BI 1744 CL With Respimat Once Daily Versus Twice Daily in COPD

Study Overview
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Brief Summary
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The primary objective of the trial is to determine the effect of BI 17444Cl on the lung function over a 24-hour period, when it is inhaled using the Respimat inhaler in patients with chronic obstructive pulmonary disease. In the trial four treatments of each 3 weeks of duration are included: 2 dosages in a once daily administration and 2 dosages for administration twice daily.

Official Title
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Randomised, Double-Blind, Cross-over Study to Determine the 24-hour FEV1-time Profile of Orally Inhaled BI 1744 CL, Delivered With the Respimat Inhaler, After 3 Weeks of Once Daily or Twice Daily Administration in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: BI 1744 CL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions All patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator FEV1 < 80% of predicted normal and a post-bronchodilator FEV1 / FVC < 70% at Visit 1 Male or female patients, 40 years of age or older Patients must be current or ex-smokers with a smoking history of more than 10 pack years Patients must be able to perform technically acceptable pulmonary function tests Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a metered dose inhaler (MDI). Exclusion Criteria: Patients with a significant disease other than COPD. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT > x2 ULN, SGPT > x2 ULN, bilirubin > x2 ULN or creatinine > x2 ULN will be excluded regardless of clinical condition. Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count more than 600/mm3, source documentation is required to verify that the increased eosinophil count is related to a non-asthmatic condition. Patients with any respiratory infection or COPD exacerbation in the 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period. Patients with any of the following conditions: a diagnosis of thyrotoxicosis; a diagnosis of paroxysmal tachycardia (>100 beats per minute) Patients with any of the following conditions: a history of myocardial infarction within 1 year of screening visit (Visit 1); unstable or life-threatening cardiac arrhythmia; have been hospitalized for heart failure within the past year; known active tuberculosis; a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five 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 Patients who have undergone thoracotomy with pulmonary resection Patients being treated with any of the following concomitant medications: oral beta2-adrenergics; oral corticosteroid medication at unstable doses (i.e., less than six 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. Patients who regularly use daytime oxygen therapy for more than one hour per day. 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 Patients with known hypersensitivity to beta-adrenergics drugs, BAC, EDTA or any other component of the Respimat inhalation solution delivery system Pregnant or nursing women Women of childbearing potential not using two effective methods of birth control (one barrier, one non-barrier). 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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Crossover Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: BI 1744 CL|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | Response was defined as change from baseline. Baseline FEV1 AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. | Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose | 
| FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | Response was defined as change from baseline. Baseline FEV1 AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. | Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | Response was defined as change from baseline. Baseline FEV1 AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres. | Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1,0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose | 
| Peak FEV1 (0-3h) Response After 3 Weeks | Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment. | Baseline, 3 weeks | 
| Trough FEV1 Response | Response was defined as change from baseline. Study baseline trough FEV1 was defined as the mean of the available pre-dose trough FEV1 values prior to first dose of treatment. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment . | Baseline, 3 weeks | 
| FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | Response was defined as change from baseline. Baseline FVC AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. | Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose | 
| FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | Response was defined as change from baseline. Baseline FVC AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. | Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose | 
| FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | Response was defined as change from baseline. Baseline FVC AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres. | Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1, 0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose | 
| Peak FVC (0-3h) Response After 3 Weeks | Response was defined as change from baseline. Study baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment. | Baseline, 3 weeks | 
| Trough FVC Response | Response was defined as change from baseline. Study baseline trough FVC was defined as the mean of the available pre-dose trough FVC values prior to first dose of treatment. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment . | Baseline, 3 weeks | 
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations). | 3 weeks | 
| Pharmacokinetics (PK): Concentration of the Analyte in Plasma Measured at 0.167 Hours Post Dosing at Steady State | Steady state concentration of the analyte in plasma measured at 0.167 hours post dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. | 3 weeks | 
| Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours | Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. | 3 weeks | 
| Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 24 Hours | Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. | 3 weeks | 
| Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours | Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. | 3 weeks | 
| Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 24 Hours | Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. | 3 weeks |