A Study to Compare the Efficacy and Safety of Different Dosings of Olodaterol Administered With the Respimat® Inhaler in Patients With Moderate to Severe Asthma

Study Overview
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Brief Summary
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This study will compare efficacy and safety of different regimens of olodaterol administration in asthma (once daily, twice daily) with placebo in a complete cross-over design each within one of the two daily dose groups (medium or high daily dose).

Official Title
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Phase II, Randomised, Double-Blind, Cross-over Study to Compare the 24-hour FEV1-time Profile of Orally Inhaled Olodaterol, Delivered With the Respimat® Inhaler, After 3 Weeks of Olodaterol Once Daily Medium Dose, Twice Daily Low Dose and Placebo or After 3 Weeks of Once Daily High Dose, Twice Daily Medium Dose and Placebo Administration in Patients With Moderate to Severe Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo twice daily
* Drug: Olodaterol low daily dose twice daily
* Drug: Olodaterol medium daily dose twice daily
* Drug: Placebo twice daily
* Drug: Olodaterol high daily dose once daily and placebo
* Drug: Olodaterol medium daily dose once daily and placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients of either sex. Aged 18 to 70 years. A current diagnosis and a documented minimum 3 month history of asthma Global Initiative for Asthma (GINA) treatment steps 3 and 4. Prebronchodilator Forced Expiratory Volume in one second (FEV1) >= 60% predicted and < 90% predicted according to European Coal and Steel Community (ECSC). Increase in FEV1 >=12% and >=200 mL 15 min. after 400 µg salbutamol (albuterol); Stable on medium to high dose inhaled corticosteroids (ICS) or low to high dose ICS in combination with a long acting beta-adrenergics (LABA) for at least 6 weeks prior to screening. Stable on ICS mono component of the former fixed LABA/ICS treatment for at least 48 hours prior to Visit 1b. Exclusion criteria: Patients with a significant disease other than asthma. History of frequent seasonal exacerbations of asthma (defined as one or more seasonal exacerbations every year for the past three years). Upper respiratory tract infection in the past 3 weeks prior to screening visit 1b. Oral or other systemic corticosteroids in the past 6 weeks. Patients with allergen desensitization therapy if started within two years, if they are not on an established maintenance regimen characterized by dose adjustments but no further increase to the tolerable maximum in the same course of immunotherapy.

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 medium daily dose<br>Olodaterol medium daily dose given either as once daily or split into two low doses daily or placebo only in randomised sequence of three cross-over treatment phases | Drug: Olodaterol low daily dose twice daily<br>* Inhaled Olodaterol medium daily dose administered as low dose twice daily<br>Drug: Placebo twice daily<br>* Inhaled Placebo of Olodaterol twice daily<br>Drug: Olodaterol medium daily dose once daily and placebo<br>* Inhaled Olodaterol medium daily dose administered as one full dose once daily and placebo once daily<br>|
| Experimental: Olodaterol high daily dose<br>Olodaterol high daily dose given either as once daily or split into two medium doses daily or placebo only in randomised sequence of three cross-over treatment phases | Drug: Placebo twice daily<br>* Inhaled Placebo of Olodaterol twice daily<br>Drug: Olodaterol medium daily dose twice daily<br>* Inhaled Olodaterol high daily dose administered as medium dose twice daily<br>Drug: Olodaterol high daily dose once daily and placebo<br>* Inhaled Olodaterol high daily dose administered as one full dose once daily and placebo once daily<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, 6 h, 8 h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 Area Under Curve 0-12 Hours (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, 6 h, 8 h, 10 h, 11 h 50 min related to morning dose after 3 weeks | 
| FEV1 Area Under Curve 12-24 Hours (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, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 morning trial drug inhalation at the end of each 3 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, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 23 h and 23 h 50 min after the last morning trial drug inhalation at the end of each 3 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 morning dose after 3 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, 6 h, 8 h, 10 h, 11 h 50 min related to morning dose after 3 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, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 morning trial drug inhalation at the end of each 3 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, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 FVC values performed at 23 h and 23 h 50 min after the last morning trial drug inhalation at the end of each 3 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 morning dose after 3 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, 6 h, 8h, 10 h, 11 h 50 min related to morning dose after 3 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, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 morning trial drug inhalation at the end of each 3 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, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 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 PEF values performed at 23 h and 23 h 50 min after the last morning trial drug inhalation at the end of each 3 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 morning dose after 3 weeks | 
| Mean Pre-dose Morning PEF (PEF a.m.) | PEF a.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. | 0-3 weeks | 
| Mean Pre-dose Evening PEF (PEF p.m.) | PEF p.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. | 0-3 weeks | 
| PEF Daily Variability | PEF daily variability was assessed by patients at home using the AM3 device (overall means obtained during each period of randomised treatment 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. | 0-3 weeks | 
| Mean Pre-dose Morning FEV1 (FEV1 a.m.) | FEV1 a.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. | 0-3 weeks | 
| Mean Pre-dose Evening FEV1 (FEV1 p.m.) | FEV1 p.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. | 0-3 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 AM3 device (overall mean number obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. | 0-3 weeks | 
| Percentage of Asthma Symptom Free Days | Percentage of asthma-symptom free days 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 AM3 device. | 0-3 weeks | 
| Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) | Assessed by patients at home using the AM3 device during each period of randomised treatment. | 0-3 weeks | 
| Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) | Assessed by patients at home using the AM3 device during each period of randomised treatment . | 0-3 weeks | 
| Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) | Assessed by patients at home using the AM3 device during each period of randomised treatment. | 0-3 weeks | 
| Total Asthma Control Questionnaire (ACQ) Score | Control of asthma as assessed by the ACQ at the end of each 3-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. | 3 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. Time frame for adverse event reporting includes 12 days into the subsequent washout or post-treatment period. | 3 weeks + 12 days |