Tiotropium Respimat Pharmacokinetic Study in COPD

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium medium
* Drug: Tiotropium low
* Drug: Tiotropium high
* Drug: Tiotropium 18mcg
* Drug: Tiotropium placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiotropium low<br>Tiotropium inhalation solution low dose | Drug: Tiotropium low<br>* Tiotropium inhalation solution low dose<br>|
| Experimental: Tiotropium medium<br>Tiotropium inhalation solution medium dose | Drug: Tiotropium medium<br>* Tiotropium inhalation solution medium dose<br>|
| Experimental: Tiotropium high<br>Tiotropium inhalation solution high dose | Drug: Tiotropium high<br>* Tiotropium inhalation solution high dose<br>|
| Active Comparator: Tiotropium 18mcg<br>Tiotropium inhalation powder 18mcg | Drug: Tiotropium 18mcg<br>* Tiotropium inhalation powder 18mcg<br>|
| Placebo Comparator: Tiotropium placebo<br>Placebo inhalation solution | Drug: Tiotropium placebo<br>* Placebo inhalation solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration at Steady-state (Cmax,ss) | Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state. | 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. | 
| 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. | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 4 weeks | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| Pre-dose Plasma Concentration at Steady-state (Cpre,ss) | Cpre,ss is the measured concentration of tiotropium in plasma before dosing at steady-state. | 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) | 
| 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. | Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing. | 
| Minimum Plasma Concentration at Steady-state (Cmin,ss) | Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state. | 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. |