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

This study has been completed.
Sponsor:
Information provided by:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01040403
First received: December 28, 2009
Last updated: June 19, 2015
Last verified: June 2015
  Purpose

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.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: olodaterol (BI 1744) low
Drug: low tiotropium bromide
Drug: olodaterol (BI 1744) high
Drug: medium tiotropium bromide
Drug: high tiotropium bromide
Drug: Placebo
Device: Respimat
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Trough FEV1 Response [ Time Frame: Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Trough Forced Vital Capacity (FVC) Response [ Time Frame: Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29 ] [ Designated as safety issue: No ]
    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.

  • FEV1 AUC 0-3h and FEV1 AUC 0-6h Response [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • FEV1 AUC 0-3h Response After the First Dose [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 ] [ Designated as safety issue: No ]
    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.

  • FEV1 Peak 0-3h Response [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29 ] [ Designated as safety issue: No ]
    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.

  • FEV1 Peak 0-3h Response After the First Dose [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 ] [ Designated as safety issue: No ]
    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.

  • FVC AUC 0-3h and FEV1 AUC 0-6h Responses [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • FVC AUC 0-3h Response After First Dose [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on days 1 ] [ Designated as safety issue: No ]
    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.

  • FVC Peak 0-3h Response [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29 ] [ Designated as safety issue: No ]
    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.

  • FVC Peak 0-3h Response After the First Dose [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 ] [ Designated as safety issue: No ]
    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.

  • PEF AUC 0-3h and AUC 0-6h Responses [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • PEF AUC 0-3h Response After the First Dose [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 ] [ Designated as safety issue: No ]
    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.

  • PEF Peak 0-3h Response [ Time Frame: Baseline 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29 ] [ Designated as safety issue: No ]
    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.

  • PEF Peak 0-3h Response After the First Dose [ Time Frame: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1 ] [ Designated as safety issue: No ]
    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.

  • Individual FEV1 Measurements at Each Time Point on Day 29 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Individual FVC Measurements at Each Time Point on Day 29 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Individual PEF Measurements at Each Time Point on Day 29 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Weekly Mean Number of Puffs of Rescue Medication Used Per Day [ Time Frame: Weeks 1 and 4 ] [ Designated as safety issue: No ]
    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).

  • Physicians Global Evaluation [ Time Frame: Days 1 and 29 ] [ Designated as safety issue: No ]

    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

  • Patients Global Rating [ Time Frame: Day 29 ] [ Designated as safety issue: No ]

    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

  • Pulse Rate Recorded in Conjunction With Spirometry [ Time Frame: Baseline and 30 min post-dose on day 29 ] [ Designated as safety issue: No ]
    Pulse rate recorded in conjunction with spirometry change from baseline at 30 minutes post-dose on day 29 in beats per minute (bpm).

  • Systolic and Diastolic Blood Pressure Recorded in Conjunction With Spirometry [ Time Frame: Baseline and 30 min post-dose on day 29 ] [ Designated as safety issue: No ]
    Systolic and diastolic blood pressure recorded in conjunction with spirometry change from baseline on day 29 in millimetres of mercury (mmHg).


Enrollment: 233
Study Start Date: January 2010
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: olodaterol (BI 1744) low and placebo
low dose inhaled olodaterol orally once daily from the Respimat inhaler
Drug: olodaterol (BI 1744) low
olodaterol (BI 1744) low
Drug: Placebo
Placebo
Device: Respimat
Respimat inhaler
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
Drug: olodaterol (BI 1744) low
olodaterol (BI 1744) low
Drug: low tiotropium bromide
low tiotropium bromide
Device: Respimat
Respimat inhaler
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
Drug: olodaterol (BI 1744) low
olodaterol (BI 1744) low
Drug: medium tiotropium bromide
medium tiotropium bromide
Device: Respimat
Respimat inhaler
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
Drug: olodaterol (BI 1744) low
olodaterol (BI 1744) low
Drug: high tiotropium bromide
high tiotropium bromide
Device: Respimat
Respimat inhaler
Experimental: olodaterol (BI 1744) high and placebo
high dose inhaled olodaterol orally once daily from the Respimat inhaler
Drug: olodaterol (BI 1744) high
olodaterol (BI 1744) high
Drug: Placebo
Placebo
Device: Respimat
Respimat inhaler
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
Drug: low tiotropium bromide
low tiotropium bromide
Drug: olodaterol (BI 1744) high
olodaterol (BI 1744) high
Device: Respimat
Respimat inhaler
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
Drug: olodaterol (BI 1744) high
olodaterol (BI 1744) high
Drug: medium tiotropium bromide
medium tiotropium bromide
Device: Respimat
Respimat inhaler
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
Drug: olodaterol (BI 1744) high
olodaterol (BI 1744) high
Drug: high tiotropium bromide
high tiotropium bromide
Device: Respimat
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
  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

  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: NCT01040403

Locations
Canada, British Columbia
1237.18.02004 Boehringer Ingelheim Investigational Site
Vancouver, British Columbia, Canada
Canada, Ontario
1237.18.02005 Boehringer Ingelheim Investigational Site
Grimsby, Ontario, Canada
1237.18.02001 Boehringer Ingelheim Investigational Site
Mississauga, Ontario, Canada
1237.18.02008 Boehringer Ingelheim Investigational Site
Toronto, Ontario, Canada
Canada, Quebec
1237.18.02002 Boehringer Ingelheim Investigational Site
Montreal, Quebec, Canada
1237.18.02003 Boehringer Ingelheim Investigational Site
Point Claire, Quebec, Canada
1237.18.02007 Boehringer Ingelheim Investigational Site
Sherbrooke, Quebec, Canada
Canada, Saskatchewan
1237.18.02011 Boehringer Ingelheim Investigational Site
Saskatoon, Saskatchewan, Canada
Canada
1237.18.02009 Boehringer Ingelheim Investigational Site
Quebec, Canada
Germany
1237.18.49009 Boehringer Ingelheim Investigational Site
Aschaffenburg, Germany
1237.18.49012 Boehringer Ingelheim Investigational Site
Bamberg, Germany
1237.18.49005 Boehringer Ingelheim Investigational Site
Berlin, Germany
1237.18.49004 Boehringer Ingelheim Investigational Site
Frankfurt, Germany
1237.18.49011 Boehringer Ingelheim Investigational Site
Hamburg, Germany
1237.18.49010 Boehringer Ingelheim Investigational Site
Koblenz, Germany
1237.18.49007 Boehringer Ingelheim Investigational Site
Mannheim, Germany
1237.18.49001 Boehringer Ingelheim Investigational Site
Potsdam, Germany
1237.18.49006 Boehringer Ingelheim Investigational Site
Rodgau-Dudenhofen, Germany
1237.18.49002 Boehringer Ingelheim Investigational Site
Rüdersdorf, Germany
1237.18.49003 Boehringer Ingelheim Investigational Site
Weinheim, Germany
1237.18.49008 Boehringer Ingelheim Investigational Site
Wiesloch, Germany
Netherlands
1237.18.31004 Boehringer Ingelheim Investigational Site
Almelo, Netherlands
1237.18.31006 Boehringer Ingelheim Investigational Site
Amsterdam, Netherlands
1237.18.31008 Boehringer Ingelheim Investigational Site
Eindhoven, Netherlands
1237.18.31001 Boehringer Ingelheim Investigational Site
Groningen, Netherlands
1237.18.31007 Boehringer Ingelheim Investigational Site
Hengelo, Netherlands
1237.18.31005 Boehringer Ingelheim Investigational Site
Hoorn, Netherlands
1237.18.31002 Boehringer Ingelheim Investigational Site
Veldhoven, Netherlands
1237.18.31003 Boehringer Ingelheim Investigational Site
Zutphen, Netherlands
Sweden
1237.18.46003 Boehringer Ingelheim Investigational Site
Boden, Sweden
1237.18.46002 Boehringer Ingelheim Investigational Site
Göteborg, Sweden
1237.18.46001 Boehringer Ingelheim Investigational Site
Lund, Sweden
1237.18.46004 Boehringer Ingelheim Investigational Site
Stockholm, Sweden
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01040403     History of Changes
Other Study ID Numbers: 1237.18, 2009-014880-38
Study First Received: December 28, 2009
Results First Received: June 19, 2015
Last Updated: June 19, 2015
Health Authority: Canada: Health Canada
Germany: Federal Institute for Drugs and Medical Devices
Netherlands: Central Committee Research Involving Human Subjects
Sweden: Medical Products Agency

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 September 02, 2015