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

Phase 2

Completed

Conditions: Pulmonary Disease, Chronic Obstructive
Asthma

Registration Number: NCT00452400

Lead Sponsor: Boehringer Ingelheim

Brief Summary: The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL inhalation solution delivered by the Respimat® inhaler for four weeks in patients with chronic obstructive pulmonary disease (COPD). The selection of the optimum dose(s) will be based on bronchodilator efficacy (how well it helps your breathing), safety evaluations and pharmacokinetic evaluations (the amount of the medication found in your blood).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 409

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 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. Patients who have never smoked cigarettes must be excluded
Patients must be able to perform technically acceptable pulmonary function tests and PEFR measurements, and must be able to maintain records (Patient Daily e-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 metered dose inhaler (MDI).

Exclusion Criteria

Selection of relevant exclusion criteria:

Patients with a history of asthma or a total blood eosinophil count 600/mm3.
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).
- a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of Long QT Syndrome)
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
- 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 who regularly use daytime oxygen therapy for more than one 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 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 (Visit 1)
Pregnant or nursing women
Women of childbearing potential not using a highly effective method of birth control
Patients who have previously been randomized in this study or are currently participating in another study
Patients who are unable to comply with medication restrictions.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Trough FEV1 Response After 4 Weeks	Baseline and 4 weeks	Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to 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 FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 (- 1 hour and - 10 minutes) prior to administration of the first dose of study medication.

Secondary Outcome Measures

Name	Time	Method
Trough FVC Response After 2 Weeks	Baseline and 2 weeks	Trough FVC was defined as the mean of the two values obtained at 1 hour and 10 minutes prior to the pulmonary function test maneuver. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment.
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Day 1	1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at day 1	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 0-3h was calculated from 0-3 hours postdose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Weekly Mean Evening PEFR After 4 Weeks	4 weeks	Baseline PEFR was defined as the mean of the evening PEFR measurements obtained during the week just prior to first dose of randomized treatment.
Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks	4 weeks	Weekly mean number of occasions of rescue therapy used per day (PRN salbutamol (albuterol))
Area Under Curve From 0 to 24 Hours at Steady State (AUC0-24,ss)	Baseline and 4 weeks	AUC0-24,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=24 at steady state.
Trough FEV1 Response After 2 Weeks	Baseline and 2 weeks	Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to 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 FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 (- 1 hour and - 10 minutes) prior to administration of the first dose of study medication.
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-6 h (AUC 0-6h) Response at Week 4	1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h, 4h, 5h, 6h relative to dose at Week 4	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 litres.
Forced Vital Capacity (FVC) Area Under Curve 0-6 h (AUC 0-6h) Response at Week 4	1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h, 4h, 5h, 6h relative to dose at Week 4	Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC 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. FVC AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres.
Peak FVC (0-3h) Response After 4 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 4 weeks	Peak (0-3h) will be the maximum post-dose value during the first 3 hours. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment.
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Week 2	1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Week 2	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 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Peak FEV1 (0-3h) Response After 1 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 1 week	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. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with baseline, treatment and centre (centre random, all other effects fixed).
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 1 Week	Baseline and 1 week	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 litres.
Trough FEV1 Response After 1 Week	Baseline and 1 week	Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to 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 FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 (- 1 hour and - 10 minutes) prior to administration of the first dose of study medication.
Trough FVC Response After 1 Week	Baseline and 1 week	Trough FVC was defined as the mean of the two values obtained at 1 hour and 10 minutes prior to the pulmonary function test maneuver. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment.
Trough FVC Response After 4 Weeks	Baseline and 4 weeks	Trough FVC was defined as the mean of the two values obtained at 1 hour and 10 minutes prior to the pulmonary function test maneuver. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment.
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Week 1	1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Week 1	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 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Peak FEV1 (0-3h) Response At Day 1	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose at day 1	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. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment.Means are adjusted using a mixed effects model with baseline,treatment and centre (centre random, all other effects fixed).
Peak FEV1 (0-3h) Response After 2 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 2 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. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with baseline, treatment and centre (centre random, all other effects fixed).
Peak FEV1 (0-3h) Response After 4 Weeks	1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose 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. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with baseline, treatment and centre (centre random, all other effects fixed).
Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks	4 weeks	Baseline PEFR was defined as the mean of the morning PEFR measurements obtained during the week just prior to first dose of randomized treatment.
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 2 Weeks	Baseline and 2 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 litres.
Area Under Curve From 0 to 3 Hours (AUC0-3)	Baseline and 4 weeks	AUC0-3 represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=3.
Maximum Concentration (Cmax)	Baseline and 4 weeks	Cmax represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma.
Time From Dosing to the Maximum Concentration (Tmax)	Baseline and 4 weeks	tmax represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma.
Area Under Curve From 0 to 3 Hours at Steady State (AUC0-3,ss)	Baseline and 4 weeks	AUC0-3,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=3 at steady state.
Maximum Concentration at Steady State (Cmax,ss)	Baseline and 4 weeks	Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state.
Clinical Relevant Abnormalities for Vital Signs, ECG and Physical Examination	4 weeks	Clinical relevant abnormalities for vital signs, ECG and physical examination. Any new or clinically relevant worsening of baseline conditions was reported as adverse events.
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response at Day 1	baseline and day1	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 litres.
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks	Baseline and 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 litres.
Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss)	Baseline and 4 weeks	tmax,ss represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state.
Laboratory Testing: Average Change From Baseline of Potassium	Baseline and day 29	Laboratory testing: Average change from baseline of potassium measured on test-days. Pre-dose value on test day 1 is the baseline value.
Area Under Curve From 0 to 6 Hours at Steady State (AUC0-6,ss)	Baseline and 4 weeks	AUC0-6,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=6 at steady state.

Trial Locations

Locations (42): 1222.5.02 Boehringer Ingelheim Investigational Site
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Philadelphia, Pennsylvania, United States
1222.5.040 Respiratory Research Lab
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Toronto, Ontario, Canada
1222.5.034 Pulmonary Care Clinic and Research Centre
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Toronto, Ontario, Canada
1222.5.20 Boehringer Ingelheim Investigational Site
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Tacoma, Washington, United States
1222.5.038 Courtice Health Centre
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Courtice, Ontario, Canada
1222.5.049 Boehringer Ingelheim Investigational Site
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Berlin, Germany
1222.5.052 Boehringer Ingelheim Investigational Site
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Gauting, Germany
1222.5.048 Boehringer Ingelheim Investigational Site
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Wiesbaden, Germany
1222.5.039 St. Boniface General Hospital & Health Science Centre
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Winnipeg, Manitoba, Canada
1222.5.19 Boehringer Ingelheim Investigational Site
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Charleston, South Carolina, United States
1222.5.18 Boehringer Ingelheim Investigational Site
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Stamford, Connecticut, United States
1222.5.04 Boehringer Ingelheim Investigational Site
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Coeur D'Alene, Idaho, United States
1222.5.11 Boehringer Ingelheim Investigational Site
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Reno, Nevada, United States
1222.5.036 Department of Respiratory Medicine
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Saskatoon, Saskatchewan, Canada
1222.5.032 Division of Respirology
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Halifax, Nova Scotia, Canada
1222.5.22 Boehringer Ingelheim Investigational Site
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Shreveport, Louisiana, United States
1222.5.033 Centre de Recherche Clinique -CHUS
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Sherbrooke, Quebec, Canada
1222.5.059 Boehringer Ingelheim Investigational Site
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Eindhoven, Netherlands
1222.5.08 Boehringer Ingelheim Investigational Site
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Charleston, South Carolina, United States
1222.5.06 Boehringer Ingelheim Investigational Site
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Spartanburg, South Carolina, United States
1222.5.03 Boehringer Ingelheim Investigational Site
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Birmingham, Alabama, United States
1222.5.13 Boehringer Ingelheim Investigational Site
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WheatRidge, Colorado, United States
1222.5.14 Boehringer Ingelheim Investigational Site
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Denver, Colorado, United States
1222.5.17 Boehringer Ingelheim Investigational Site
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Wheat Ridge, Colorado, United States
1222.5.07 Boehringer Ingelheim Investigational Site
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Lakewood, California, United States
1222.5.15 Boehringer Ingelheim Investigational Site
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Panama City, Florida, United States
1222.5.12 Boehringer Ingelheim Investigational Site
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Raleigh, North Carolina, United States
1222.5.24 Boehringer Ingelheim Investigational Site
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New York, New York, United States
1222.5.10 Boehringer Ingelheim Investigational Site
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Medford, Oregon, United States
1222.5.05 Boehringer Ingelheim Investigational Site
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Hershey, Pennsylvania, United States
1222.5.21 Boehringer Ingelheim Investigational Site
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Kileen, Texas, United States
1222.5.23 Boehringer Ingelheim Investigational Site
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Richmond, Virginia, United States
1222.5.01 Boehringer Ingelheim Investigational Site
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San Antonio, Texas, United States
1222.5.037 Kingston General Hospital
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Kingston, Ontario, Canada
1222.5.031 Alpha Medical Research Inc.
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Mississauga, Ontario, Canada
1222.5.035 Hopital Laval
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Ste-Foy, Quebec, Canada
1222.5.046 Boehringer Ingelheim Investigational Site
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Berlin, Germany
1222.5.058 Boehringer Ingelheim Investigational Site
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Almelo, Netherlands
1222.5.051 Boehringer Ingelheim Investigational Site
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Großhansdorf, Germany
1222.5.057 Boehringer Ingelheim Investigational Site
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Heerlen, Netherlands
1222.5.047 Boehringer Ingelheim Investigational Site
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Rüdersdorf, Germany
1222.5.056 Boehringer Ingelheim Investigational Site
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Breda, Netherlands