Tiotropium Respimat Pharmacokinetic Study in COPD

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)

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Tiotropium low; Drug: Tiotropium medium; Drug: Tiotropium high; Drug: Tiotropium 18mcg; Drug: Tiotropium placebo

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Genk, Belgium
    • 205.458.32003 Boehringer Ingelheim Investigational Site
  • Gent, Belgium
    • 205.458.32001 Boehringer Ingelheim Investigational Site
  • Hasselt, Belgium
    • 205.458.32002 Boehringer Ingelheim Investigational Site
• Denmark
  • Copenhagen K, Denmark
    • 205.458.45001 Boehringer Ingelheim Investigational Site
  • København NV, Denmark
    • 205.458.45003 Boehringer Ingelheim Investigational Site
  • Odense C, Denmark
    • 205.458.45002 Boehringer Ingelheim Investigational Site
• Finland
  • Helsinki, Finland
    • 205.458.35801 Boehringer Ingelheim Investigational Site
  • Tampere, Finland
    • 205.458.35802 Boehringer Ingelheim Investigational Site
• Germany
  • Hannover, Germany
    • 205.458.49001 Boehringer Ingelheim Investigational Site
• Netherlands
  • Heerlen, Netherlands
    • 205.458.31001 Atrium Medisch Centrum Parkstad
  • Winschoten, Netherlands
    • 205.458.31002 Ommelander ziekenhuis groep, locatie Lucas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: October 15, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (Estimate): October 18, 2010

Study Record Updates

• Last Update Posted (Estimate): May 16, 2014
• Last Update Submitted That Met QC Criteria: May 7, 2014
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide
• Other Study ID Numbers: 205.458; 2009-016251-21 (EudraCT Number: EudraCT)