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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00720499
First received: July 21, 2008
Last updated: July 20, 2015
Last verified: July 2015
  Purpose

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).


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: BI 1744 CL plus tiotropium bromide
Device: Respimat® Inhaler
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Trough Forced Expiratory Volume in One Second (FEV1) Response [L] After Four Weeks of Treatment. [ Time Frame: 1 hour (h), 10 minutes (min) before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 ] [ Designated as safety issue: No ]

    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).



Secondary Outcome Measures:
  • Trough FEV1 Response [L] After 2 Weeks of Treatment [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 15 ] [ Designated as safety issue: No ]

    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).


  • Individual FEV1 Measurements [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 ] [ Designated as safety issue: No ]

    Individual FEV1 measurements [L] at each time point on Day 29.

    The presented means are adjusted.


  • FEV1 AUC 0-3h, Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 ] [ Designated as safety issue: No ]

    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).


  • FEV1 Peak 0-3h Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 ] [ Designated as safety issue: No ]

    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).


  • FEV1, AUC (0-6h) Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 ] [ Designated as safety issue: No ]

    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).


  • FEV1 (Unsupervised) AUC (6-12h) Response [ Time Frame: 6 hours (h), 9h and 12h after drug administration on day 29 ] [ Designated as safety issue: No ]

    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).


  • Trough FVC Response [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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).


  • Individual FVC Measurements [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 ] [ Designated as safety issue: No ]

    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.


  • FVC AUC (0-3h) Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 ] [ Designated as safety issue: No ]

    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).


  • FVC AUC (0-6h) Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29 ] [ Designated as safety issue: No ]

    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).


  • FVC Peak 0-3h Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 29 ] [ Designated as safety issue: No ]

    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).


  • PEFR AUC (0-3h) Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 ] [ Designated as safety issue: No ]

    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).


  • PEFR Peak 0-3h Response [ Time Frame: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29 ] [ Designated as safety issue: No ]

    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).


  • PEFR AUC (6-12h) Response [ Time Frame: 1 hour (h) and 10 minutes before drug administration on day 1 and 6h, 9h and 12h after drug administration on day 29 ] [ Designated as safety issue: No ]

    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).


  • Weekly Mean Morning PEFR [ Time Frame: Weeks 1,2,3 and 4 ] [ Designated as safety issue: No ]

    Weekly mean morning PEFR [L/min] on weeks 1,2,3 and 4.

    The presented means are adjusted.


  • Weekly Mean Evening PEFR [ Time Frame: Weeks 1,2,3 and 4 ] [ Designated as safety issue: No ]

    Weekly mean evening PEFR [L/min] on weeks 1,2,3 and 4.

    The presented means are adjusted.


  • Weekly Mean Number of Occasions of Rescue Therapy Used Per Day (PRN Salbutamol [Albuterol]) [ Time Frame: Weeks 1,2,3 and 4 ] [ Designated as safety issue: No ]

    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.


  • Patient Global Rating [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

    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.


  • Physician's Global Evaluation [ Time Frame: Days 15 and 29 ] [ Designated as safety issue: No ]

    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


  • Clinically Significant Abnormalities for Blood Chemistry, Haematology, Urinalysis and Physical Examination [ Time Frame: 14 weeks ] [ Designated as safety issue: No ]
    Clinically significant abnormalities for blood chemistry, haematology, urinalysis and physical examination

  • Overall Marked Changes From Baseline in Vital Signs [ Time Frame: Baseline to week 14 ] [ Designated as safety issue: No ]
    Overall marked changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate.

  • 12-lead ECG Heart Rate [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • 12-lead ECG PR Intervals [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • 12-lead ECG QRS Intervals [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • 12-lead ECG QTcF Intervals [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • 12-lead ECG QTcB Intervals [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • 12-lead ECG QT Intervals [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • 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) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    • 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.


Enrollment: 141
Study Start Date: July 2008
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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
Device: Respimat® Inhaler
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
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
Device: Respimat® Inhaler

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00720499

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

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00720499     History of Changes
Other Study ID Numbers: 1237.9, EudtaCT No: 2008-000562-23
Study First Received: July 21, 2008
Results First Received: June 19, 2015
Last Updated: July 20, 2015
Health Authority: Belgium: Federal Agency for Medicines and Health Products, FAMHP
Canada: Health Canada
Germany: BfArM-Bundesinstitut fuer Arzneimittel und Medizinprodukte (Federal Authoriteis for Drugs and Medica
United States: Food and Drug Administration

Additional relevant MeSH terms:
Chronic Disease
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Disease Attributes
Lung Diseases, Obstructive
Pathologic Processes
Respiratory Tract Diseases
Bromides
Tiotropium
Anti-Asthmatic Agents
Anticonvulsants
Autonomic Agents
Bronchodilator Agents
Central Nervous System Agents
Cholinergic Agents
Cholinergic Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Parasympatholytics
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 27, 2015