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| ID | Type | Description | Link |
|---|---|---|---|
| 2009-016251-21 | EudraCT Number | EudraCT |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tiotropium low | Experimental | Tiotropium inhalation solution low dose |
|
| Tiotropium medium | Experimental | Tiotropium inhalation solution medium dose |
|
| Tiotropium high | Experimental | Tiotropium inhalation solution high dose |
|
| Tiotropium 18mcg | Active Comparator | Tiotropium inhalation powder 18mcg |
|
| Tiotropium placebo | Placebo Comparator | Placebo inhalation solution |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tiotropium medium | Drug | Tiotropium inhalation solution medium dose |
| |
| 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. |
| 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 |
| 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) |
Inclusion criteria:
Exclusion criteria:
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)
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| Name | Affiliation | Role |
|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| 205.458.32003 Boehringer Ingelheim Investigational Site | Genk | Belgium | ||||
| 205.458.32001 Boehringer Ingelheim Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25496316 | Derived | 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. | |
| 24165906 | Derived |
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| ID | Title | Description |
|---|---|---|
| FG000 | Study Overall | Total number of patients randomised and treated in the study. This was a randomised 5-period crossover trial. 154 patients were randomised to one of 15 sequences and treated. The trial was blinded within the 4 Respimat treatments, but open for the HandiHaler treatment. Each of the 5 treatment regimens was taken for 4 weeks without washouts between treatment periods. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Study Overall | Total number of patients randomised and treated in the study. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Plasma Concentration at Steady-state (Cmax,ss) | Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state. | Pharmacokinetic (PK) Set. This analysis set includes all patients in the treated set who had at least one blood sample drawn or one urine sample collected for PK analysis. Patients with an important protocol violation relevant to the PK population were excluded. No PK data for placebo. All patients with analysable data. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/ml | 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. |
|
4 weeks + 30 days if in last period
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Matching Placebo once daily (qd) delivered by the Respimat inhaler |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Colitis ischaemic | Gastrointestinal disorders | MEDDRA 15.0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | MEDDRA 15.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim Call Center | Boehringer Ingelheim Pharmaceuticals | 1-800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| ID | Term |
|---|---|
| D000069447 | Tiotropium Bromide |
| ID | Term |
|---|---|
| D012602 | Scopolamine Derivatives |
| D014326 | Tropanes |
| D053961 | Azabicyclo Compounds |
| D001372 | Aza Compounds |
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| Tiotropium low |
| Drug |
Tiotropium inhalation solution low dose |
|
| Tiotropium high | Drug | Tiotropium inhalation solution high dose |
|
| Tiotropium 18mcg | Drug | Tiotropium inhalation powder 18mcg |
|
| Tiotropium placebo | Drug | Placebo inhalation solution |
|
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. |
| 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) |
| Ghent |
| Belgium |
| 205.458.32002 Boehringer Ingelheim Investigational Site | Hasselt | Belgium |
| 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 |
| 205.458.35801 Boehringer Ingelheim Investigational Site | Helsinki | Finland |
| 205.458.35802 Boehringer Ingelheim Investigational Site | Tampere | Finland |
| 205.458.49001 Boehringer Ingelheim Investigational Site | Hanover | Germany |
| 205.458.31001 Atrium Medisch Centrum Parkstad | Heerlen | Netherlands |
| 205.458.31002 Ommelander ziekenhuis groep, locatie Lucas | Winschoten | Netherlands |
| 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. |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | Tio R1.25 | Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning |
| OG002 | Tio R2.5 | Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning |
| OG003 | Tio R5 | Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning |
| OG004 | Tio HH18 | Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning |
|
|
|
| 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. | PK Set. No PK data for Placebo. The low number of non-missing AUC0-6h,ss results for the Tio R 1.25 and Tio R 2.5 cohorts is due to the exclusion of results below the limit of quantification. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/ml | 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 | 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. | Full analysis set (FAS) with imputed data. FAS includes all patients in the treated set who have analysable data for at least one efficacy endpoint during the relevant crossover period. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
|
| 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. | FAS with imputed data. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
|
| 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. | FAS with imputed data. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
|
| 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. | FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
|
| 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. | FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
|
| 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. | FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
|
| 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. | FAS with imputed data. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
| 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. | FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period. | Posted | Mean | Standard Error | Liter | 4 weeks |
|
|
|
| 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. | PK Set. All patients with analysable data. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | 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 | 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. | PK Set. All patients with analysable data. | Posted | Median | Full Range | hours | 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. |
|
|
|
| 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. | PK Set. All patients with analysable data. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng | 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. |
|
|
|
| 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. | PK Set. All patients with analysable data. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | 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) |
|
|
|
| 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. | PK Set. All patients with analysable data. | Posted | Geometric Mean | Geometric Coefficient of Variation | mL/min | Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing. |
|
|
|
| Secondary | Minimum Plasma Concentration at Steady-state (Cmin,ss) | Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state. | PK Set. All patients with analysable data. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | 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 | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded). | Posted | Mean | Standard Deviation | bpm | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Mean | Standard Deviation | bpm | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| Other Pre-specified | 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. | ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded) | Posted | Number | participants | 6.5 hours (including pre dose) |
|
|
|
| 3 |
| 147 |
| 20 |
| 147 |
| EG001 | Tio R1.25 | Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning | 2 | 147 | 11 | 147 |
| EG002 | Tio R2.5 | Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning | 0 | 145 | 4 | 145 |
| EG003 | Tio R5 | Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning | 3 | 150 | 16 | 150 |
| EG004 | Tio HH18 | Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning | 2 | 146 | 10 | 146 |
| Haemorrhoidal haemorrhage | Gastrointestinal disorders | MEDDRA 15.0 |
|
| Pancreatitis | Gastrointestinal disorders | MEDDRA 15.0 |
|
| Infective exacerbation of chronic obstructive airways disease | Infections and infestations | MEDDRA 15.0 |
|
| Pneumonia | Infections and infestations | MEDDRA 15.0 |
|
| Tendon rupture | Injury, poisoning and procedural complications | MEDDRA 15.0 |
|
| Spinal column stenosis | Musculoskeletal and connective tissue disorders | MEDDRA 15.0 |
|
| Prostate cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MEDDRA 15.0 |
|
| Cerebrovascular accident | Nervous system disorders | MEDDRA 15.0 |
|
| Azotaemia | Renal and urinary disorders | MEDDRA 15.0 |
|
| Renal tubular necrosis | Renal and urinary disorders | MEDDRA 15.0 |
|
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MEDDRA 15.0 |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MEDDRA 15.0 | Systematic Assessment |
|
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication
| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009930 |
| Organic Chemicals |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D019086 | Bridged Bicyclo Compounds, Heterocyclic |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
Adjusted for sequence, patients within sequences, period and treatment.
| <0.0001 |
| Mean Difference (Final Values) |
| 0.101 |
| Standard Error of the Mean |
| 0.014 |
| 95 |
| 0.074 |
| 0.128 |
Tio R2.5-Placebo |
| No |
| Superiority or Other |
| ANOVA | Adjusted for sequence, patients within sequences, period and treatment. | <0.0001 | Mean Difference (Final Values) | 0.121 | Standard Error of the Mean | 0.014 | 95 | 0.094 | 0.148 | Tio R5-Placebo | No | Superiority or Other |
Adjusted for sequence, patients within sequences, period and treatment.
| <0.0001 |
| Mean Difference (Final Values) |
| 0.185 |
| Standard Error of the Mean |
| 0.012 |
| 95 |
| 0.161 |
| 0.209 |
Tio R2.5-Placebo |
| No |
| Superiority or Other |
| ANOVA | Adjusted for sequence, patients within sequences, period and treatment. | <0.0001 | Mean Difference (Final Values) | 0.191 | Standard Error of the Mean | 0.012 | 95 | 0.167 | 0.216 | Tio R5-Placebo | No | Superiority or Other |
Adjusted for sequence, patients within sequences, period and treatment.
| <0.0001 |
| Mean Difference (Final Values) |
| 0.180 |
| Standard Error of the Mean |
| 0.013 |
| 95 |
| 0.155 |
| 0.205 |
Tio R2.5-Placebo |
| No |
| Superiority or Other |
| ANOVA | Adjusted for sequence, patients within sequences, period and treatment. | <0.0001 | Mean Difference (Final Values) | 0.187 | Standard Error of the Mean | 0.013 | 95 | 0.162 | 0.211 | Tio R5-Placebo | No | Superiority or Other |
Adjusted for sequence, patients within sequences, period and treatment.
| <0.0001 |
| Mean Difference (Final Values) |
| 0.188 |
| Standard Error of the Mean |
| 0.028 |
| 95 |
| 0.133 |
| 0.244 |
Tio R2.5-Placebo |
| No |
| Superiority or Other |
| ANOVA | Adjusted for sequence, patients within sequences, period and treatment. | <0.0001 | Mean Difference (Final Values) | 0.236 | Standard Error of the Mean | 0.028 | 95 | 0.180 | 0.292 | Tio R5-Placebo | No | Superiority or Other |
Adjusted for sequence, patients within sequences, period and treatment.
| <0.0001 |
| Mean Difference (Final Values) |
| 0.319 |
| Standard Error of the Mean |
| 0.022 |
| 95 |
| 0.276 |
| 0.362 |
Tio R2.5-Placebo |
| No |
| Superiority or Other |
| ANOVA | Adjusted for sequence, patients within sequences, period and treatment. | <0.0001 | Mean Difference (Final Values) | 0.335 | Standard Error of the Mean | 0.022 | 95 | 0.292 | 0.378 | Tio R5-Placebo | No | Superiority or Other |
Adjusted for sequence, patients within sequences, period and treatment.
| <0.0001 |
| Mean Difference (Final Values) |
| 0.324 |
| Standard Error of the Mean |
| 0.023 |
| 95 |
| 0.279 |
| 0.369 |
Tio R2.5-Placebo |
| No |
| Superiority or Other |
| ANOVA | Adjusted for sequence, patients within sequences, period and treatment. | <0.0001 | Mean Difference (Final Values) | 0.339 | Standard Error of the Mean | 0.023 | 95 | 0.294 | 0.384 | Tio R5-Placebo | No | Superiority or Other |
| Timepoint 0:30 |
|
| Timepoint 1:00 |
|
| Timepoint 2:00 |
|
| Timepoint 3:00 |
|
| Timepoint 4:00 |
|
| Timepoint 5:00 |
|
| Timepoint 6:00 |
|
| Timepoint 0:30 |
|
| Timepoint 1:00 |
|
| Timepoint 2:00 |
|
| Timepoint 3:00 |
|
| Timepoint 4:00 |
|
| Timepoint 5:00 |
|
| Timepoint 6:00 |
|
| Day 29 1st h(N=114,113,115,115,111) |
|
| Day 26 6.5 h(N=115,110,113,110,112) |
|
| Day 26 1st h(N=115,109,113,107,109) |
|
| Day 29 1st h(N=114,113,115,115,111) |
|
| Day 26 6.5 h(N=115,110,113,110,112) |
|
| Day 26 1st h(N=115,109,113,107,109) |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|
| Day 29 1st h |
|
| Day 26 6.5 h |
|
| Day 26 1st h |
|