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

Pulmonary Disease, Chronic Obstructive Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00720499
• Other study ID #: 1237.9
• Secondary ID: EudtaCT No: 2008
• Status: Completed
• Phase: Phase 2
• First received: July 21, 2008
• Last updated: July 20, 2015
• Start date: July 2008

Study information

• Verified date: July 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicines and Health Products, FAMHPCanada: Health CanadaGermany: BfArM-Bundesinstitut fuer Arzneimittel und Medizinprodukte (Federal Authoriteis for Drugs and MedicaUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 141
• Est. primary completion date: February 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

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

Locations

Country	Name	City	State
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
Canada	1237.9.00255 Boehringer Ingelheim Investigational Site	Mississauga	Ontario
Canada	1237.9.00253 Boehringer Ingelheim Investigational Site	Ste-Foy	Quebec
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
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	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
United States	1237.9.00152 Boehringer Ingelheim Investigational Site	Clearwater	Florida
United States	1237.9.00154 Boehringer Ingelheim Investigational Site	Killeen	Texas
United States	1237.9.00151 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1237.9.00153 Boehringer Ingelheim Investigational Site	Spokane	Washington
United States	1237.9.00155 Boehringer Ingelheim Investigational Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Clinically Significant Abnormalities for Blood Chemistry, Haematology, Urinalysis and Physical Examination	Clinically significant abnormalities for blood chemistry, haematology, urinalysis and physical examination	14 weeks	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

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