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CompletedNCT01222533Updated May 16, 2014Results posted

Tiotropium Respimat Pharmacokinetic Study in COPD

A Phase 2 interventional study of Tiotropium medium and Tiotropium low in Pulmonary Disease, Chronic Obstructive, sponsored by Boehringer Ingelheim. Completed at 11 sites in 5 countries. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2014-05-16.

Sponsored by Boehringer Ingelheim · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
154
Allocation
Randomized
Ages
40 Years and older
Sex
All
01

Study 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.

02

Conditions studied

  • Pulmonary Disease, Chronic Obstructive
03

In context

Pulmonary Disease, Chronic Obstructive

4,252 studies on the registry are indexed under Pulmonary Disease, Chronic Obstructive; 707 are open to participants now.

This study's enrollment of 154 is above the median of 70 across 3,008 interventional studies indexed under Pulmonary Disease, Chronic Obstructive.

Browse Pulmonary Disease, Chronic Obstructive studies →

Lead sponsor

Boehringer Ingelheim is the lead sponsor of 2,297 studies on the registry; 56 are open to participants now.

Of its 166 completed or terminated interventional studies of FDA-regulated products, 121 (73%) have results posted.

Browse Boehringer Ingelheim studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
40 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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)

05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Double
Enrollment
154 participants (actual)

Study arms

  • Experimental
    Tiotropium low

    Tiotropium inhalation solution low dose

    Drug: Tiotropium low

  • Experimental
    Tiotropium medium

    Tiotropium inhalation solution medium dose

    Drug: Tiotropium medium

  • Experimental
    Tiotropium high

    Tiotropium inhalation solution high dose

    Drug: Tiotropium high

  • Active comparator
    Tiotropium 18mcg

    Tiotropium inhalation powder 18mcg

    Drug: Tiotropium 18mcg

  • Placebo comparator
    Tiotropium placebo

    Placebo inhalation solution

    Drug: Tiotropium placebo

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

  • DrugTiotropium placebo

    Placebo inhalation solution

06

What researchers measure

Primary outcomes

  1. 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.

  2. 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.

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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)

  13. 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.

  14. 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.

Other outcomes

  1. 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)

  2. 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)

  3. 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)

  4. 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)

  5. 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)

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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)

07

Results

Posted Dec 10, 2012

Participant flow

Participant flow — Overall Study
MilestoneStudy Overall
Started154
Received placebo147
Received tio r1.25147
Received tio r2.5145
Received tio r5150
Received tio hh18146
Completed140
Not completed14
Withdrew: Adverse event5
Withdrew: Withdrawal by subject5
Withdrew: Other4

Outcome measures

PrimaryMaximum 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.
Reported as:
Geometric mean · pg/ml
Maximum Plasma Concentration at Steady-state (Cmax,ss)
pg/mlPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Maximum Plasma Concentration at Steady-state (Cmax,ss)—2.81 ± 53.05.07 ± 61.810.5 ± 66.412.9 ± 64.6
Statistical analysis
  • Tio R5 vs Tio HH18 · ANOVA · p = 0.4423 (Maximum of two one-sided p-values for geometric mean ratio being outside interval 80 percent to 125 percent.) · Geometric mean ratio (percentage): 80.66 · 90% CI 73.49 to 88.52Standard deviation is actually the geometric coefficient of variation.
PrimaryArea 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.
Reported as:
Geometric mean · pg*h/ml
Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss)
pg*h/mlPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss)—10.0 ± 25.312.8 ± 29.922.1 ± 47.828.4 ± 52.4
Statistical analysis
  • Tio R5 vs Tio HH18 · ANOVA · p = 0.8683 (Maximum of two one-sided p-values for geometric mean ratio being outside interval 80 percent to 125 percent.) · Geometric mean ratio (percentage): 75.99 · 90% CI 70.44 to 81.98Standard deviation is actually the geometric coefficient of variation.
SecondaryTrough 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
Reported as:
Mean · Liter
Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period1.345 ± 0.0451.432 ± 0.0451.446 ± 0.0451.466 ± 0.0451.473 ± 0.045
Statistical analysis
  • Placebo vs Tio R1.25 · Mean difference (final values): 0.087 · 95% CI 0.060 to 0.114Tio R1.25-Placebo
  • Placebo vs Tio R2.5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.101 · 95% CI 0.074 to 0.128Tio R2.5-Placebo
  • Placebo vs Tio R5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.121 · 95% CI 0.094 to 0.148Tio R5-Placebo
SecondaryFEV1 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
Reported as:
Mean · Liter
FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period1.371 ± 0.0461.535 ± 0.0461.556 ± 0.0461.562 ± 0.0461.567 ± 0.046
Statistical analysis
  • Placebo vs Tio R1.25 · Mean difference (final values): 0.165 · 95% CI 0.141 to 0.189Tio R1.25-Placebo.
  • Placebo vs Tio R2.5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.185 · 95% CI 0.161 to 0.209Tio R2.5-Placebo
  • Placebo vs Tio R5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.191 · 95% CI 0.167 to 0.216Tio R5-Placebo
SecondaryFEV1 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
Reported as:
Mean · Liter
FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period1.366 ± 0.0461.521 ± 0.0461.546 ± 0.0461.553 ± 0.0461.558 ± 0.046
Statistical analysis
  • Placebo vs Tio R1.25 · Mean difference (final values): 0.155 · 95% CI 0.130 to 0.180Tio R1.25-Placebo
  • Placebo vs Tio R2.5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.180 · 95% CI 0.155 to 0.205Tio R2.5-Placebo
  • Placebo vs Tio R5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.187 · 95% CI 0.162 to 0.211Tio R5-Placebo
SecondaryTrough 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
Reported as:
Mean · Liter
Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period3.116 ± 0.0773.254 ± 0.0773.304 ± 0.0773.352 ± 0.0773.351 ± 0.077
Statistical analysis
  • Placebo vs Tio R1.25 · Mean difference (final values): 0.138 · 95% CI 0.083 to 0.194Tio R1.25-Placebo
  • Placebo vs Tio R2.5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.188 · 95% CI 0.133 to 0.244Tio R2.5-Placebo
  • Placebo vs Tio R5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.236 · 95% CI 0.180 to 0.292Tio R5-Placebo
SecondaryFVC 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
Reported as:
Mean · Liter
FVC AUC0-6h at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
FVC AUC0-6h at the End of Each Treatment Period3.153 ± 0.0793.436 ± 0.0783.472 ± 0.0783.488 ± 0.0783.483 ± 0.079
Statistical analysis
  • Placebo vs Tio R1.25 · Mean difference (final values): 0.283 · 95% CI 0.241 to 0.326Tio R1.25-Placebo
  • Placebo vs Tio R2.5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.319 · 95% CI 0.276 to 0.362Tio R2.5-Placebo
  • Placebo vs Tio R5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.335 · 95% CI 0.292 to 0.378Tio R5-Placebo
SecondaryFVC 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
Reported as:
Mean · Liter
FVC AUC0-3h at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
FVC AUC0-3h at the End of Each Treatment Period3.140 ± 0.0783.421 ± 0.0783.465 ± 0.0783.479 ± 0.0783.480 ± 0.078
Statistical analysis
  • Placebo vs Tio R1.25 · Mean difference (final values): 0.281 · 95% CI 0.236 to 0.325Tio R1.25-Placebo
  • Placebo vs Tio R2.5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.324 · 95% CI 0.279 to 0.369Tio R2.5-Placebo
  • Placebo vs Tio R5 · ANOVA · p = <0.0001 · Mean difference (final values): 0.339 · 95% CI 0.294 to 0.384Tio R5-Placebo
SecondaryFEV1 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
Reported as:
Mean · Liter
FEV1 at Each Planned Time at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Timepoint 0:00 (trough)1.349 ± 0.0451.436 ± 0.0451.450 ± 0.0451.470 ± 0.0451.477 ± 0.045
Timepoint 0:301.366 ± 0.0461.501 ± 0.0461.522 ± 0.0461.541 ± 0.0461.554 ± 0.046
Timepoint 1:001.371 ± 0.0461.529 ± 0.0461.552 ± 0.0461.560 ± 0.0461.571 ± 0.046
Timepoint 2:001.375 ± 0.0461.543 ± 0.0461.573 ± 0.0461.572 ± 0.0461.571 ± 0.046
Timepoint 3:001.375 ± 0.0471.556 ± 0.0471.582 ± 0.0471.584 ± 0.0471.580 ± 0.047
Timepoint 4:001.374 ± 0.0471.557 ± 0.0471.575 ± 0.0471.578 ± 0.0471.582 ± 0.047
Timepoint 5:001.394 ± 0.0471.562 ± 0.0471.571 ± 0.0471.579 ± 0.0471.588 ± 0.047
Timepoint 6:001.375 ± 0.0471.536 ± 0.0481.551 ± 0.0471.558 ± 0.0471.570 ± 0.048
SecondaryFVC 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
Reported as:
Mean · Liter
FVC at Each Planned Time at the End of Each Treatment Period
LiterPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Timepoint 0:00 (trough)3.118 ± 0.0763.255 ± 0.0763.307 ± 0.0763.356 ± 0.0763.351 ± 0.076
Timepoint 0:303.131 ± 0.0773.390 ± 0.0773.435 ± 0.0773.473 ± 0.0773.496 ± 0.077
Timepoint 1:003.152 ± 0.0783.449 ± 0.0783.484 ± 0.0783.488 ± 0.0783.499 ± 0.078
Timepoint 2:003.146 ± 0.0783.443 ± 0.0783.489 ± 0.0783.499 ± 0.0783.487 ± 0.078
Timepoint 3:003.156 ± 0.0783.466 ± 0.0783.513 ± 0.0783.516 ± 0.0783.497 ± 0.078
Timepoint 4:003.161 ± 0.0793.468 ± 0.0793.495 ± 0.0793.505 ± 0.0793.501 ± 0.079
Timepoint 5:003.191 ± 0.0793.459 ± 0.0793.467 ± 0.0793.501 ± 0.0793.488 ± 0.079
Timepoint 6:003.168 ± 0.0793.417 ± 0.0793.470 ± 0.0793.473 ± 0.0793.469 ± 0.079
SecondaryArea 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.
Reported as:
Geometric mean · pg*h/mL
Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss)
pg*h/mLPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss)—2.08 ± 32.33.16 ± 44.46.13 ± 58.37.79 ± 54.9
SecondaryTime 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.
Reported as:
Median · hours
Time to Maximum Plasma Concentration at Steady-state (Tmax,ss)
hoursPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Time to Maximum Plasma Concentration at Steady-state (Tmax,ss)—0.100 (0.0330 to 2.00)0.0830 (0.0330 to 6.00)0.117 (0.0330 to 0.333)0.117 (0.0330 to 1.00)
SecondaryAmount 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.
Reported as:
Geometric mean · ng
Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss)
ngPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss)—88.7 ± 68.0177 ± 68.0387 ± 65.9522 ± 53.8
SecondaryPre-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)
Reported as:
Geometric mean · pg/mL
Pre-dose Plasma Concentration at Steady-state (Cpre,ss)
pg/mLPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Pre-dose Plasma Concentration at Steady-state (Cpre,ss)—1.57 ± 43.11.39 ± 22.81.60 ± 35.81.71 ± 42.5
SecondaryRenal 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.
Reported as:
Geometric mean · mL/min
Renal Clearance at Steady-state (CL R,0-6h,ss)
mL/minPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Renal Clearance at Steady-state (CL R,0-6h,ss)—256 ± 32.1277 ± 55.8307 ± 39.6310 ± 40.4
SecondaryMinimum 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.
Reported as:
Geometric mean · pg/mL
Minimum Plasma Concentration at Steady-state (Cmin,ss)
pg/mLPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Minimum Plasma Concentration at Steady-state (Cmin,ss)—1.16 ± 14.51.25 ± 17.71.57 ± 32.31.76 ± 42.3
Other pre-specifiedMaximum 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)
Reported as:
Mean · bpm
Maximum Heart Rate (HR)
bpmPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h(N=115,115,115,116,113)109.29 ± 15.23109.57 ± 15.29109.93 ± 15.47109.34 ± 14.36108.68 ± 14.28
Day 29 1st h(N=114,113,115,115,111)97.83 ± 13.6599.20 ± 14.6598.43 ± 14.6897.16 ± 13.9797.33 ± 13.00
Day 26 6.5 h(N=115,110,113,110,112)108.35 ± 16.32107.37 ± 14.04108.90 ± 15.85107.65 ± 16.37109.57 ± 14.70
Day 26 1st h(N=115,109,113,107,109)91.73 ± 12.4491.51 ± 12.8792.59 ± 15.4091.60 ± 12.0792.74 ± 12.75
Other pre-specifiedMean 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)
Reported as:
Mean · bpm
Mean Heart Rate (HR)
bpmPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h(N=115,115,115,116,113)76.97 ± 10.3976.37 ± 10.6977.75 ± 10.9576.87 ± 10.8277.31 ± 10.45
Day 29 1st h(N=114,113,115,115,111)73.87 ± 10.0773.76 ± 10.6074.39 ± 10.8273.82 ± 11.0673.71 ± 9.80
Day 26 6.5 h(N=115,110,113,110,112)75.76 ± 10.8875.00 ± 10.8776.25 ± 12.0075.35 ± 10.8675.81 ± 10.39
Day 26 1st h(N=115,109,113,107,109)70.75 ± 10.2070.33 ± 10.6671.11 ± 11.9370.67 ± 10.7770.21 ± 9.58
Other pre-specifiedSVPB 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)
Reported as:
Number · participants
SVPB Total
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h109112109108107
Day 29 1st h8379758475
Day 26 6.5 h11110310698105
Day 26 1st h8274756266
Other pre-specifiedSVPB 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)
Reported as:
Number · participants
SVPB Runs
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h4736443439
Day 29 1st h916856
Day 26 6.5 h3534293634
Day 26 1st h12691110
Other pre-specifiedSVPB 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)
Reported as:
Number · participants
SVPB Pairs
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h4852554953
Day 29 1st h1720192016
Day 26 6.5 h4146294245
Day 26 1st h1813101413
Other pre-specifiedSVPB 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)
Reported as:
Number · participants
SVPB Singles
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h109112109108107
Day 29 1st h8277728273
Day 26 6.5 h11110210698105
Day 26 1st h7874746164
Other pre-specifiedVPB 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)
Reported as:
Number · participants
VPB Total
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h9199909696
Day 29 1st h5963585059
Day 26 6.5 h9282838988
Day 26 1st h5949494956
Other pre-specifiedVPB 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)
Reported as:
Number · participants
VPB Runs
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h354109
Day 29 1st h03221
Day 26 6.5 h87899
Day 26 1st h02143
Other pre-specifiedVPB 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)
Reported as:
Number · participants
VPB Pairs
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h2419211622
Day 29 1st h86667
Day 26 6.5 h2420192122
Day 26 1st h7107610
Other pre-specifiedVPB 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)
Reported as:
Number · participants
VPB Singles
participantsPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
Day 29 6.5 h9199899496
Day 29 1st h5963585058
Day 26 6.5 h9282818888
Day 26 1st h5949484955

Adverse events

Collected over 4 weeks + 30 days if in last period. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo—3/147 (2%)20/147 (13.6%)
Tio R1.25—2/147 (1.4%)11/147 (7.5%)
Tio R2.5—0/145 (0%)4/145 (2.8%)
Tio R5—3/150 (2%)16/150 (10.7%)
Tio HH18—2/146 (1.4%)10/146 (6.8%)
Most frequent serious events
Showing 10 of 12
Most frequent serious events
EventPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
PneumoniaInfections and infestations0/1470/1470/1450/1501/146
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders1/1470/1470/1450/1501/146
Haemorrhoidal haemorrhageGastrointestinal disorders1/1470/1470/1450/1500/146
Infective exacerbation of chronic obstructive airways diseaseInfections and infestations1/1470/1470/1450/1500/146
Tendon ruptureInjury, poisoning and procedural complications1/1470/1470/1450/1500/146
Spinal column stenosisMusculoskeletal and connective tissue disorders0/1471/1470/1450/1500/146
Prostate cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/1471/1470/1450/1500/146
Cerebrovascular accidentNervous system disorders0/1471/1470/1450/1500/146
Colitis ischaemicGastrointestinal disorders0/1470/1470/1451/1500/146
PancreatitisGastrointestinal disorders0/1470/1470/1451/1500/146
Most frequent other events
Most frequent other events
EventPlaceboTio R1.25Tio R2.5Tio R5Tio HH18
DyspnoeaRespiratory, thoracic and mediastinal disorders14/1475/1472/1453/1503/146
NasopharyngitisInfections and infestations6/1479/1472/14514/1507/146

Baseline characteristics

Age, Continuous
Age, Continuous(years)Study Overall
Mean63.1 ± 7.8
Sex: Female, Male
Sex: Female, Male(Participants)Study Overall
Female37
Male117
08

Study locations

11 sites
  • 205.458.32003 Boehringer Ingelheim Investigational Site
    Genk, Belgium
  • 205.458.32001 Boehringer Ingelheim Investigational Site
    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
09

References and documents

Publications

  • Hohlfeld JM, Furtwaengler A, Konen-Bergmann M, Wallenstein G, Walter B, Bateman ED. Cardiac safety of tiotropium in patients with COPD: a combined analysis of Holter-ECG data from four randomised clinical trials. Int J Clin Pract. 2015 Jan;69(1):72-80. doi: 10.1111/ijcp.12596. Epub 2014 Dec 11. PubMed 25496316 ↗
  • 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. PubMed 24165906 ↗
10

Timeline

Tracking since Sep 25, 2026
Not marked actual or estimatedDates not marked actual or estimated

The record gives a start of Oct 2010 and a primary completion of Nov 2011. It does not say whether these dates are actual or estimated.

Results were first posted in Dec 2012, 1 year 1 month after primary completion.

How these figures are worked out, and which studies are left out of them.

Registered
Oct 15, 2010
First posted
Oct 18, 2010
Start
Oct 2010
Primary completionActual
Nov 2011
Results first posted
Dec 10, 2012
Last update
May 16, 2014
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on May 16, 2014, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01222533
Lead sponsor
Boehringer Ingelheim
Responsible party
Sponsor
First posted
Oct 18, 2010
Start date
Oct 2010
Primary completion
Nov 2011
Results posted
Dec 10, 2012
Last update
May 16, 2014

Study contacts

Boehringer Ingelheim
study chair · Boehringer Ingelheim
View the source record on ClinicalTrials.gov ↗

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