Efficacy and Safety of 4 Weeks of Treatment With Orally Inhaled BI1744/Tiotropium Bromide in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Randomised, Double-blind, Cross-over Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of 2 Doses of Orally Inhaled BI 1744 CL, Each in Fixed Dose Combination (FDC) With 5 Microgram Tiotropium Bromide (Delivered by the Respimat® Inhaler) in Patients With COPD

The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL administered with 5 microgram tiotropium bromide solution for inhalation, delivered by the Respimat® inhaler, once daily for four weeks in patients with chronic obstructive pulmonary disease (COPD).

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Device: Respimat® Inhaler; Drug: BI 1744 CL plus tiotropium bromide

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium
    • 1237.9.03253 Boehringer Ingelheim Investigational Site
  • Bruxelles, Belgium
    • 1237.9.03255 Boehringer Ingelheim Investigational Site
  • Edegem, Belgium
    • 1237.9.03254 Boehringer Ingelheim Investigational Site
  • Gent, Belgium
    • 1237.9.03251 Boehringer Ingelheim Investigational Site
  • Leuven, Belgium
    • 1237.9.03252 Boehringer Ingelheim Investigational Site
• Canada
  • Ontario
    • Mississauga, Ontario, Canada
      • 1237.9.00255 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1237.9.00251 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1237.9.00252 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1237.9.00254 Boehringer Ingelheim Investigational Site
  • Quebec
    • Ste-Foy, Quebec, Canada
      • 1237.9.00253 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 1237.9.04952 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1237.9.04953 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1237.9.04954 Boehringer Ingelheim Investigational Site
  • Bruchsal, Germany
    • 1237.9.04955 Boehringer Ingelheim Investigational Site
  • Gelnhausen, Germany
    • 1237.9.04959 Boehringer Ingelheim Investigational Site
  • Großhansdorf, Germany
    • 1237.9.04960 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1237.9.04958 Boehringer Ingelheim Investigational Site
  • Tübingen, Germany
    • 1237.9.04951 Boehringer Ingelheim Investigational Site
  • Wiesloch, Germany
    • 1237.9.04956 Boehringer Ingelheim Investigational Site
• United States
  • Florida
    • Clearwater, Florida, United States
      • 1237.9.00152 Boehringer Ingelheim Investigational Site
    • Tampa, Florida, United States
      • 1237.9.00155 Boehringer Ingelheim Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • 1237.9.00151 Boehringer Ingelheim Investigational Site
  • Texas
    • Killeen, Texas, United States
      • 1237.9.00154 Boehringer Ingelheim Investigational Site
  • Washington
    • Spokane, Washington, United States
      • 1237.9.00153 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions

2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria:

   Patients must have relatively stable 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

3. Male or female patients, 40 years of age or older
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years
5. Patients must be able to perform technically acceptable pulmonary function tests and PEF measurements, and must be able to maintain records (Patient Daily e-Diary) during the study period as required in the protocol
6. Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a metered dose inhaler (MDI).
7. additional inclusion criteria apply.

Exclusion Criteria:

1. Patients with a significant disease other than COPD
2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis;
3. Patients with a history of asthma or a total blood eosinophil count >= 600/mm3.
4. 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 QTcF* 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)
5. 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, a history of life-threatening pulmonary obstruction, a history of cystic fibrosis, clinically evident bronchiectasis, a history of significant alcohol or drug abuse
6. Patients who have undergone thoracotomy with pulmonary resection
7. 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.
8. Pregnant or nursing women
9. Women of childbearing potential not using two effective method of birth control (one barrier and one non-barrier). Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years
10. Patients who have previously been randomized in this study or are currently participating in another study
11. Patients who are unable to comply with pulmonary medication restrictions prior to randomization
12. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening Visit
13. additional exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 1744 CL low dose+tiotropium bromide; BI 1744 CL low dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation	Device: Respimat® Inhaler; Drug: BI 1744 CL plus tiotropium bromide; BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation
Experimental: BI 1744 CL medium dose+tiotropium bromide; BI 1744 CL medium dose plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation	Device: Respimat® Inhaler; Drug: BI 1744 CL plus tiotropium bromide; BI 1744 CL plus tiotropium bromide fixed dose combination; Solution for inhalation via Respimat® Inhaler (A5); Oral inhalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough Forced Expiratory Volume in One Second (FEV1) Response [L] After Four Weeks of Treatment.	Trough FEV1 was defined as the mean of the 2 FEV1 values at the end of the dosing interval, 24 hours post-drug administration. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1 hour (h), 10 minutes (min) before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough FEV1 Response [L] After 2 Weeks of Treatment	Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 15
Individual FEV1 Measurements	Individual FEV1 measurements [L] at each time point on Day 29. The presented means are adjusted.	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
FEV1 AUC 0-3h, Response	FEV1 Area Under the Curve (AUC) 0-3h, response [L] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
FEV1 Peak 0-3h Response	FEV1 peak value over the time from 0 to 3 hours (peak 0-3h) response [L] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
FEV1, AUC (0-6h) Response	FEV1, AUC (0-6h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
FEV1 (Unsupervised) AUC (6-12h) Response	FEV1 (unsupervised) AUC (6-12h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	6 hours (h), 9h and 12h after drug administration on day 29
Trough FVC Response	Trough Forced Vital Capacity (FVC) response [L] on days 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 15, in addition 4h, 5h, 6h after drug administration on day 29
Individual FVC Measurements	Individual FVC measurements [L] at each time point The categories correspond to the planned times for FVC measurements on Day 29. The presented means are adjusted.	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
FVC AUC (0-3h) Response	FVC AUC (0-3h) response [L] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
FVC AUC (0-6h) Response	FVC AUC (0-6h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
FVC Peak 0-3h Response	FVC peak 0-3h response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 29
PEFR AUC (0-3h) Response	Peak Expiratory Flow Rate (PEFR) AUC (0-3h) response [L/min] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
PEFR Peak 0-3h Response	PEFR peak 0-3h response [L/min] on days 1, 15 and 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
PEFR AUC (6-12h) Response	PEFR AUC (6-12h) response [L] on day 29. Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period. The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed).	1 hour (h) and 10 minutes before drug administration on day 1 and 6h, 9h and 12h after drug administration on day 29
Weekly Mean Morning PEFR	Weekly mean morning PEFR [L/min] on weeks 1,2,3 and 4. The presented means are adjusted.	Weeks 1,2,3 and 4
Weekly Mean Evening PEFR	Weekly mean evening PEFR [L/min] on weeks 1,2,3 and 4. The presented means are adjusted.	Weeks 1,2,3 and 4
Weekly Mean Number of Occasions of Rescue Therapy Used Per Day (PRN Salbutamol [Albuterol])	Weekly mean number of occasions of rescue therapy used per day (as occasion require (PRN) salbutamol [albuterol]) on weeks 1,2,3 and 4. The means presented are the adjusted mean of weekly mean.	Weeks 1,2,3 and 4
Patient Global Rating	Patient global rating scores treatment comparison after 4 weeks The score was evaluated on a 7-point scale : 1 : very much better; 2 : much better; 3 : a little better; 4 : no change; 5 : a little worse; 6 : much worse; 7 : very much worse The presented means are adjusted.	4 weeks
Physician's Global Evaluation	Physician's global evaluation score on days 15 and 29 The score was evaluated on a 8-points scale : Poor : 1,2; Fair : 3,4; Good : 5,6; Excellent : 7,8 The presented means are adjusted	Days 15 and 29
Clinically Significant Abnormalities for Blood Chemistry, Haematology, Urinalysis and Physical Examination	Clinically significant abnormalities for blood chemistry, haematology, urinalysis and physical examination	14 weeks
Overall Marked Changes From Baseline in Vital Signs	Overall marked changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate.	Baseline to week 14
12-lead ECG Heart Rate	12-lead Electrocardiogram (ECG) Heart rate baseline and change from baseline values at other time points in Beats Per Minute (BPM) Statistics for each planned time from baseline to day 29.	Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
12-lead ECG PR Intervals	12-lead ECG PR intervals baseline and change from baseline at other timepoints in milliseconds. Statistics for each planned time from baseline to day 29.	Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
12-lead ECG QRS Intervals	12-lead ECG QRS intervals baseline and change from baseline at other time points in milliseconds Statistics for each planned time from baseline to day 29.	Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
12-lead ECG QTcF Intervals	12-lead ECG corrected heart rate (QT) interval, using Fridericia method (QTcF), baseline and change from baseline at other time points in milliseconds. Statistics for each planned time from baseline to day 29.	Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
12-lead ECG QTcB Intervals	12-lead ECG heart rate corrected QT interval, using Bazett method (QTcB), baseline and change from baseline at other time points in milliseconds. Statistics for each planned time from baseline to day 29.	Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
12-lead ECG QT Intervals	12-lead ECG QT intervals baseline and change from baseline at other time points in milliseconds. Statistics for each planned time from baseline to day 29.	Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
AUC (0-6H) FEV1 (Unsupervised), AUC (0-6H) PEFR (Unsupervised), FVC Peak (0-3h), AUC (6-12h) FEV1 (Unsupervised), AUC (6-12h) PEFR (Unsupervised), Individual PEFR Measurements (Supervised and Unsupervised), Individual PEFR Measurements (Unsupervised)	AUC (0-6h) for FEV1, and PEFR (unsupervised) after first dose and after 2 and 4 weeks of treatment were not analysed in the study report because the pertinent information from the unsupervised Pulmonary Function Tests (PFTs) was for the time interval from 6 to 12 hours post-dosing.; FVC peak 0-3h response after the first dose and at Week 2 (supervised) and AUC (6-12h) for FEV1 and PEFR after the first dose and at Week 2 (unsupervised) were not analysed in the study report.; Individual PEFR (supervised) measurements and individual FEV1 and PEFR (unsupervised) measurements at each time point were not analysed in the study report.	4 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: July 21, 2008
• First Submitted That Met QC Criteria: July 21, 2008
• First Posted (Estimate): July 22, 2008

Study Record Updates

• Last Update Posted (Estimate): August 17, 2015
• Last Update Submitted That Met QC Criteria: July 20, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Anticonvulsants; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide; Bromides; Olodaterol
• Other Study ID Numbers: 1237.9; EudtaCT No: 2008-000562-23