Efficacy and Safety of 4 Weeks Treatment With Inhaled BI 1744 CL in Japanese Patients With COPD

Study Overview
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Brief Summary
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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.

Official Title
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Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL Delivered by the Respimat Inhaler in Japanese Patients With COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: BI 1744 CL 2 Âµg
* Drug: BI 1744 CL 5 Âµg
* Drug: BI 1744 CL 10 Âµg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must sign an informed consent consistent with GCP guidelines prior to participation in the trial. 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 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. Pack-Years = [Number of cigarettes/day/20] - years of smoking Patients who have never smoked cigarettes must be excluded. 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. Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a MDI. 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 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) 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 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. 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 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) 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. 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 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 Patients who have taken an investigational drug within 1 month or 6 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 suspect of pregnant or women who are willing to become pregnant during the study period or nursing women Patients who have previously been participated in this study or are currently participating in another study Patients who are unable to comply with pulmonary medication restrictions prior to randomisation 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

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 1744 CL 5 Âµg<br>2 puffs of 2.5 Âµg/actuation | Drug: BI 1744 CL 5 Âµg<br>* 2 puffs of 2.5 Âµg/actuation delivered by the RespimatÂ® inhaler<br>|
| Experimental: BI 1744 CL 10 Âµg<br>2 puffs of 5 Âµg/actuation | Drug: BI 1744 CL 10 Âµg<br>* 2 puffs of 5 Âµg/actuation delivered by RespimatÂ®<br>|
| Placebo Comparator: Placebo<br>2 puffs | Drug: Placebo<br>* 2 puffs delivered by the RespimatÂ® inhaler<br>|
| Experimental: BI 1744 CL 2 Âµg<br>2 puffs of 1 Âµg/actuation | Drug: BI 1744 CL 2 Âµg<br>* 2 puffs of 1 Âµg/actuation delivered by the RespimatÂ® inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | baseline and after 4 weeks treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | baseline and after 2 weeks treatment | 
| 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. | baseline and after 4 weeks treatment | 
| FEV1 Peak(0-3) Response at 4 Weeks | The change from baseline in FEV1 peak(0-3) after 4 weeks of treatment. | baseline and after 4 weeks treatment | 
| Trough FVC Response at Week 4 | The change from baseline in Trough FVC after 4 weeks of treatment | baseline and after 4 weeks treatment | 
| 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. | baseline and after 4 weeks treatment | 
| FVC Peak(0-3) Response | The change from baseline in FVC peak(0-3) response after 4 weeks of treatment. | baseline and after 4 weeks treatment | 
| 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. | baseline and after 4weeks treatment | 
| 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. | Baseline and after 4weeks treatment | 
| 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. | Week 4 | 
| 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. | Week 4 | 
| Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks | Weekly mean number of occasions of rescue therapy used per day (PRN salbutamol ) | Week 4 | 
| 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). | 4 weeks | 
| 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. | Baseline, Week 4 | 
| 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 | after first inhalated administration | 
| 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 | visit at week 4 | 
| 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 | after first inhalated administration | 
| 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 | visit at week 4 |