Tiotropium Respimat Pharmacokinetic Study in COPD

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01222533
First received: October 15, 2010
Last updated: May 7, 2014
Last verified: August 2013
  Purpose

The purpose of this study is compare the effect of different doses of tiotropium delivered by the HandiHaler and Respimat device on lung function. Additionally, the study will investigate the pharmacokinetic profile of these different doses. Studying the pharmacokinetic profile shows what happens to the medication in the body over a period of hours and provides information on potential effects of the medication.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: Tiotropium medium
Drug: Tiotropium low
Drug: Tiotropium high
Drug: Tiotropium 18mcg
Drug: Tiotropium placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Multicenter, Randomised, Placebo- and Active-controlled, 5 Way, Crossover Trial to Characterise the Pharmacokinetics and Evaluate the Bronchodilator Efficacy and Safety of Once-daily Tiotropium Delivered (Double-blind) From the Respimat Inhaler as Solution for Inhalation (1.25, 2.5, 5 mcg or Placebo) and as Inhalation Powder (18mcg) From the HandiHaler (Open Label) After 4 Week-treatment Periods in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Maximum Plasma Concentration at Steady-state (Cmax,ss) [ Time Frame: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing. ] [ Designated as safety issue: No ]
    Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state.

  • Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss) [ Time Frame: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing. ] [ Designated as safety issue: No ]
    AUC0-6h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 6 hours post-dose at steady-state. AUC0-6h,ss was calculated using the linear up/log down algorithm.


Secondary Outcome Measures:
  • Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Defined as FEV1 measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment.

  • FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    FEV1 AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

  • FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    FEV1 AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

  • Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Defined as the pre-dose FVC measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment.

  • FVC AUC0-6h at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    FVC AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

  • FVC AUC0-3h at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    FVC AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

  • FEV1 at Each Planned Time at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.

  • FVC at Each Planned Time at the End of Each Treatment Period [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.

  • Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss) [ Time Frame: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing. ] [ Designated as safety issue: No ]
    AUC0-1h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 1 hour post-dose at steady-state. AUC0-1h,ss was calculated using the linear up/log down algorithm.

  • Time to Maximum Plasma Concentration at Steady-state (Tmax,ss) [ Time Frame: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing. ] [ Designated as safety issue: No ]
    Tmax,ss is the time from dosing to the maximum concentration of tiotropium in plasma-venous blood at steady-state.

  • Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss) [ Time Frame: Based on urine sampling for PK assessments done at 4 weeks in the following intervals: -1 to 0 hour (h), 0 to 2 h and 2 to 6 h post-dosing. ] [ Designated as safety issue: No ]
    Total quantity of the analyte that is excreted in urine over the time interval 0 to 6 hours at steady state.

  • Pre-dose Plasma Concentration at Steady-state (Cpre,ss) [ Time Frame: Based on blood sampling for PK assessments done at 4 weeks at the following time point: 5 minutes (min) before first dosing of study drug (baseline) ] [ Designated as safety issue: No ]
    Cpre,ss is the measured concentration of tiotropium in plasma before dosing at steady-state.

  • Renal Clearance at Steady-state (CL R,0-6h,ss) [ Time Frame: Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing. ] [ Designated as safety issue: No ]
    Renal clearance of the drug over the time interval 0 to 6 hours at steady-state. CL R,0-6h,ss was calculated as the quotient of Ae0-6h,ss and AUC0-6h,ss.

  • Minimum Plasma Concentration at Steady-state (Cmin,ss) [ Time Frame: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing. ] [ Designated as safety issue: No ]
    Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state.


Other Outcome Measures:
  • Maximum Heart Rate (HR) [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    Maximum HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • Mean Heart Rate (HR) [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    Mean HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • SVPB Total [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • SVPB Runs [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • SVPB Pairs [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • SVPB Singles [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • VPB Total [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • VPB Runs [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • VPB Pairs [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

  • VPB Singles [ Time Frame: 6.5 hours (including pre dose) ] [ Designated as safety issue: No ]
    The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.


Enrollment: 154
Study Start Date: October 2010
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tiotropium low
Tiotropium inhalation solution low dose
Drug: Tiotropium low
Tiotropium inhalation solution low dose
Experimental: Tiotropium medium
Tiotropium inhalation solution medium dose
Drug: Tiotropium medium
Tiotropium inhalation solution medium dose
Experimental: Tiotropium high
Tiotropium inhalation solution high dose
Drug: Tiotropium high
Tiotropium inhalation solution high dose
Active Comparator: Tiotropium 18mcg
Tiotropium inhalation powder 18mcg
Drug: Tiotropium 18mcg
Tiotropium inhalation powder 18mcg
Placebo Comparator: Tiotropium placebo
Placebo inhalation solution
Drug: Tiotropium placebo
Placebo inhalation solution

  Eligibility

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

Inclusion criteria:

  1. All patient must sign an informed consent consistent with IInternational Conference on Harmonisation- Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to any study-related procedures, including medication washout and restrictions.
  2. Relatively stable, moderate to very severe Chronic Obstructive Pulmonary Disease (COPD)
  3. Current or ex-smokers (smoking history of at least 10 pack years)
  4. Able to perform lung function tests
  5. Able to use study inhalers

Exclusion criteria:

  1. Significant diseases other than COPD
  2. Recent myocardial infarction, unstable or life-threatening cardiac arrhythmia, hospitalisation for cardiac failure.
  3. Malignancy requiring resection, radiation therapy or chemotherapy within the last 5 years
  4. History of asthma, life-threatening pulmonary obstruction, cystic fibrosis or clinically evident bronchiectasis 5 Active tuberculosis

6. History of alcohol or drug abuse 7. Pulmonary resection 8. Recent completion of a pulmonary rehabilitation program or current participation which will not be continued 9. Daytime oxygen therapy for more than 1 hour per day. 10. Use of other investigational drugs, restrictions on the use of some respiratory medications during the study period.

11. Current participation in another clinical trial 12. Pregnant or nursing women 13. Women of childbearing potential not using a highly effective method of contraception (e.g: implants, injectable, oral contraceptives)

  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: NCT01222533

Locations
Belgium
205.458.32003 Boehringer Ingelheim Investigational Site
Genk, Belgium
205.458.32001 Boehringer Ingelheim Investigational Site
Gent, Belgium
205.458.32002 Boehringer Ingelheim Investigational Site
Hasselt, Belgium
Denmark
205.458.45001 Boehringer Ingelheim Investigational Site
Copenhagen K, Denmark
205.458.45003 Boehringer Ingelheim Investigational Site
København NV, Denmark
205.458.45002 Boehringer Ingelheim Investigational Site
Odense C, Denmark
Finland
205.458.35801 Boehringer Ingelheim Investigational Site
Helsinki, Finland
205.458.35802 Boehringer Ingelheim Investigational Site
Tampere, Finland
Germany
205.458.49001 Boehringer Ingelheim Investigational Site
Hannover, Germany
Netherlands
205.458.31001 Atrium Medisch Centrum Parkstad
Heerlen, Netherlands
205.458.31002 Ommelander ziekenhuis groep, locatie Lucas
Winschoten, Netherlands
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: NCT01222533     History of Changes
Other Study ID Numbers: 205.458, 2009-016251-21
Study First Received: October 15, 2010
Results First Received: November 13, 2012
Last Updated: May 7, 2014
Health Authority: Belgium: Federal Agency for Medicinal and Health Products
Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
Netherlands: Central Committee Research Involving Human Subjects

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

ClinicalTrials.gov processed this record on September 30, 2014