants | From drug administration until 14 days following the last drug administration |
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| 0 |
| 47 |
| 6 |
| 47 |
| EG001 | Olodaterol 10 µg | Oral inhalation of Olodaterol 10 µg (5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning, for 21 days. | 0 | 47 | 10 | 47 |
| EG002 | Tiotropium 5 µg | Oral inhalation of Tiotropium 5 µg (2.5 µg per actuation), 2 puffs from the Respimat inhaler, once daily, in the morning, for 21 days. | 0 | 47 | 9 | 47 |
| Headache | Nervous system disorders | MedDRA 11.1 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Systematic Assessment |
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Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009930 |
| Organic Chemicals |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D019086 | Bridged Bicyclo Compounds, Heterocyclic |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| C(0.333_21,ss) (N=43, 40) |
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| C(0.333_21,ss) (N=46, 44) |
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