Back to resultsTiotropium Respimat Pharmacokinetic Study in COPD
Primary Purpose
Pulmonary Disease, Chronic Obstructive
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tiotropium medium
Tiotropium low
Tiotropium high
Tiotropium 18mcg
Tiotropium placebo
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive
Eligibility Criteria
Inclusion criteria:
- 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.
- Relatively stable, moderate to very severe Chronic Obstructive Pulmonary Disease (COPD)
- Current or ex-smokers (smoking history of at least 10 pack years)
- Able to perform lung function tests
- Able to use study inhalers
Exclusion criteria:
- Significant diseases other than COPD
- Recent myocardial infarction, unstable or life-threatening cardiac arrhythmia, hospitalisation for cardiac failure.
- Malignancy requiring resection, radiation therapy or chemotherapy within the last 5 years
- 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)
Sites / Locations
- 205.458.32003 Boehringer Ingelheim Investigational Site
- 205.458.32001 Boehringer Ingelheim Investigational Site
- 205.458.32002 Boehringer Ingelheim Investigational Site
- 205.458.45001 Boehringer Ingelheim Investigational Site
- 205.458.45003 Boehringer Ingelheim Investigational Site
- 205.458.45002 Boehringer Ingelheim Investigational Site
- 205.458.35801 Boehringer Ingelheim Investigational Site
- 205.458.35802 Boehringer Ingelheim Investigational Site
- 205.458.49001 Boehringer Ingelheim Investigational Site
- 205.458.31001 Atrium Medisch Centrum Parkstad
- 205.458.31002 Ommelander ziekenhuis groep, locatie Lucas
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Active Comparator
Placebo Comparator
Arm Label
Tiotropium low
Tiotropium medium
Tiotropium high
Tiotropium 18mcg
Tiotropium placebo
Arm Description
Tiotropium inhalation solution low dose
Tiotropium inhalation solution medium dose
Tiotropium inhalation solution high dose
Tiotropium inhalation powder 18mcg
Placebo inhalation solution
Outcomes
Primary Outcome Measures
Maximum Plasma Concentration at Steady-state (Cmax,ss)
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)
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
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
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
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
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
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
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
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
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)
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)
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)
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)
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)
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)
Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01222533
Brief Title
Tiotropium Respimat Pharmacokinetic Study in COPD
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)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2013
Overall Recruitment Status
Completed
Study Start Date
October 2010 (undefined)
Primary Completion Date
November 2011 (Actual)
Study Completion Date
undefined (undefined)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim
4. Oversight
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Disease, Chronic Obstructive
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
Double
Allocation
Randomized
Enrollment
154 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tiotropium low
Arm Type
Experimental
Arm Description
Tiotropium inhalation solution low dose
Arm Title
Tiotropium medium
Arm Type
Experimental
Arm Description
Tiotropium inhalation solution medium dose
Arm Title
Tiotropium high
Arm Type
Experimental
Arm Description
Tiotropium inhalation solution high dose
Arm Title
Tiotropium 18mcg
Arm Type
Active Comparator
Arm Description
Tiotropium inhalation powder 18mcg
Arm Title
Tiotropium placebo
Arm Type
Placebo Comparator
Arm Description
Placebo inhalation solution
Intervention Type
Drug
Intervention Name(s)
Tiotropium medium
Intervention Description
Tiotropium inhalation solution medium dose
Intervention Type
Drug
Intervention Name(s)
Tiotropium low
Intervention Description
Tiotropium inhalation solution low dose
Intervention Type
Drug
Intervention Name(s)
Tiotropium high
Intervention Description
Tiotropium inhalation solution high dose
Intervention Type
Drug
Intervention Name(s)
Tiotropium 18mcg
Intervention Description
Tiotropium inhalation powder 18mcg
Intervention Type
Drug
Intervention Name(s)
Tiotropium placebo
Intervention Description
Placebo inhalation solution
Primary Outcome Measure Information:
Title
Maximum Plasma Concentration at Steady-state (Cmax,ss)
Description
Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state.
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.
Title
Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss)
Description
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.
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.
Secondary Outcome Measure Information:
Title
Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period
Description
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.
Time Frame
4 weeks
Title
FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period
Description
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.
Time Frame
4 weeks
Title
FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period
Description
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.
Time Frame
4 weeks
Title
Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period
Description
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.
Time Frame
4 weeks
Title
FVC AUC0-6h at the End of Each Treatment Period
Description
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.
Time Frame
4 weeks
Title
FVC AUC0-3h at the End of Each Treatment Period
Description
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.
Time Frame
4 weeks
Title
FEV1 at Each Planned Time at the End of Each Treatment Period
Description
Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.
Time Frame
4 weeks
Title
FVC at Each Planned Time at the End of Each Treatment Period
Description
Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.
Time Frame
4 weeks
Title
Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss)
Description
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 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.
Title
Time to Maximum Plasma Concentration at Steady-state (Tmax,ss)
Description
Tmax,ss is the time from dosing to the maximum concentration of tiotropium in plasma-venous blood at steady-state.
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.
Title
Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss)
Description
Total quantity of the analyte that is excreted in urine over the time interval 0 to 6 hours at steady state.
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.
Title
Pre-dose Plasma Concentration at Steady-state (Cpre,ss)
Description
Cpre,ss is the measured concentration of tiotropium in plasma before dosing at steady-state.
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)
Title
Renal Clearance at Steady-state (CL R,0-6h,ss)
Description
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.
Time Frame
Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing.
Title
Minimum Plasma Concentration at Steady-state (Cmin,ss)
Description
Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state.
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.
Other Pre-specified Outcome Measures:
Title
Maximum Heart Rate (HR)
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
Mean Heart Rate (HR)
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
SVPB Total
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
SVPB Runs
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
SVPB Pairs
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
SVPB Singles
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
VPB Total
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
VPB Runs
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
VPB Pairs
Description
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.
Time Frame
6.5 hours (including pre dose)
Title
VPB Singles
Description
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.
Time Frame
6.5 hours (including pre dose)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria:
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.
Relatively stable, moderate to very severe Chronic Obstructive Pulmonary Disease (COPD)
Current or ex-smokers (smoking history of at least 10 pack years)
Able to perform lung function tests
Able to use study inhalers
Exclusion criteria:
Significant diseases other than COPD
Recent myocardial infarction, unstable or life-threatening cardiac arrhythmia, hospitalisation for cardiac failure.
Malignancy requiring resection, radiation therapy or chemotherapy within the last 5 years
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boehringer Ingelheim
Organizational Affiliation
Boehringer Ingelheim
Official's Role
Study Chair
Facility Information:
Facility Name
205.458.32003 Boehringer Ingelheim Investigational Site
City
Genk
Country
Belgium
Facility Name
205.458.32001 Boehringer Ingelheim Investigational Site
City
Gent
Country
Belgium
Facility Name
205.458.32002 Boehringer Ingelheim Investigational Site
City
Hasselt
Country
Belgium
Facility Name
205.458.45001 Boehringer Ingelheim Investigational Site
City
Copenhagen K
Country
Denmark
Facility Name
205.458.45003 Boehringer Ingelheim Investigational Site
City
København NV
Country
Denmark
Facility Name
205.458.45002 Boehringer Ingelheim Investigational Site
City
Odense C
Country
Denmark
Facility Name
205.458.35801 Boehringer Ingelheim Investigational Site
City
Helsinki
Country
Finland
Facility Name
205.458.35802 Boehringer Ingelheim Investigational Site
City
Tampere
Country
Finland
Facility Name
205.458.49001 Boehringer Ingelheim Investigational Site
City
Hannover
Country
Germany
Facility Name
205.458.31001 Atrium Medisch Centrum Parkstad
City
Heerlen
Country
Netherlands
Facility Name
205.458.31002 Ommelander ziekenhuis groep, locatie Lucas
City
Winschoten
Country
Netherlands
12. IPD Sharing Statement
Citations:
PubMed Identifier
25496316
Citation
Hohlfeld JM, Furtwaengler A, Konen-Bergmann M, Wallenstein G, Walter B, Bateman ED. Cardiac safety of tiotropium in patients with COPD: a combined analysis of Holter-ECG data from four randomised clinical trials. Int J Clin Pract. 2015 Jan;69(1):72-80. doi: 10.1111/ijcp.12596. Epub 2014 Dec 11.
Results Reference
derived
PubMed Identifier
24165906
Citation
Hohlfeld JM, Sharma A, van Noord JA, Cornelissen PJ, Derom E, Towse L, Peterkin V, Disse B. Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. J Clin Pharmacol. 2014 Apr;54(4):405-14. doi: 10.1002/jcph.215. Epub 2013 Nov 27.
Results Reference
derived
Links:
URL
http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.458_U13-1531-01-DS.pdf
Description
Related Info
URL
http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.458_Literature.pdf
Description
Related Info
Learn more about this trial
Tiotropium Respimat Pharmacokinetic Study in COPD
We'll reach out to this number within 24 hrs