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

• ClinicalTrials.gov Identifier: NCT01311661
• Recruitment Status: Completed
• First Posted: March 9, 2011
• Results First Posted: May 1, 2014
• Last Update Posted: May 1, 2014
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: Placebo twice daily; Drug: Olodaterol low daily dose twice daily; Drug: Olodaterol medium daily dose twice daily; Drug: Olodaterol high daily dose once daily and placebo; Drug: Olodaterol medium daily dose once daily and placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 206 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: March 2011
• Actual Primary Completion Date: December 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Olodaterol medium daily dose; 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; Inhaled Olodaterol medium daily dose administered as low dose twice daily; Drug: Placebo twice daily; Inhaled Placebo of Olodaterol twice daily; Drug: Olodaterol medium daily dose once daily and placebo; Inhaled Olodaterol medium daily dose administered as one full dose once daily and placebo once daily
Experimental: Olodaterol high daily dose; 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; Inhaled Placebo of Olodaterol twice daily; Drug: Olodaterol medium daily dose twice daily; Inhaled Olodaterol high daily dose administered as medium dose twice daily; Drug: Olodaterol high daily dose once daily and placebo; Inhaled Olodaterol high daily dose administered as one full dose once daily and placebo once daily

Outcome Measures

Primary Outcome Measures :

1. Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period [ Time Frame: 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 ]
   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.

Secondary Outcome Measures :

1. FEV1 Area Under Curve 0-12 Hours (AUC 0-12h) Response at the End of Each Treatment Period [ Time Frame: 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 ]
   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.
2. FEV1 Area Under Curve 12-24 Hours (AUC 12-24h) Response at the End of Each Treatment Period [ Time Frame: 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 ]
   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.
3. Peak FEV1 Within 24 Hours Post-dose Response [ Time Frame: 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 ]
   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.
4. Trough FEV1 Response [ Time Frame: 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 ]
   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.
5. Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response [ Time Frame: 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 ]
   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.
6. FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response [ Time Frame: 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 ]
   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.
7. FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response [ Time Frame: 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 ]
   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.
8. Peak FVC Within 24 Hours Post-dose Response [ Time Frame: 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 ]
   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.
9. Trough FVC Response [ Time Frame: 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 ]
   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.
10. Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response [ Time Frame: 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 ]
    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.
11. PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response [ Time Frame: 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 ]
    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.
12. Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response [ Time Frame: 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 ]
    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.
13. Peak PEF Within 24 Hours Post-dose Response [ Time Frame: 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 ]
    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.
14. Trough PEF Response [ Time Frame: 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 ]
    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.
15. Mean Pre-dose Morning PEF (PEF a.m.) [ Time Frame: 0-3 weeks ]
    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.
16. Mean Pre-dose Evening PEF (PEF p.m.) [ Time Frame: 0-3 weeks ]
    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.
17. PEF Daily Variability [ Time Frame: 0-3 weeks ]
    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.
18. Mean Pre-dose Morning FEV1 (FEV1 a.m.) [ Time Frame: 0-3 weeks ]
    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.
19. Mean Pre-dose Evening FEV1 (FEV1 p.m.) [ Time Frame: 0-3 weeks ]
    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.
20. Mean Number of Puffs of Rescue Medication During the Whole Day [ Time Frame: 0-3 weeks ]
    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.
21. Percentage of Asthma Symptom Free Days [ Time Frame: 0-3 weeks ]
    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.
22. Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall) [ Time Frame: 0-3 weeks ]
    Assessed by patients at home using the AM3 device during each period of randomised treatment.
23. Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall) [ Time Frame: 0-3 weeks ]
    Assessed by patients at home using the AM3 device during each period of randomised treatment .
24. Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall) [ Time Frame: 0-3 weeks ]
    Assessed by patients at home using the AM3 device during each period of randomised treatment.
25. Total Asthma Control Questionnaire (ACQ) Score [ Time Frame: 3 weeks ]
    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.
26. Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG [ Time Frame: 3 weeks + 12 days ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Patients of either sex.
2. Aged 18 to 70 years.
3. A current diagnosis and a documented minimum 3 month history of asthma Global Initiative for Asthma (GINA) treatment steps 3 and 4.
4. Prebronchodilator Forced Expiratory Volume in one second (FEV1) >= 60% predicted and < 90% predicted according to European Coal and Steel Community (ECSC).
5. Increase in FEV1 >=12% and >=200 mL 15 min. after 400 µg salbutamol (albuterol);
6. 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:

1. Patients with a significant disease other than asthma.
2. History of frequent seasonal exacerbations of asthma (defined as one or more seasonal exacerbations every year for the past three years).
3. Upper respiratory tract infection in the past 3 weeks prior to screening visit 1b.
4. Oral or other systemic corticosteroids in the past 6 weeks.
5. 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.

Contacts and Locations

Locations

United States, California

1222.29.11006 Boehringer Ingelheim Investigational Site

Huntington Beach, California, United States

United States, Colorado

1222.29.11001 Boehringer Ingelheim Investigational Site

Centennial, Colorado, United States

1222.29.11012 Boehringer Ingelheim Investigational Site

Wheat Ridge, Colorado, United States

United States, Kansas

1222.29.11002 Boehringer Ingelheim Investigational Site

Overland Park, Kansas, United States

United States, Massachusetts

1222.29.11004 Boehringer Ingelheim Investigational Site

North Dartmouth, Massachusetts, United States

United States, Missouri

1222.29.11011 Boehringer Ingelheim Investigational Site

St. Louis, Missouri, United States

United States, New Jersey

1222.29.11009 Boehringer Ingelheim Investigational Site

Skillman, New Jersey, United States

United States, North Carolina

1222.29.11003 Boehringer Ingelheim Investigational Site

Raleigh, North Carolina, United States

United States, Ohio

1222.29.11008 Boehringer Ingelheim Investigational Site

Canton, Ohio, United States

1222.29.11007 Boehringer Ingelheim Investigational Site

Cincinnati, Ohio, United States

United States, South Carolina

1222.29.11005 Boehringer Ingelheim Investigational Site

Spartanburg, South Carolina, United States

United States, Virginia

1222.29.11010 Boehringer Ingelheim Investigational Site

Richmond, Virginia, United States

Austria

1222.29.43003 Boehringer Ingelheim Investigational Site

Linz, Austria

1222.29.43002 Boehringer Ingelheim Investigational Site

Schlüsslberg, Austria

1222.29.43001 Boehringer Ingelheim Investigational Site

Thalheim bei Wels, Austria

1222.29.43004 Boehringer Ingelheim Investigational Site

Wels, Austria

Germany

1222.29.49004 Boehringer Ingelheim Investigational Site

Berlin, Germany

1222.29.49006 Boehringer Ingelheim Investigational Site

Berlin, Germany

1222.29.49007 Boehringer Ingelheim Investigational Site

Berlin, Germany

1222.29.49008 Boehringer Ingelheim Investigational Site

Berlin, Germany

1222.29.49002 Boehringer Ingelheim Investigational Site

Frankfurt, Germany

1222.29.49010 Boehringer Ingelheim Investigational Site

Großhansdorf, Germany

1222.29.49003 Boehringer Ingelheim Investigational Site

Lübeck, Germany

1222.29.49005 Boehringer Ingelheim Investigational Site

Rüdersdorf, Germany

1222.29.49001 Boehringer Ingelheim Investigational Site

Wiesbaden, Germany

1222.29.49009 Boehringer Ingelheim Investigational Site

Wiesloch, Germany

Hungary

1222.29.36002 Boehringer Ingelheim Investigational Site

Mosonmagyarovar, Hungary

1222.29.36003 Boehringer Ingelheim Investigational Site

Nyiregyhaza, Hungary

1222.29.36001 Boehringer Ingelheim Investigational Site

Sopron, Hungary

1222.29.36004 Boehringer Ingelheim Investigational Site

Zalaegerszeg, Hungary

Slovakia

1222.29.42001 Boehringer Ingelheim Investigational Site

Bardejov, Slovakia

1222.29.42002 Boehringer Ingelheim Investigational Site

Martin, Slovakia

1222.29.42004 Boehringer Ingelheim Investigational Site

Nitra, Slovakia

1222.29.42003 Boehringer Ingelheim Investigational Site

Spisska Nova Ves, Slovakia

Slovenia

1222.29.38003 Boehringer Ingelheim Investigational Site

Golnik, Slovenia

1222.29.38002 Boehringer Ingelheim Investigational Site

Kamnik, Slovenia

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Beeh KM, LaForce C, Gahlemann M, Wenz A, Toorawa R, Fležar M. Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat® in patients with moderate to severe persistent asthma. Respir Res. 2015 Jul 16;16:87. doi: 10.1186/s12931-015-0243-1.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01311661
• Other Study ID Numbers: 1222.29; 2008-006625-14 ( EudraCT Number: EudraCT )
• First Posted: March 9, 2011
• Results First Posted: May 1, 2014
• Last Update Posted: May 1, 2014
• Last Verified: March 2014

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Olodaterol; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents