Determining Optimal Free Dose Combination of Tiotropium Bromide and BI 1744 CL in Chronic Obstructive Pulmonary Disease (COPD)

A Randomised, Double-blind, 8 Treatments, 4 Periods, Incomplete Crossover Study to Determine the Optimal Free Dose Combination of BI 1744 CL and Tiotropium Bromide (Both Delivered by the Respimat® Inhaler) After 4 Weeks Once Daily Treatment in Patients With COPD

The primary objective of this study is to determine the optimum once daily dose of BI 1744 CL and tiotropium in free dose combination (delivered by the Respimat inhaler) after four week treatment in patients with COPD.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Placebo; Device: Respimat; Drug: olodaterol (BI 1744) low; Drug: low tiotropium bromide; Drug: medium tiotropium bromide; Drug: high tiotropium bromide; Drug: olodaterol (BI 1744) high

• Study Type: Interventional
• Enrollment (Actual): 233
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada
    • 1237.18.02009 Boehringer Ingelheim Investigational Site
  • British Columbia
    • Vancouver, British Columbia, Canada
      • 1237.18.02004 Boehringer Ingelheim Investigational Site
  • Ontario
    • Grimsby, Ontario, Canada
      • 1237.18.02005 Boehringer Ingelheim Investigational Site
    • Mississauga, Ontario, Canada
      • 1237.18.02001 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1237.18.02008 Boehringer Ingelheim Investigational Site
  • Quebec
    • Montreal, Quebec, Canada
      • 1237.18.02002 Boehringer Ingelheim Investigational Site
    • Point Claire, Quebec, Canada
      • 1237.18.02003 Boehringer Ingelheim Investigational Site
    • Sherbrooke, Quebec, Canada
      • 1237.18.02007 Boehringer Ingelheim Investigational Site
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • 1237.18.02011 Boehringer Ingelheim Investigational Site
• Germany
  • Aschaffenburg, Germany
    • 1237.18.49009 Boehringer Ingelheim Investigational Site
  • Bamberg, Germany
    • 1237.18.49012 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1237.18.49005 Boehringer Ingelheim Investigational Site
  • Frankfurt, Germany
    • 1237.18.49004 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1237.18.49011 Boehringer Ingelheim Investigational Site
  • Koblenz, Germany
    • 1237.18.49010 Boehringer Ingelheim Investigational Site
  • Mannheim, Germany
    • 1237.18.49007 Boehringer Ingelheim Investigational Site
  • Potsdam, Germany
    • 1237.18.49001 Boehringer Ingelheim Investigational Site
  • Rodgau-Dudenhofen, Germany
    • 1237.18.49006 Boehringer Ingelheim Investigational Site
  • Rüdersdorf, Germany
    • 1237.18.49002 Boehringer Ingelheim Investigational Site
  • Weinheim, Germany
    • 1237.18.49003 Boehringer Ingelheim Investigational Site
  • Wiesloch, Germany
    • 1237.18.49008 Boehringer Ingelheim Investigational Site
• Netherlands
  • Almelo, Netherlands
    • 1237.18.31004 Boehringer Ingelheim Investigational Site
  • Amsterdam, Netherlands
    • 1237.18.31006 Boehringer Ingelheim Investigational Site
  • Eindhoven, Netherlands
    • 1237.18.31008 Boehringer Ingelheim Investigational Site
  • Groningen, Netherlands
    • 1237.18.31001 Boehringer Ingelheim Investigational Site
  • Hengelo, Netherlands
    • 1237.18.31007 Boehringer Ingelheim Investigational Site
  • Hoorn, Netherlands
    • 1237.18.31005 Boehringer Ingelheim Investigational Site
  • Veldhoven, Netherlands
    • 1237.18.31002 Boehringer Ingelheim Investigational Site
  • Zutphen, Netherlands
    • 1237.18.31003 Boehringer Ingelheim Investigational Site
• Sweden
  • Boden, Sweden
    • 1237.18.46003 Boehringer Ingelheim Investigational Site
  • Göteborg, Sweden
    • 1237.18.46002 Boehringer Ingelheim Investigational Site
  • Lund, Sweden
    • 1237.18.46001 Boehringer Ingelheim Investigational Site
  • Stockholm, Sweden
    • 1237.18.46004 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
2. All patients must have a diagnosis of chronic obstructive pulmonary disease (COPD) must meet the following spirometric criteria:

a post-bronchodilator forced expiratory flow in 1 second (FEV1) =<30% of predicted normal and <80% of predicted normal and a post bronchodilator FEV1 / forced vital capacity (FVC) <70% at Visit 1 4. Male or female patients, 40 years of age or older. 5. Patients must be current or ex-smokers with a smoking history of more than 10 pack years

Exclusion criteria:

• Patients with a significant disease other than COPD;
• Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis;
• 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 (due to the known class side effect profile of ß2-agonists) a diagnosis of paroxysmal tachycardia - Patients with any of the following conditions: a history of myocardial infarction within 1 year of screening visit a diagnosis of clinically relevant cardiac arrhythmia a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years

• Patients who have undergone thoracotomy with pulmonary resection
• Patients being treated with the following concomitant medications:

medications that prolong the QT/QTc interval oral Beta-adrenergics oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day

- Pregnant or nursing women

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: olodaterol (BI 1744) low and placebo; low dose inhaled olodaterol orally once daily from the Respimat inhaler	Drug: Placebo; Placebo; Device: Respimat; Respimat inhaler; Drug: olodaterol (BI 1744) low; olodaterol (BI 1744) low
Experimental: olodaterol (BI 1744) low and low tio; low dose inhaled olodaterol and low dose inhaled tiotropium, both from the Respimat inhaler and once daily	Device: Respimat; Respimat inhaler; Drug: olodaterol (BI 1744) low; olodaterol (BI 1744) low; Drug: low tiotropium bromide; low tiotropium bromide
Experimental: olodaterol (BI 1744) low and medium tio; low dose inhaled olodaterol and medium dose inhaled tiotropium, both from the Respimat inhaler and once daily	Device: Respimat; Respimat inhaler; Drug: olodaterol (BI 1744) low; olodaterol (BI 1744) low; Drug: medium tiotropium bromide; medium tiotropium bromide
Experimental: olodaterol (BI 1744) low and high tio; low dose inhaled olodaterol and high dose inhaled tiotropium, both from the Respimat inhaler and once daily	Device: Respimat; Respimat inhaler; Drug: olodaterol (BI 1744) low; olodaterol (BI 1744) low; Drug: high tiotropium bromide; high tiotropium bromide
Experimental: olodaterol (BI 1744) high and placebo; high dose inhaled olodaterol orally once daily from the Respimat inhaler	Drug: Placebo; Placebo; Device: Respimat; Respimat inhaler; Drug: olodaterol (BI 1744) high; olodaterol (BI 1744) high
Experimental: Olodaterol (BI 1744) high and low tio; high dose inhaled olodaterol and low dose inhaled tiotropium, both from the Respimat inhaler and once daily	Device: Respimat; Respimat inhaler; Drug: low tiotropium bromide; low tiotropium bromide; Drug: olodaterol (BI 1744) high; olodaterol (BI 1744) high
Experimental: Olodaterol (BI 1744) high and medium tio; high dose inhaled olodaterol and medium dose inhaled tiotropium, both from the Respimat inhaler and once daily	Device: Respimat; Respimat inhaler; Drug: medium tiotropium bromide; medium tiotropium bromide; Drug: olodaterol (BI 1744) high; olodaterol (BI 1744) high
Experimental: Olodaterol (BI 1744) high and high tio; high dose inhaled olodaterol and high dose inhaled tiotropium, both from the Respimat inhaler and once daily	Device: Respimat; Respimat inhaler; Drug: high tiotropium bromide; high tiotropium bromide; Drug: olodaterol (BI 1744) high; olodaterol (BI 1744) high

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough FEV1 Response	Adjusted means of the trough forced expiratory volume in one second (FEV1) response (L) after four weeks treatment. The trough was defined as the mean of the 1 h pre-dose and 10 min pre-dose measurements on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough Forced Vital Capacity (FVC) Response	Adjusted means of trough FVC (forced vital capacity) response [L] after 4 weeks treatment. The trough was defined as the mean of the 1 h pre-dose and 10 min pre-dose measurements on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29
FEV1 AUC 0-3h and FEV1 AUC 0-6h Response	Adjusted means of forced expiratory volume in one second (FEV1) area under the curve (AUC) 0-3 hour and AUC 0-6 hour responses [L] after 4 weeks treatment calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29
FEV1 AUC 0-3h Response After the First Dose	Adjusted means of Forced Expiratory Volume in One Second (FEV1) Area Under Curve (AUC) 0-3h response [L] after the first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
FEV1 Peak 0-3h Response	Adjusted means of the FEV1 peak value over the time from 0 to 3 hours (peak 0-3h) response [L] after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29
FEV1 Peak 0-3h Response After the First Dose	Adjusted means of the FEV1 peak 0-3h response [L] after the first dose of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
FVC AUC 0-3h and FEV1 AUC 0-6h Responses	Adjusted means of the FVC AUC 0-3h and AUC 0-6h responses [L] after 4 weeks of treatment, calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29
FVC AUC 0-3h Response After First Dose	Adjusted means of the FVC AUC 0-3h response [L] after first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on days 1
FVC Peak 0-3h Response	Adjusted means of the FVC peak 0-3h response [L] after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29
FVC Peak 0-3h Response After the First Dose	Adjusted mean of the FVC peak 0-3h response [L] after the first dose. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
PEF AUC 0-3h and AUC 0-6h Responses	Adjusted means of the Peak Expiratory Flow (PEF) AUC 0-3h and AUC 0-6h responses in Litres / minute (L/min) after 4 weeks of treatment, calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29
PEF AUC 0-3h Response After the First Dose	Adjusted means of the Area under the curve from 0 to 3 h response in Litres / minutes of the peak expiratory flow after the first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
PEF Peak 0-3h Response	Adjusted means of the peak expiratory flow from 0 to 3 hours (PEF peak 0-3h) response in L/min after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29
PEF Peak 0-3h Response After the First Dose	Adjusted means of the Peak Expiratory flow from 0 to 3 hours response in L/min after the first dose of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
Individual FEV1 Measurements at Each Time Point on Day 29	Adjusted means of the FEV1 measurements [L] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29
Individual FVC Measurements at Each Time Point on Day 29	Adjusted means of the FVC measurements [L] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29
Individual PEF Measurements at Each Time Point on Day 29	Adjusted means of the PEF measurements [L/min] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.	Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29
Weekly Mean Number of Puffs of Rescue Medication Used Per Day	Adjusted means of the weekly mean number of puffs of rescue medication during the whole day : the rescue medication was a salbutamol [albuterol] dose (100 mcg per puff).	Weeks 1 and 4
Physicians Global Evaluation	Adjusted means of the Physicians Global Evaluation of the patient's respiratory condition on days 1 and 29. The score was evaluated on a 8-points scale : Poor : 1,2; Fair : 3,4; Good : 5,6; Excellent : 7,8	Days 1 and 29
Patients Global Rating	Adjusted means of the Global Rating of the patients' health (respiratory condition) on day 29. 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	Day 29
Pulse Rate Recorded in Conjunction With Spirometry	Pulse rate recorded in conjunction with spirometry change from baseline at 30 minutes post-dose on day 29 in beats per minute (bpm).	Baseline and 30 min post-dose on day 29
Systolic and Diastolic Blood Pressure Recorded in Conjunction With Spirometry	Systolic and diastolic blood pressure recorded in conjunction with spirometry change from baseline on day 29 in millimetres of mercury (mmHg).	Baseline and 30 min post-dose on day 29

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Aalbers R, Maleki-Yazdi MR, Hamilton A, Waitere-Wijker S, Zhao Y, Amatto VC, Schmidt O, Bjermer L. Randomized, Double-Blind, Dose-Finding Study for Tiotropium when Added to Olodaterol, Administered via the Respimat(R) Inhaler in Patients with Chronic Obstructive Pulmonary Disease. Adv Ther. 2015 Sep;32(9):809-22. doi: 10.1007/s12325-015-0239-8. Epub 2015 Sep 24.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: December 28, 2009
• First Submitted That Met QC Criteria: December 28, 2009
• First Posted (Estimate): December 29, 2009

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: June 19, 2015
• Last Verified: June 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: 1237.18; 2009-014880-38 (EudraCT Number: EudraCT)