Tiotropium Respimat Pharmacokinetic Study in COPD

• ClinicalTrials.gov Identifier: NCT01222533
• Recruitment Status: Completed
• First Posted: October 18, 2010
• Results First Posted: December 10, 2012
• Last Update Posted: May 16, 2014
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Tiotropium medium; Drug: Tiotropium low; Drug: Tiotropium high; Drug: Tiotropium 18mcg; Drug: Tiotropium placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 154 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double
• 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)
• Study Start Date: October 2010
• Actual Primary Completion Date: November 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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. ]
   Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state.
2. 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. ]
   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 :

1. Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   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.
2. FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   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.
3. FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   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. Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   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.
5. FVC AUC0-6h at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   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.
6. FVC AUC0-3h at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   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.
7. FEV1 at Each Planned Time at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.
8. FVC at Each Planned Time at the End of Each Treatment Period [ Time Frame: 4 weeks ]
   Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.
9. 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. ]
   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.
10. 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. ]
    Tmax,ss is the time from dosing to the maximum concentration of tiotropium in plasma-venous blood at steady-state.
11. 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. ]
    Total quantity of the analyte that is excreted in urine over the time interval 0 to 6 hours at steady state.
12. 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) ]
    Cpre,ss is the measured concentration of tiotropium in plasma before dosing at steady-state.
13. 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. ]
    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.
14. 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. ]
    Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state.

Other Outcome Measures:

1. Maximum Heart Rate (HR) [ Time Frame: 6.5 hours (including pre dose) ]
   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.
2. Mean Heart Rate (HR) [ Time Frame: 6.5 hours (including pre dose) ]
   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.
3. SVPB Total [ Time Frame: 6.5 hours (including pre dose) ]
   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.
4. SVPB Runs [ Time Frame: 6.5 hours (including pre dose) ]
   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.
5. SVPB Pairs [ Time Frame: 6.5 hours (including pre dose) ]
   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. SVPB Singles [ Time Frame: 6.5 hours (including pre dose) ]
   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.
7. VPB Total [ Time Frame: 6.5 hours (including pre dose) ]
   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.
8. VPB Runs [ Time Frame: 6.5 hours (including pre dose) ]
   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.
9. VPB Pairs [ Time Frame: 6.5 hours (including pre dose) ]
   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.
10. VPB Singles [ Time Frame: 6.5 hours (including pre dose) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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:

Related Info 

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hohlfeld JM, Furtwaengler A, Könen-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.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01222533
• Other Study ID Numbers: 205.458; 2009-016251-21 ( EudraCT Number: EudraCT )
• First Posted: October 18, 2010
• Results First Posted: December 10, 2012
• Last Update Posted: May 16, 2014
• Last Verified: August 2013

Additional relevant MeSH terms:

Lung Diseases; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases; Lung Diseases, Obstructive; Tiotropium Bromide; 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