Pulmonary Disease, Chronic Obstructive
Conditions
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.
Interventions
DRUGTiotropium medium
Tiotropium inhalation solution medium dose
DRUGTiotropium low
Tiotropium inhalation solution low dose
DRUGTiotropium high
Tiotropium inhalation solution high dose
DRUGTiotropium 18mcg
Tiotropium inhalation powder 18mcg
Placebo inhalation solution
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration at Steady-state (Cmax,ss) | 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. |
| Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss) | 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
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period | 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. |
| Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period | 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. |
| FVC AUC0-6h at the End of Each Treatment Period | 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. |
| FVC AUC0-3h at the End of Each Treatment Period | 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. |
| FEV1 at Each Planned Time at the End of Each Treatment Period | 4 weeks | Means are adjusted for period, planned time, period\*planned time, patient\*planned time and patient\*treatment\*planned time. |
| FVC at Each Planned Time at the End of Each Treatment Period | 4 weeks | Means are adjusted for period, planned time, period\*planned time, patient\*planned time and patient\*treatment\*planned time. |
| Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss) | 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. |
| Time to Maximum Plasma Concentration at Steady-state (Tmax,ss) | 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. |
| Pre-dose Plasma Concentration at Steady-state (Cpre,ss) | 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. |
| Renal Clearance at Steady-state (CL R,0-6h,ss) | 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. |
| Minimum Plasma Concentration at Steady-state (Cmin,ss) | 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. |
| Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss) | 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. |
| Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period | 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. |
| FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| SVPB Runs | 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. |
| SVPB Pairs | 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. |
| SVPB Singles | 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. |
| VPB Total | 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. |
| VPB Runs | 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. |
| VPB Pairs | 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. |
| VPB Singles | 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. |
| Maximum Heart Rate (HR) | 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. |
| SVPB Total | 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. |
| Mean Heart Rate (HR) | 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. |
Countries
Belgium, Denmark, Finland, Germany, Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Overall Total number of patients randomised and treated in the study. | 154 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Other | 4 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Study Overall |
|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 7.8 |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 147 | 11 / 147 | 4 / 145 | 16 / 150 | 10 / 146 |
| serious Total, serious adverse events | 3 / 147 | 2 / 147 | 0 / 145 | 3 / 150 | 2 / 146 |
Outcome results
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.
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.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tio R1.25 | Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss) | 10.0 pg*h/ml | Geometric Coefficient of Variation 25.3 |
| Tio R2.5 | Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss) | 12.8 pg*h/ml | Geometric Coefficient of Variation 29.9 |
| Tio R5 | Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss) | 22.1 pg*h/ml | Geometric Coefficient of Variation 47.8 |
| Tio HH18 | Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss) | 28.4 pg*h/ml | Geometric Coefficient of Variation 52.4 |
p-value: 0.868390% CI: [70.44, 81.98]ANOVA
Primary
Maximum Plasma Concentration at Steady-state (Cmax,ss)
Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state.
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.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tio R1.25 | Maximum Plasma Concentration at Steady-state (Cmax,ss) | 2.81 pg/ml | Geometric Coefficient of Variation 53 |
| Tio R2.5 | Maximum Plasma Concentration at Steady-state (Cmax,ss) | 5.07 pg/ml | Geometric Coefficient of Variation 61.8 |
| Tio R5 | Maximum Plasma Concentration at Steady-state (Cmax,ss) | 10.5 pg/ml | Geometric Coefficient of Variation 66.4 |
| Tio HH18 | Maximum Plasma Concentration at Steady-state (Cmax,ss) | 12.9 pg/ml | Geometric Coefficient of Variation 64.6 |
p-value: 0.442390% CI: [73.49, 88.52]ANOVA
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.
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.
Population: PK Set. All patients with analysable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tio R1.25 | Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss) | 88.7 ng | Geometric Coefficient of Variation 68 |
| Tio R2.5 | Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss) | 177 ng | Geometric Coefficient of Variation 68 |
| Tio R5 | Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss) | 387 ng | Geometric Coefficient of Variation 65.9 |
| Tio HH18 | Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss) | 522 ng | Geometric Coefficient of Variation 53.8 |
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.
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.
Population: PK Set. All patients with analysable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tio R1.25 | Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss) | 2.08 pg*h/mL | Geometric Coefficient of Variation 32.3 |
| Tio R2.5 | Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss) | 3.16 pg*h/mL | Geometric Coefficient of Variation 44.4 |
| Tio R5 | Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss) | 6.13 pg*h/mL | Geometric Coefficient of Variation 58.3 |
| Tio HH18 | Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss) | 7.79 pg*h/mL | Geometric Coefficient of Variation 54.9 |
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.
Time frame: 4 weeks
Population: FAS with imputed data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period | 1.366 Liter | Standard Error 0.046 |
| Tio R1.25 | FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period | 1.521 Liter | Standard Error 0.046 |
| Tio R2.5 | FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period | 1.546 Liter | Standard Error 0.046 |
| Tio R5 | FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period | 1.553 Liter | Standard Error 0.046 |
| Tio HH18 | FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period | 1.558 Liter | Standard Error 0.046 |
95% CI: [0.13, 0.18]
p-value: <0.000195% CI: [0.155, 0.205]ANOVA
p-value: <0.000195% CI: [0.162, 0.211]ANOVA
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.
Time frame: 4 weeks
Population: FAS with imputed data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period | 1.371 Liter | Standard Error 0.046 |
| Tio R1.25 | FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period | 1.535 Liter | Standard Error 0.046 |
| Tio R2.5 | FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period | 1.556 Liter | Standard Error 0.046 |
| Tio R5 | FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period | 1.562 Liter | Standard Error 0.046 |
| Tio HH18 | FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period | 1.567 Liter | Standard Error 0.046 |
95% CI: [0.141, 0.189]
p-value: <0.000195% CI: [0.161, 0.209]ANOVA
p-value: <0.000195% CI: [0.167, 0.216]ANOVA
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.
Time frame: 4 weeks
Population: FAS with imputed data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 1.371 Liter | Standard Error 0.046 |
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 1.374 Liter | Standard Error 0.047 |
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 1.394 Liter | Standard Error 0.047 |
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 1.375 Liter | Standard Error 0.047 |
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 1.375 Liter | Standard Error 0.046 |
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 1.375 Liter | Standard Error 0.047 |
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 1.349 Liter | Standard Error 0.045 |
| Placebo | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 1.366 Liter | Standard Error 0.046 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 1.436 Liter | Standard Error 0.045 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 1.529 Liter | Standard Error 0.046 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 1.556 Liter | Standard Error 0.047 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 1.557 Liter | Standard Error 0.047 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 1.536 Liter | Standard Error 0.048 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 1.501 Liter | Standard Error 0.046 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 1.543 Liter | Standard Error 0.046 |
| Tio R1.25 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 1.562 Liter | Standard Error 0.047 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 1.573 Liter | Standard Error 0.046 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 1.575 Liter | Standard Error 0.047 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 1.571 Liter | Standard Error 0.047 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 1.551 Liter | Standard Error 0.047 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 1.522 Liter | Standard Error 0.046 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 1.552 Liter | Standard Error 0.046 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 1.450 Liter | Standard Error 0.045 |
| Tio R2.5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 1.582 Liter | Standard Error 0.047 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 1.572 Liter | Standard Error 0.046 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 1.578 Liter | Standard Error 0.047 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 1.470 Liter | Standard Error 0.045 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 1.541 Liter | Standard Error 0.046 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 1.560 Liter | Standard Error 0.046 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 1.584 Liter | Standard Error 0.047 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 1.579 Liter | Standard Error 0.047 |
| Tio R5 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 1.558 Liter | Standard Error 0.047 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 1.571 Liter | Standard Error 0.046 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 1.554 Liter | Standard Error 0.046 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 1.477 Liter | Standard Error 0.045 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 1.571 Liter | Standard Error 0.046 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 1.570 Liter | Standard Error 0.048 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 1.580 Liter | Standard Error 0.047 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 1.582 Liter | Standard Error 0.047 |
| Tio HH18 | FEV1 at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 1.588 Liter | Standard Error 0.047 |
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.
Time frame: 4 weeks
Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 3.146 Liter | Standard Error 0.078 |
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 3.191 Liter | Standard Error 0.079 |
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 3.161 Liter | Standard Error 0.079 |
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 3.118 Liter | Standard Error 0.076 |
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 3.156 Liter | Standard Error 0.078 |
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 3.131 Liter | Standard Error 0.077 |
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 3.152 Liter | Standard Error 0.078 |
| Placebo | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 3.168 Liter | Standard Error 0.079 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 3.255 Liter | Standard Error 0.076 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 3.466 Liter | Standard Error 0.078 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 3.443 Liter | Standard Error 0.078 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 3.468 Liter | Standard Error 0.079 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 3.417 Liter | Standard Error 0.079 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 3.459 Liter | Standard Error 0.079 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 3.449 Liter | Standard Error 0.078 |
| Tio R1.25 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 3.390 Liter | Standard Error 0.077 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 3.470 Liter | Standard Error 0.079 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 3.489 Liter | Standard Error 0.078 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 3.513 Liter | Standard Error 0.078 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 3.484 Liter | Standard Error 0.078 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 3.495 Liter | Standard Error 0.079 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 3.467 Liter | Standard Error 0.079 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 3.435 Liter | Standard Error 0.077 |
| Tio R2.5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 3.307 Liter | Standard Error 0.076 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 3.356 Liter | Standard Error 0.076 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 3.505 Liter | Standard Error 0.079 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 3.473 Liter | Standard Error 0.077 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 3.488 Liter | Standard Error 0.078 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 3.499 Liter | Standard Error 0.078 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 3.516 Liter | Standard Error 0.078 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 3.501 Liter | Standard Error 0.079 |
| Tio R5 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 3.473 Liter | Standard Error 0.079 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 1:00 | 3.499 Liter | Standard Error 0.078 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 6:00 | 3.469 Liter | Standard Error 0.079 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 5:00 | 3.488 Liter | Standard Error 0.079 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:30 | 3.496 Liter | Standard Error 0.077 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 4:00 | 3.501 Liter | Standard Error 0.079 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 0:00 (trough) | 3.351 Liter | Standard Error 0.076 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 3:00 | 3.497 Liter | Standard Error 0.078 |
| Tio HH18 | FVC at Each Planned Time at the End of Each Treatment Period | Timepoint 2:00 | 3.487 Liter | Standard Error 0.078 |
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.
Time frame: 4 weeks
Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC0-3h at the End of Each Treatment Period | 3.140 Liter | Standard Error 0.078 |
| Tio R1.25 | FVC AUC0-3h at the End of Each Treatment Period | 3.421 Liter | Standard Error 0.078 |
| Tio R2.5 | FVC AUC0-3h at the End of Each Treatment Period | 3.465 Liter | Standard Error 0.078 |
| Tio R5 | FVC AUC0-3h at the End of Each Treatment Period | 3.479 Liter | Standard Error 0.078 |
| Tio HH18 | FVC AUC0-3h at the End of Each Treatment Period | 3.480 Liter | Standard Error 0.078 |
95% CI: [0.236, 0.325]
p-value: <0.000195% CI: [0.279, 0.369]ANOVA
p-value: <0.000195% CI: [0.294, 0.384]ANOVA
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.
Time frame: 4 weeks
Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC0-6h at the End of Each Treatment Period | 3.153 Liter | Standard Error 0.079 |
| Tio R1.25 | FVC AUC0-6h at the End of Each Treatment Period | 3.436 Liter | Standard Error 0.078 |
| Tio R2.5 | FVC AUC0-6h at the End of Each Treatment Period | 3.472 Liter | Standard Error 0.078 |
| Tio R5 | FVC AUC0-6h at the End of Each Treatment Period | 3.488 Liter | Standard Error 0.078 |
| Tio HH18 | FVC AUC0-6h at the End of Each Treatment Period | 3.483 Liter | Standard Error 0.079 |
95% CI: [0.241, 0.326]
p-value: <0.000195% CI: [0.276, 0.362]ANOVA
p-value: <0.000195% CI: [0.292, 0.378]ANOVA
Secondary
Minimum Plasma Concentration at Steady-state (Cmin,ss)
Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state.
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.
Population: PK Set. All patients with analysable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tio R1.25 | Minimum Plasma Concentration at Steady-state (Cmin,ss) | 1.16 pg/mL | Geometric Coefficient of Variation 14.5 |
| Tio R2.5 | Minimum Plasma Concentration at Steady-state (Cmin,ss) | 1.25 pg/mL | Geometric Coefficient of Variation 17.7 |
| Tio R5 | Minimum Plasma Concentration at Steady-state (Cmin,ss) | 1.57 pg/mL | Geometric Coefficient of Variation 32.3 |
| Tio HH18 | Minimum Plasma Concentration at Steady-state (Cmin,ss) | 1.76 pg/mL | Geometric Coefficient of Variation 42.3 |
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.
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)
Population: PK Set. All patients with analysable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tio R1.25 | Pre-dose Plasma Concentration at Steady-state (Cpre,ss) | 1.57 pg/mL | Geometric Coefficient of Variation 43.1 |
| Tio R2.5 | Pre-dose Plasma Concentration at Steady-state (Cpre,ss) | 1.39 pg/mL | Geometric Coefficient of Variation 22.8 |
| Tio R5 | Pre-dose Plasma Concentration at Steady-state (Cpre,ss) | 1.60 pg/mL | Geometric Coefficient of Variation 35.8 |
| Tio HH18 | Pre-dose Plasma Concentration at Steady-state (Cpre,ss) | 1.71 pg/mL | Geometric Coefficient of Variation 42.5 |
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.
Time frame: Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing.
Population: PK Set. All patients with analysable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tio R1.25 | Renal Clearance at Steady-state (CL R,0-6h,ss) | 256 mL/min | Geometric Coefficient of Variation 32.1 |
| Tio R2.5 | Renal Clearance at Steady-state (CL R,0-6h,ss) | 277 mL/min | Geometric Coefficient of Variation 55.8 |
| Tio R5 | Renal Clearance at Steady-state (CL R,0-6h,ss) | 307 mL/min | Geometric Coefficient of Variation 39.6 |
| Tio HH18 | Renal Clearance at Steady-state (CL R,0-6h,ss) | 310 mL/min | Geometric Coefficient of Variation 40.4 |
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.
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.
Population: PK Set. All patients with analysable data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tio R1.25 | Time to Maximum Plasma Concentration at Steady-state (Tmax,ss) | 0.100 hours |
| Tio R2.5 | Time to Maximum Plasma Concentration at Steady-state (Tmax,ss) | 0.0830 hours |
| Tio R5 | Time to Maximum Plasma Concentration at Steady-state (Tmax,ss) | 0.117 hours |
| Tio HH18 | Time to Maximum Plasma Concentration at Steady-state (Tmax,ss) | 0.117 hours |
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.
Time frame: 4 weeks
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period | 1.345 Liter | Standard Error 0.045 |
| Tio R1.25 | Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period | 1.432 Liter | Standard Error 0.045 |
| Tio R2.5 | Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period | 1.446 Liter | Standard Error 0.045 |
| Tio R5 | Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period | 1.466 Liter | Standard Error 0.045 |
| Tio HH18 | Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period | 1.473 Liter | Standard Error 0.045 |
95% CI: [0.06, 0.114]
p-value: <0.000195% CI: [0.074, 0.128]ANOVA
p-value: <0.000195% CI: [0.094, 0.148]ANOVA
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.
Time frame: 4 weeks
Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period | 3.116 Liter | Standard Error 0.077 |
| Tio R1.25 | Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period | 3.254 Liter | Standard Error 0.077 |
| Tio R2.5 | Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period | 3.304 Liter | Standard Error 0.077 |
| Tio R5 | Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period | 3.352 Liter | Standard Error 0.077 |
| Tio HH18 | Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period | 3.351 Liter | Standard Error 0.077 |
95% CI: [0.083, 0.194]
p-value: <0.000195% CI: [0.133, 0.244]ANOVA
p-value: <0.000195% CI: [0.18, 0.292]ANOVA
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.
Time frame: 6.5 hours (including pre dose)
Population: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 109.29 bpm | Standard Deviation 15.23 |
| Placebo | Maximum Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 97.83 bpm | Standard Deviation 13.65 |
| Placebo | Maximum Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 108.35 bpm | Standard Deviation 16.32 |
| Placebo | Maximum Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 91.73 bpm | Standard Deviation 12.44 |
| Tio R1.25 | Maximum Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 109.57 bpm | Standard Deviation 15.29 |
| Tio R1.25 | Maximum Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 91.51 bpm | Standard Deviation 12.87 |
| Tio R1.25 | Maximum Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 107.37 bpm | Standard Deviation 14.04 |
| Tio R1.25 | Maximum Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 99.20 bpm | Standard Deviation 14.65 |
| Tio R2.5 | Maximum Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 92.59 bpm | Standard Deviation 15.4 |
| Tio R2.5 | Maximum Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 109.93 bpm | Standard Deviation 15.47 |
| Tio R2.5 | Maximum Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 98.43 bpm | Standard Deviation 14.68 |
| Tio R2.5 | Maximum Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 108.90 bpm | Standard Deviation 15.85 |
| Tio R5 | Maximum Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 97.16 bpm | Standard Deviation 13.97 |
| Tio R5 | Maximum Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 107.65 bpm | Standard Deviation 16.37 |
| Tio R5 | Maximum Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 109.34 bpm | Standard Deviation 14.36 |
| Tio R5 | Maximum Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 91.60 bpm | Standard Deviation 12.07 |
| Tio HH18 | Maximum Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 97.33 bpm | Standard Deviation 13 |
| Tio HH18 | Maximum Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 108.68 bpm | Standard Deviation 14.28 |
| Tio HH18 | Maximum Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 109.57 bpm | Standard Deviation 14.7 |
| Tio HH18 | Maximum Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 92.74 bpm | Standard Deviation 12.75 |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 76.97 bpm | Standard Deviation 10.39 |
| Placebo | Mean Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 73.87 bpm | Standard Deviation 10.07 |
| Placebo | Mean Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 75.76 bpm | Standard Deviation 10.88 |
| Placebo | Mean Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 70.75 bpm | Standard Deviation 10.2 |
| Tio R1.25 | Mean Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 76.37 bpm | Standard Deviation 10.69 |
| Tio R1.25 | Mean Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 70.33 bpm | Standard Deviation 10.66 |
| Tio R1.25 | Mean Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 73.76 bpm | Standard Deviation 10.6 |
| Tio R1.25 | Mean Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 75.00 bpm | Standard Deviation 10.87 |
| Tio R2.5 | Mean Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 71.11 bpm | Standard Deviation 11.93 |
| Tio R2.5 | Mean Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 74.39 bpm | Standard Deviation 10.82 |
| Tio R2.5 | Mean Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 76.25 bpm | Standard Deviation 12 |
| Tio R2.5 | Mean Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 77.75 bpm | Standard Deviation 10.95 |
| Tio R5 | Mean Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 76.87 bpm | Standard Deviation 10.82 |
| Tio R5 | Mean Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 73.82 bpm | Standard Deviation 11.06 |
| Tio R5 | Mean Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 70.67 bpm | Standard Deviation 10.77 |
| Tio R5 | Mean Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 75.35 bpm | Standard Deviation 10.86 |
| Tio HH18 | Mean Heart Rate (HR) | Day 26 1st h(N=115,109,113,107,109) | 70.21 bpm | Standard Deviation 9.58 |
| Tio HH18 | Mean Heart Rate (HR) | Day 26 6.5 h(N=115,110,113,110,112) | 75.81 bpm | Standard Deviation 10.39 |
| Tio HH18 | Mean Heart Rate (HR) | Day 29 1st h(N=114,113,115,115,111) | 73.71 bpm | Standard Deviation 9.8 |
| Tio HH18 | Mean Heart Rate (HR) | Day 29 6.5 h(N=115,115,115,116,113) | 77.31 bpm | Standard Deviation 10.45 |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | SVPB Pairs | Day 29 6.5 h | 48 participants |
| Placebo | SVPB Pairs | Day 29 1st h | 17 participants |
| Placebo | SVPB Pairs | Day 26 6.5 h | 41 participants |
| Placebo | SVPB Pairs | Day 26 1st h | 18 participants |
| Tio R1.25 | SVPB Pairs | Day 29 6.5 h | 52 participants |
| Tio R1.25 | SVPB Pairs | Day 26 1st h | 13 participants |
| Tio R1.25 | SVPB Pairs | Day 29 1st h | 20 participants |
| Tio R1.25 | SVPB Pairs | Day 26 6.5 h | 46 participants |
| Tio R2.5 | SVPB Pairs | Day 26 1st h | 10 participants |
| Tio R2.5 | SVPB Pairs | Day 29 1st h | 19 participants |
| Tio R2.5 | SVPB Pairs | Day 26 6.5 h | 29 participants |
| Tio R2.5 | SVPB Pairs | Day 29 6.5 h | 55 participants |
| Tio R5 | SVPB Pairs | Day 29 6.5 h | 49 participants |
| Tio R5 | SVPB Pairs | Day 29 1st h | 20 participants |
| Tio R5 | SVPB Pairs | Day 26 1st h | 14 participants |
| Tio R5 | SVPB Pairs | Day 26 6.5 h | 42 participants |
| Tio HH18 | SVPB Pairs | Day 26 1st h | 13 participants |
| Tio HH18 | SVPB Pairs | Day 26 6.5 h | 45 participants |
| Tio HH18 | SVPB Pairs | Day 29 1st h | 16 participants |
| Tio HH18 | SVPB Pairs | Day 29 6.5 h | 53 participants |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | SVPB Runs | Day 29 6.5 h | 47 participants |
| Placebo | SVPB Runs | Day 29 1st h | 9 participants |
| Placebo | SVPB Runs | Day 26 6.5 h | 35 participants |
| Placebo | SVPB Runs | Day 26 1st h | 12 participants |
| Tio R1.25 | SVPB Runs | Day 29 6.5 h | 36 participants |
| Tio R1.25 | SVPB Runs | Day 26 1st h | 6 participants |
| Tio R1.25 | SVPB Runs | Day 29 1st h | 16 participants |
| Tio R1.25 | SVPB Runs | Day 26 6.5 h | 34 participants |
| Tio R2.5 | SVPB Runs | Day 26 1st h | 9 participants |
| Tio R2.5 | SVPB Runs | Day 29 1st h | 8 participants |
| Tio R2.5 | SVPB Runs | Day 26 6.5 h | 29 participants |
| Tio R2.5 | SVPB Runs | Day 29 6.5 h | 44 participants |
| Tio R5 | SVPB Runs | Day 29 6.5 h | 34 participants |
| Tio R5 | SVPB Runs | Day 29 1st h | 5 participants |
| Tio R5 | SVPB Runs | Day 26 1st h | 11 participants |
| Tio R5 | SVPB Runs | Day 26 6.5 h | 36 participants |
| Tio HH18 | SVPB Runs | Day 26 1st h | 10 participants |
| Tio HH18 | SVPB Runs | Day 26 6.5 h | 34 participants |
| Tio HH18 | SVPB Runs | Day 29 1st h | 6 participants |
| Tio HH18 | SVPB Runs | Day 29 6.5 h | 39 participants |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | SVPB Singles | Day 29 6.5 h | 109 participants |
| Placebo | SVPB Singles | Day 26 1st h | 78 participants |
| Placebo | SVPB Singles | Day 29 1st h | 82 participants |
| Placebo | SVPB Singles | Day 26 6.5 h | 111 participants |
| Tio R1.25 | SVPB Singles | Day 29 1st h | 77 participants |
| Tio R1.25 | SVPB Singles | Day 26 1st h | 74 participants |
| Tio R1.25 | SVPB Singles | Day 29 6.5 h | 112 participants |
| Tio R1.25 | SVPB Singles | Day 26 6.5 h | 102 participants |
| Tio R2.5 | SVPB Singles | Day 29 6.5 h | 109 participants |
| Tio R2.5 | SVPB Singles | Day 26 6.5 h | 106 participants |
| Tio R2.5 | SVPB Singles | Day 26 1st h | 74 participants |
| Tio R2.5 | SVPB Singles | Day 29 1st h | 72 participants |
| Tio R5 | SVPB Singles | Day 29 6.5 h | 108 participants |
| Tio R5 | SVPB Singles | Day 26 1st h | 61 participants |
| Tio R5 | SVPB Singles | Day 29 1st h | 82 participants |
| Tio R5 | SVPB Singles | Day 26 6.5 h | 98 participants |
| Tio HH18 | SVPB Singles | Day 29 1st h | 73 participants |
| Tio HH18 | SVPB Singles | Day 29 6.5 h | 107 participants |
| Tio HH18 | SVPB Singles | Day 26 6.5 h | 105 participants |
| Tio HH18 | SVPB Singles | Day 26 1st h | 64 participants |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | SVPB Total | Day 26 6.5 h | 111 participants |
| Placebo | SVPB Total | Day 26 1st h | 82 participants |
| Placebo | SVPB Total | Day 29 6.5 h | 109 participants |
| Placebo | SVPB Total | Day 29 1st h | 83 participants |
| Tio R1.25 | SVPB Total | Day 29 6.5 h | 112 participants |
| Tio R1.25 | SVPB Total | Day 29 1st h | 79 participants |
| Tio R1.25 | SVPB Total | Day 26 1st h | 74 participants |
| Tio R1.25 | SVPB Total | Day 26 6.5 h | 103 participants |
| Tio R2.5 | SVPB Total | Day 26 1st h | 75 participants |
| Tio R2.5 | SVPB Total | Day 29 6.5 h | 109 participants |
| Tio R2.5 | SVPB Total | Day 26 6.5 h | 106 participants |
| Tio R2.5 | SVPB Total | Day 29 1st h | 75 participants |
| Tio R5 | SVPB Total | Day 29 1st h | 84 participants |
| Tio R5 | SVPB Total | Day 26 1st h | 62 participants |
| Tio R5 | SVPB Total | Day 26 6.5 h | 98 participants |
| Tio R5 | SVPB Total | Day 29 6.5 h | 108 participants |
| Tio HH18 | SVPB Total | Day 29 6.5 h | 107 participants |
| Tio HH18 | SVPB Total | Day 26 6.5 h | 105 participants |
| Tio HH18 | SVPB Total | Day 29 1st h | 75 participants |
| Tio HH18 | SVPB Total | Day 26 1st h | 66 participants |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | VPB Pairs | Day 29 6.5 h | 24 participants |
| Placebo | VPB Pairs | Day 26 6.5 h | 24 participants |
| Placebo | VPB Pairs | Day 26 1st h | 7 participants |
| Placebo | VPB Pairs | Day 29 1st h | 8 participants |
| Tio R1.25 | VPB Pairs | Day 26 1st h | 10 participants |
| Tio R1.25 | VPB Pairs | Day 29 6.5 h | 19 participants |
| Tio R1.25 | VPB Pairs | Day 26 6.5 h | 20 participants |
| Tio R1.25 | VPB Pairs | Day 29 1st h | 6 participants |
| Tio R2.5 | VPB Pairs | Day 29 6.5 h | 21 participants |
| Tio R2.5 | VPB Pairs | Day 26 1st h | 7 participants |
| Tio R2.5 | VPB Pairs | Day 26 6.5 h | 19 participants |
| Tio R2.5 | VPB Pairs | Day 29 1st h | 6 participants |
| Tio R5 | VPB Pairs | Day 29 6.5 h | 16 participants |
| Tio R5 | VPB Pairs | Day 26 1st h | 6 participants |
| Tio R5 | VPB Pairs | Day 26 6.5 h | 21 participants |
| Tio R5 | VPB Pairs | Day 29 1st h | 6 participants |
| Tio HH18 | VPB Pairs | Day 29 6.5 h | 22 participants |
| Tio HH18 | VPB Pairs | Day 26 1st h | 10 participants |
| Tio HH18 | VPB Pairs | Day 29 1st h | 7 participants |
| Tio HH18 | VPB Pairs | Day 26 6.5 h | 22 participants |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | VPB Runs | Day 29 6.5 h | 3 participants |
| Placebo | VPB Runs | Day 29 1st h | 0 participants |
| Placebo | VPB Runs | Day 26 6.5 h | 8 participants |
| Placebo | VPB Runs | Day 26 1st h | 0 participants |
| Tio R1.25 | VPB Runs | Day 29 6.5 h | 5 participants |
| Tio R1.25 | VPB Runs | Day 26 1st h | 2 participants |
| Tio R1.25 | VPB Runs | Day 29 1st h | 3 participants |
| Tio R1.25 | VPB Runs | Day 26 6.5 h | 7 participants |
| Tio R2.5 | VPB Runs | Day 26 1st h | 1 participants |
| Tio R2.5 | VPB Runs | Day 29 1st h | 2 participants |
| Tio R2.5 | VPB Runs | Day 26 6.5 h | 8 participants |
| Tio R2.5 | VPB Runs | Day 29 6.5 h | 4 participants |
| Tio R5 | VPB Runs | Day 29 6.5 h | 10 participants |
| Tio R5 | VPB Runs | Day 29 1st h | 2 participants |
| Tio R5 | VPB Runs | Day 26 1st h | 4 participants |
| Tio R5 | VPB Runs | Day 26 6.5 h | 9 participants |
| Tio HH18 | VPB Runs | Day 26 1st h | 3 participants |
| Tio HH18 | VPB Runs | Day 26 6.5 h | 9 participants |
| Tio HH18 | VPB Runs | Day 29 1st h | 1 participants |
| Tio HH18 | VPB Runs | Day 29 6.5 h | 9 participants |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | VPB Singles | Day 29 6.5 h | 91 participants |
| Placebo | VPB Singles | Day 29 1st h | 59 participants |
| Placebo | VPB Singles | Day 26 6.5 h | 92 participants |
| Placebo | VPB Singles | Day 26 1st h | 59 participants |
| Tio R1.25 | VPB Singles | Day 29 6.5 h | 99 participants |
| Tio R1.25 | VPB Singles | Day 26 1st h | 49 participants |
| Tio R1.25 | VPB Singles | Day 29 1st h | 63 participants |
| Tio R1.25 | VPB Singles | Day 26 6.5 h | 82 participants |
| Tio R2.5 | VPB Singles | Day 26 1st h | 48 participants |
| Tio R2.5 | VPB Singles | Day 29 1st h | 58 participants |
| Tio R2.5 | VPB Singles | Day 26 6.5 h | 81 participants |
| Tio R2.5 | VPB Singles | Day 29 6.5 h | 89 participants |
| Tio R5 | VPB Singles | Day 29 6.5 h | 94 participants |
| Tio R5 | VPB Singles | Day 29 1st h | 50 participants |
| Tio R5 | VPB Singles | Day 26 1st h | 49 participants |
| Tio R5 | VPB Singles | Day 26 6.5 h | 88 participants |
| Tio HH18 | VPB Singles | Day 26 1st h | 55 participants |
| Tio HH18 | VPB Singles | Day 26 6.5 h | 88 participants |
| Tio HH18 | VPB Singles | Day 29 1st h | 58 participants |
| Tio HH18 | VPB Singles | Day 29 6.5 h | 96 participants |
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.
Time frame: 6.5 hours (including pre dose)
Population: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | VPB Total | Day 29 6.5 h | 91 participants |
| Placebo | VPB Total | Day 29 1st h | 59 participants |
| Placebo | VPB Total | Day 26 6.5 h | 92 participants |
| Placebo | VPB Total | Day 26 1st h | 59 participants |
| Tio R1.25 | VPB Total | Day 29 6.5 h | 99 participants |
| Tio R1.25 | VPB Total | Day 26 1st h | 49 participants |
| Tio R1.25 | VPB Total | Day 29 1st h | 63 participants |
| Tio R1.25 | VPB Total | Day 26 6.5 h | 82 participants |
| Tio R2.5 | VPB Total | Day 26 1st h | 49 participants |
| Tio R2.5 | VPB Total | Day 29 1st h | 58 participants |
| Tio R2.5 | VPB Total | Day 26 6.5 h | 83 participants |
| Tio R2.5 | VPB Total | Day 29 6.5 h | 90 participants |
| Tio R5 | VPB Total | Day 29 6.5 h | 96 participants |
| Tio R5 | VPB Total | Day 29 1st h | 50 participants |
| Tio R5 | VPB Total | Day 26 1st h | 49 participants |
| Tio R5 | VPB Total | Day 26 6.5 h | 89 participants |
| Tio HH18 | VPB Total | Day 26 1st h | 56 participants |
| Tio HH18 | VPB Total | Day 26 6.5 h | 88 participants |
| Tio HH18 | VPB Total | Day 29 1st h | 59 participants |
| Tio HH18 | VPB Total | Day 29 6.5 h | 96 participants |