Tiotropium Respimat Pharmacokinetic Study in COPD

Pulmonary Disease, Chronic Obstructive Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01222533
• Other study ID #: 205.458
• Secondary ID: 2009-016251-21
• Status: Completed
• Phase: Phase 2
• First received: October 15, 2010
• Last updated: May 7, 2014
• Start date: October 2010

Study information

• Verified date: August 2013
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal and Health ProductsDenmark: Danish Medicines AgencyFinland: Finnish Medicines AgencyGermany: Federal Institute for Drugs and Medical DevicesNetherlands: Central Committee Research Involving Human Subjects
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 154
• Est. primary completion date: November 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Tiotropium medium
Tiotropium inhalation solution medium dose
• Tiotropium low
Tiotropium inhalation solution low dose
• Tiotropium high
Tiotropium inhalation solution high dose
• Tiotropium 18mcg
Tiotropium inhalation powder 18mcg
• Tiotropium placebo
Placebo inhalation solution

Locations

Country	Name	City	State
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
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
Finland	205.458.35801 Boehringer Ingelheim Investigational Site	Helsinki
Finland	205.458.35802 Boehringer Ingelheim Investigational Site	Tampere
Germany	205.458.49001 Boehringer Ingelheim Investigational Site	Hannover
Netherlands	205.458.31001 Atrium Medisch Centrum Parkstad	Heerlen
Netherlands	205.458.31002 Ommelander ziekenhuis groep, locatie Lucas	Winschoten

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

Belgium,  Denmark,  Finland,  Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Maximum Heart Rate (HR)	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.	6.5 hours (including pre dose)	No
Other	Mean Heart Rate (HR)	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.	6.5 hours (including pre dose)	No
Other	SVPB Total	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.	6.5 hours (including pre dose)	No
Other	SVPB Runs	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.	6.5 hours (including pre dose)	No
Other	SVPB Pairs	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.	6.5 hours (including pre dose)	No
Other	SVPB Singles	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.	6.5 hours (including pre dose)	No
Other	VPB Total	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.	6.5 hours (including pre dose)	No
Other	VPB Runs	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.	6.5 hours (including pre dose)	No
Other	VPB Pairs	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.	6.5 hours (including pre dose)	No
Other	VPB Singles	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.	6.5 hours (including pre dose)	No
Primary	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.	No
Primary	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.	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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)	No
Secondary	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.	No
Secondary	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.	No

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