A Study of the Safety and Efficacy of 4 Doses of BI 1744 CL Delivered Via the Respimat in Patients With Asthma.

Study Overview
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Brief Summary
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The primary objective of this study is to determine the efficacy and safety of 4 doses of BI 1744 CL inhalation solution delivered by the Respimat® inhaler once daily for four weeks in patients with asthma in comparison to placebo.

Official Title
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A Randomised, Double-Blind, Placebo- and Active-Controlled, Incomplete Crossover Efficacy and Safety Comparison of 4-week Treatment Periods of Once Daily Treatment of 4 Doses of BI 1744 CL Inhalation Solution Delivered by the Respimat® in Patients With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo
* Drug: Olodaterol (BI 1744) high
* Drug: Olodaterol (BI 1744) medium
* Drug: Olodaterol (BI 1744) very low
* Drug: Formoterol 12 mcg
* Drug: Olodaterol (BI 1744) low


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All patients must sign an informed consent consistent with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, i.e. prior to any study procedures which includes medication washout and restrictions. A separate informed consent is required for pharmacogenomic sampling. Male or female patients, aged between 18 and 70 years of age, diurnally active A history of asthma diagnosed by physician at least 3 months prior to Visit 1 at GINA treatment steps 3 or 4. The diagnosis of asthma must have been made before the age of 40. Pre-bronchodilator FEV1 between 60% predicted and 90% predicted at Visit 1. Increase in FEV1 greater or equal to 12% and 200 ml 15 minutes after 400mcg salbutamol (albuterol) at Visit 1. Patient must have been taking inhaled corticosteroids (ICS) for at least 12 weeks prior to screening, and must have been receiving at a stable dose for at least 6 weeks prior to screening either: - a medium to high dose ICS or - a low to high dose ICS in combination with Long acting beta agonist (LABA). All patients must be symptomatic. Exclusion criteria: Patients with a significant disease other than asthma; 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 who have been hospitalised for an asthma exacerbation within 3 months or had an admission to an intensive care unit for asthma within 3 years of Visit 1 Patients will be excluded when they have: - an aspartate aminotransferase (AST) >80 IU/L, alanine aminotransferase (ALT) >80 IU/L, bilirubin >1.5 X upper limit of normal (ULN) or creatinine >1.5 X ULN - clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis 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 at Visit 1 (e.g., repeated demonstration of a QTc interval >450 ms) as recommended by ICH E14 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 of screening visit (Visit 1) a diagnosis of clinically relevant cardiac arrhythmia a history of cor pulmonale 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 chronic obstructive pulmonary disease history of cystic fibrosis clinically evident bronchiectasis a history of significant alcohol or drug abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olodaterol (BI 1744) low<br>Low dose inhaled orally once daily from the Respimat inhaler | Drug: Olodaterol (BI 1744) low<br>* Determine efficacy and safety of 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat<br>|
| Experimental: Olodaterol (BI 1744) very low<br>Very low dose inhaled orally once daily from the Respimat inhaler | Drug: Olodaterol (BI 1744) very low<br>* Determination of efficacy in 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat<br>|
| Experimental: Olodaterol (BI 1744) medium<br>Medium dose inhaled orally once daily from the Respimat inhaler | Drug: Olodaterol (BI 1744) medium<br>* Determination of efficacy in 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat<br>|
| Experimental: Olodaterol (BI 1744) high<br>High dose inhaled orally once daily from the Respimat inhaler | Drug: Olodaterol (BI 1744) high<br>* Determine efficacy and safety in 4 different doses of Olodaterol (BI 1744) inhaled once daily via the Respimat<br>|
| Active Comparator: Formoterol 12 mcg<br>12mcg inhaled twice daily from the Aerolizer inhaler | Drug: Formoterol 12 mcg<br>* Determine efficacy and safety of 12 mcg Formoterol dose inhaled orally twice daily from the Aerolizer in comparison to other treatment groups<br>|
| Placebo Comparator: Placebo<br>Olodaterol (BI 1744) placebo inhaled once daily from the Respimat inhaler and/or Formoterol placebo inhaled twice daily from the Aerolizer inhaler | Drug: Placebo<br>* Determine efficacy and safety of Placebo inhaled once daily from the Respimat inhaler and/or twice daily from the Aerolizer inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks | 
| FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Peak FEV1 Within 24 Hours Post-dose Response | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Peak FEV1 within 24 hours post dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Trough FEV1 Response | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h , 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks | 
| FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 min, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Peak FVC Within 24 Hours Post-dose Response | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Peak FVC within 24 hours post dose measured following the trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Trough FVC Response | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks | 
| PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Peak PEF Within 24 Hours Post-dose Response | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Peak PEF within 24 hours post-dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Trough PEF Response | Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. | 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks | 
| Mean Pre-dose Morning PEF (PEF a.m.) | PEF a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. | 2-4 weeks | 
| Mean Pre-dose Evening PEF (PEF p.m.) | PEF p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. | 2-4 weeks | 
| PEF Daily Variability | PEF daily variability was assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). PEF daily variability is the absolute difference between the morning and the evening PEF value divided by the mean of these two values, expressed as a percent. Means are adjusted for treatment, period, patient and study baseline. | 2-4 weeks | 
| Mean Pre-dose Morning FEV1 (FEV1 a.m.) | FEV1 a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. | 2-4 weeks | 
| Mean Pre-dose Evening FEV1 (FEV1 p.m.) | FEV1 p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. | 2-4 weeks | 
| Mean Number of Puffs of Rescue Medication During the Whole Day | Mean of daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. | 2-4 weeks | 
| Percentage of Asthma Symptom Free Days | Percentage of asthma-symptom free days after the first 2 weeks of each treatment period was calculated as the number of symptom-free days divided by the number of days on treatment multiplied by 100. A symptom-free day was defined as a day in which no asthma symptoms were recorded, no rescue medication was recorded, activities during the day were not at all limited due to asthma, no shortness of breath during the day was recorded, no wheezing or coughing during the day and no night-time awakenings due to asthma were recorded. Assessed by patients at home using the AM2+ device. | 2-4 weeks | 
| Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. | 2-4 weeks | 
| Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. | 2-4 weeks | 
| Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. | 2-4 weeks | 
| Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score | Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ (s)) at the end of each 4 week treatment period. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items. | 4 weeks | 
| Total Asthma Control Questionnaire (ACQ) Score | Control of asthma as assessed by the ACQ at the end of each 4-week treatment period.The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items. | 4 weeks | 
| Potassium 1 Hour Pre-dose | Effect on potassium evaluated 1 hour pre-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. | 4 weeks | 
| Potassium 1 Hour Post-dose | Effect on potassium evaluated 1 hour post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. | 4 weeks | 
| Potassium 3 Hours Post-dose | Effect on potassium evaluated 3 hours post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. | 4 weeks | 
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. | 4 weeks |