Cystic Fibrosis
Conditions
Brief summary
This study evaluates the effects of 12-week treatment with two doses of tiotropium bromide (2.5 mcg q.d. and 5 mcg q.d.) compared to placebo administered via the Respimat device on lung function in patients with Cystic Fibrosis. The selection of the optimal dose will be based on bronchodilator efficacy, safety evaluations and pharmacokinetic evaluations
Interventions
DRUGPlacebo Respimat
patient to receive placebo matching active drug once daily
DRUGTiotropium bromide 5 mcg
patient to recieve high dose tiotropium once daily
DRUGtiotropium bromide-low dose-2.5mcg
patient to receive low dose tiotropium once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Male or female patients 2. Diagnosis of Cystic Fibrosis (positive sweat chloride test or two identifiable mutations) 3. Pre-bronchodilator FEV1 greater/equal 25% of predicted values
Exclusion criteria
1. Significant history of allergy/hypersensitivity 2. Hypersensitivity to study drug 3. Participation in another trial 4. Female patients who are pregnant or lactating 5. Female patients of childbearing potential 6. Patients who have started a new medication for CF within 4 weeks of screening 7. Patients with known substance abuse 8. Clinically significant disease other than CF
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Predicted FEV1 AUC0-4 Response at the End of Week 12 | Baseline, Week 12 | Outcome measure description: Change from baseline in percent predicted Forced Expiratory Volume in one second (FEV1) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline. |
| Percent Predicted FEV1 Trough Response at the End of Week 12 | Baseline, Week 12 | Outcome measure description: Change from baseline in percent predicted trough Forced Expiratory Volume in one second. Calculated as percent predicted at week 12 minus percent predicted at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pre-bronchodilator FEF25-75 Percent Predicted at the End of Week 12 | Baseline, Week 12 | Forced Expiratory Flow at 25-75% of vital capacity (FEF25-75). Calculated as percent predicted at week 12 minus percent predicted at baseline. |
| Change From Baseline in Residual Volume/Total Lung Capacity (RV/TLC) at the End of Week 12 | Baseline, Week 12 | Change from baseline in static lung hyperinflation as measured by RV/TLC. Calculated as percent predicted at week 12 minus percent predicted at baseline. |
| Respiratory and Systemic Symptoms Questionnaire (RSSQ) | 12 weeks | Outcome measure description: The RSSQ questionnaire is used to determine the presence or absence of an exacerbation during the recall period. |
| Change From Baseline in CFQ Scores - Adult Group | 12 weeks | The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adults with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health. |
| Change From Baseline in CFQ Scores - Adolescents Group | 12 weeks | The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents (age 6-13) with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health. |
| Percent Predicted FVC AUC0-4 Response at the End of Week 12 | Baseline, Week 12 | Change from baseline in percent predicted Forced Vital Capacity (FVC) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline. |
| Change From Baseline in CFQ Scores - Parent Questionnaire | 12 weeks | The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents with CF - parent questionnaire. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health. |
| Maximum Measured Concentration at Steady State (Cmax,ss) | pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose | Cmax,ss represents the maximum measured concentration of tiotropium in plasma at steady state. |
| Time From Dosing to the Maximum Concentration (Tmax,ss) | pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose | Tmax,ss represents the time from dosing to the maximum concentration of tiotropium in plasma |
| Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | From first drug administration until 30 days after last drug administration (up to 121 days) | Clinical Relevant Abnormalities for Vital Signs and Laboratory evaluation. Any new or clinically relevant worsening of baseline conditions was reported as Adverse Event. |
| Amount of Tiotropium Eliminated in Urine From 0 to 4 Hours at Steady State (Ae0-4,ss) | pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose | Ae0-4,ss represents the amount of tiotropium that is eliminated in urine from time 0 to 4 hours at steady state |
| Percent Predicted FVC Trough Response at the End of Week 12 | Baseline, Week 12 | Change from baseline in percent predicted trough Forced Vital Capacity (FVC). Calculated as percent predicted at week 12 minus percent predicted at baseline. |
Countries
Australia, Belgium, France, Germany, Italy, Netherlands, New Zealand, Portugal, Russia, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomised to receive matching placebo | 168 |
| Tiotropium Respimat 2.5 Micrograms Patients randomised to receive Tiotropium Respimat 2.5 micrograms once daily | 166 |
| Tiotropium Respimat 5 Micrograms Patients randomised to receive Tiotropium Respimat 5.0 micrograms once daily | 176 |
| Total | 510 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 5 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Reason discontinued not explained above | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Total | Tiotropium Respimat 5 Micrograms | Tiotropium Respimat 2.5 Micrograms | Placebo |
|---|---|---|---|---|
| Age, Continuous | 20.9 years STANDARD_DEVIATION 11.6 | 20.7 years STANDARD_DEVIATION 11.3 | 21.5 years STANDARD_DEVIATION 12 | 20.4 years STANDARD_DEVIATION 11.6 |
| Age, Customized <= 11 years | 138 years | 52 years | 42 years | 44 years |
| Age, Customized >= 12 years | 372 years | 124 years | 124 years | 124 years |
| Alcohol history Drinks alcohol but could interfere with trial | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Alcohol history Drinks alcohol but should not interfere with trial | 135 Participants | 43 Participants | 54 Participants | 38 Participants |
| Alcohol history Drinks no alcohol | 374 Participants | 132 Participants | 112 Participants | 130 Participants |
| Body Mass Index | 20.1 kilogram/square meter STANDARD_DEVIATION 4.2 | 20.0 kilogram/square meter STANDARD_DEVIATION 4.1 | 19.9 kilogram/square meter STANDARD_DEVIATION 4 | 20.3 kilogram/square meter STANDARD_DEVIATION 4.4 |
| Height | 156.9 centimeters STANDARD_DEVIATION 17.5 | 155.7 centimeters STANDARD_DEVIATION 18.2 | 157.7 centimeters STANDARD_DEVIATION 17 | 157.4 centimeters STANDARD_DEVIATION 17.2 |
| Race/Ethnicity, Customized American Indian / Alaskan native | 8 participants | 3 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 2 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Black/African American | 5 participants | 2 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized Missing | 111 participants | 37 participants | 35 participants | 39 participants |
| Race/Ethnicity, Customized White | 383 participants | 132 participants | 124 participants | 127 participants |
| Sex: Female, Male Female | 235 Participants | 82 Participants | 81 Participants | 72 Participants |
| Sex: Female, Male Male | 275 Participants | 94 Participants | 85 Participants | 96 Participants |
| Smoking history Currently smokes | 8 Participants | 2 Participants | 4 Participants | 2 Participants |
| Smoking history Ex-smoker | 19 Participants | 7 Participants | 5 Participants | 7 Participants |
| Smoking history Never smoked | 483 Participants | 167 Participants | 157 Participants | 159 Participants |
| Weight | 51.2 kilograms STANDARD_DEVIATION 18.1 | 50.4 kilograms STANDARD_DEVIATION 18.2 | 51.0 kilograms STANDARD_DEVIATION 17.3 | 52.1 kilograms STANDARD_DEVIATION 19 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 87 / 168 | 95 / 166 | 110 / 176 |
| serious Total, serious adverse events | 21 / 168 | 28 / 166 | 21 / 176 |
Outcome results
Primary
Percent Predicted FEV1 AUC0-4 Response at the End of Week 12
Outcome measure description: Change from baseline in percent predicted Forced Expiratory Volume in one second (FEV1) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline.
Time frame: Baseline, Week 12
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Predicted FEV1 AUC0-4 Response at the End of Week 12 | -1.74 Percentage change | Standard Error 0.65 |
| Tiotropium Respimat 2.5 Micrograms | Percent Predicted FEV1 AUC0-4 Response at the End of Week 12 | 1.20 Percentage change | Standard Error 0.66 |
| Tiotropium Respimat 5 Micrograms | Percent Predicted FEV1 AUC0-4 Response at the End of Week 12 | 1.65 Percentage change | Standard Error 0.63 |
Comparison: Comparison of Tiotropium 2.5 microgram dose versus placebop-value: 0.00195% CI: [1.19, 4.7]Mixed Models Analysis
Comparison: Comparison of Tiotropium 5.0 microgram dose versus placebop-value: 0.000195% CI: [1.67, 5.12]Mixed Models Analysis
Primary
Percent Predicted FEV1 Trough Response at the End of Week 12
Outcome measure description: Change from baseline in percent predicted trough Forced Expiratory Volume in one second. Calculated as percent predicted at week 12 minus percent predicted at baseline.
Time frame: Baseline, Week 12
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Predicted FEV1 Trough Response at the End of Week 12 | -1.44 Percentage change | Standard Error 0.71 |
| Tiotropium Respimat 2.5 Micrograms | Percent Predicted FEV1 Trough Response at the End of Week 12 | 0.81 Percentage change | Standard Error 0.71 |
| Tiotropium Respimat 5 Micrograms | Percent Predicted FEV1 Trough Response at the End of Week 12 | 0.78 Percentage change | Standard Error 0.69 |
Comparison: Comparison of Tiotropium 2.5 microgram dose versus placebop-value: 0.018495% CI: [0.38, 4.11]Mixed Models Analysis
Comparison: Comparison of Tiotropium 5.0 microgram dose versus placebop-value: 0.017995% CI: [0.38, 4.06]Mixed Models Analysis
Secondary
Amount of Tiotropium Eliminated in Urine From 0 to 4 Hours at Steady State (Ae0-4,ss)
Ae0-4,ss represents the amount of tiotropium that is eliminated in urine from time 0 to 4 hours at steady state
Time frame: pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement - patients \>= 12 years
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Amount of Tiotropium Eliminated in Urine From 0 to 4 Hours at Steady State (Ae0-4,ss) | 114 ng | Geometric Coefficient of Variation 73 |
| Tiotropium Respimat 2.5 Micrograms | Amount of Tiotropium Eliminated in Urine From 0 to 4 Hours at Steady State (Ae0-4,ss) | 245 ng | Geometric Coefficient of Variation 67.5 |
Secondary
Change From Baseline in CFQ Scores - Adolescents Group
The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents (age 6-13) with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health.
Time frame: 12 weeks
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | Physical (N=46, 42, 54) | 1.1 units on a scale | Standard Deviation 18 |
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | School (N=46, 42, 55) | 1.1 units on a scale | Standard Deviation 14.3 |
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | Body (N=46, 42, 55) | 2.8 units on a scale | Standard Deviation 13.9 |
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | School (N=46, 42, 55) | 1.2 units on a scale | Standard Deviation 18.8 |
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | Eat (N=46, 42, 55) | -1.4 units on a scale | Standard Deviation 19.7 |
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | Treat (N=46, 42, 55) | 0.2 units on a scale | Standard Deviation 16.5 |
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | Respirat (N=46, 42, 55) | -1.4 units on a scale | Standard Deviation 15.2 |
| Placebo | Change From Baseline in CFQ Scores - Adolescents Group | Digest (N=46, 42, 55) | -5.1 units on a scale | Standard Deviation 26.3 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Body (N=46, 42, 55) | -0.3 units on a scale | Standard Deviation 16.1 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Respirat (N=46, 42, 55) | 1.2 units on a scale | Standard Deviation 16.7 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | School (N=46, 42, 55) | 4.2 units on a scale | Standard Deviation 19.2 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Eat (N=46, 42, 55) | -2.4 units on a scale | Standard Deviation 17.3 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Treat (N=46, 42, 55) | -1.9 units on a scale | Standard Deviation 20.1 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Physical (N=46, 42, 54) | 3.2 units on a scale | Standard Deviation 14.8 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | School (N=46, 42, 55) | -1.6 units on a scale | Standard Deviation 10.9 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Digest (N=46, 42, 55) | 2.4 units on a scale | Standard Deviation 26.9 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Body (N=46, 42, 55) | -0.1 units on a scale | Standard Deviation 15.7 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | School (N=46, 42, 55) | -1.1 units on a scale | Standard Deviation 13.5 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Physical (N=46, 42, 54) | -1.9 units on a scale | Standard Deviation 15 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | School (N=46, 42, 55) | 2.4 units on a scale | Standard Deviation 20.9 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Respirat (N=46, 42, 55) | -3.0 units on a scale | Standard Deviation 20.2 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Treat (N=46, 42, 55) | 5.7 units on a scale | Standard Deviation 19.5 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Eat (N=46, 42, 55) | 1.6 units on a scale | Standard Deviation 22.8 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adolescents Group | Digest (N=46, 42, 55) | -3.0 units on a scale | Standard Deviation 35.3 |
Secondary
Change From Baseline in CFQ Scores - Adult Group
The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adults with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health.
Time frame: 12 weeks
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Physical (N=99, 102, 105) | -2.5 units on a scale | Standard Deviation 14.8 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Role (N=94, 100, 103) | 0.7 units on a scale | Standard Deviation 12 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Vitality (N=99, 101, 105) | -2.3 units on a scale | Standard Deviation 15 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Emotion (N=99, 101, 105) | -1.1 units on a scale | Standard Deviation 11.5 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Social (N=99, 101, 106) | -1.1 units on a scale | Standard Deviation 12.3 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Body (N=99,101, 106) | 0.4 units on a scale | Standard Deviation 18.4 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Eat (N=99,101,106) | 1.5 units on a scale | Standard Deviation 9.5 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Treat (N=99, 101, 106) | 0.9 units on a scale | Standard Deviation 15.5 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Health (N=99, 101, 106) | -1.9 units on a scale | Standard Deviation 15.1 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Weight (N=95, 101, 103) | 1.4 units on a scale | Standard Deviation 22.2 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Respirat (N=93, 101, 103) | -1.3 units on a scale | Standard Deviation 14.8 |
| Placebo | Change From Baseline in CFQ Scores - Adult Group | Digest (N=93, 101, 103) | 0.8 units on a scale | Standard Deviation 14.9 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Digest (N=93, 101, 103) | -1.3 units on a scale | Standard Deviation 13.7 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Physical (N=99, 102, 105) | -0.0 units on a scale | Standard Deviation 14.1 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Eat (N=99,101,106) | 0.2 units on a scale | Standard Deviation 10.3 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Health (N=99, 101, 106) | -3.2 units on a scale | Standard Deviation 18.3 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Role (N=94, 100, 103) | -2.7 units on a scale | Standard Deviation 12 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Body (N=99,101, 106) | -0.9 units on a scale | Standard Deviation 15.3 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Respirat (N=93, 101, 103) | -3.7 units on a scale | Standard Deviation 15.8 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Vitality (N=99, 101, 105) | -1.8 units on a scale | Standard Deviation 16.4 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Treat (N=99, 101, 106) | -1.4 units on a scale | Standard Deviation 14.1 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Social (N=99, 101, 106) | -1.0 units on a scale | Standard Deviation 10.7 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Emotion (N=99, 101, 105) | -1.3 units on a scale | Standard Deviation 13.5 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Weight (N=95, 101, 103) | -3.3 units on a scale | Standard Deviation 28.9 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Emotion (N=99, 101, 105) | 0.1 units on a scale | Standard Deviation 12.1 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Social (N=99, 101, 106) | -0.8 units on a scale | Standard Deviation 11.1 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Weight (N=95, 101, 103) | -0.0 units on a scale | Standard Deviation 26 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Body (N=99,101, 106) | 1.7 units on a scale | Standard Deviation 16.4 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Eat (N=99,101,106) | 0.0 units on a scale | Standard Deviation 16.4 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Treat (N=99, 101, 106) | -1.7 units on a scale | Standard Deviation 12.7 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Respirat (N=93, 101, 103) | -1.8 units on a scale | Standard Deviation 14.3 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Physical (N=99, 102, 105) | -2.9 units on a scale | Standard Deviation 11.4 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Role (N=94, 100, 103) | -2.1 units on a scale | Standard Deviation 15.1 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Health (N=99, 101, 106) | -0.6 units on a scale | Standard Deviation 18.1 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Vitality (N=99, 101, 105) | -3.3 units on a scale | Standard Deviation 17.7 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Adult Group | Digest (N=93, 101, 103) | 0.3 units on a scale | Standard Deviation 14.9 |
Secondary
Change From Baseline in CFQ Scores - Parent Questionnaire
The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents with CF - parent questionnaire. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health.
Time frame: 12 weeks
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Health (N=46, 45, 52) | -2.7 units on a scale | Standard Deviation 21.4 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Eat (N=46, 43, 49) | -2.2 units on a scale | Standard Deviation 23.7 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Digest (N=46, 43, 50) | -0.7 units on a scale | Standard Deviation 15.6 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Treat (N=46, 45, 52) | -2.4 units on a scale | Standard Deviation 18.6 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Body (N=46, 45, 52) | -3.9 units on a scale | Standard Deviation 18.6 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Physical (N=46, 45, 53) | -0.1 units on a scale | Standard Deviation 15.4 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Vitality (N=46, 44, 53) | -0.1 units on a scale | Standard Deviation 12.3 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Emotion (N=46, 45, 52) | -0.3 units on a scale | Standard Deviation 11.2 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Respirat (N=45, 43, 50) | -2.8 units on a scale | Standard Deviation 16.4 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | School (N=46, 45, 52) | -4.8 units on a scale | Standard Deviation 19.5 |
| Placebo | Change From Baseline in CFQ Scores - Parent Questionnaire | Weight (N=45, 45, 49) | -5.2 units on a scale | Standard Deviation 35.5 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Body (N=46, 45, 52) | -1.7 units on a scale | Standard Deviation 21.7 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Physical (N=46, 45, 53) | 4.9 units on a scale | Standard Deviation 15.9 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Emotion (N=46, 45, 52) | 0.0 units on a scale | Standard Deviation 16 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Vitality (N=46, 44, 53) | 3.3 units on a scale | Standard Deviation 13.1 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | School (N=46, 45, 52) | 2.2 units on a scale | Standard Deviation 26.3 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Eat (N=46, 43, 49) | -0.8 units on a scale | Standard Deviation 21.2 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Treat (N=46, 45, 52) | 2.5 units on a scale | Standard Deviation 16.4 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Health (N=46, 45, 52) | 3.5 units on a scale | Standard Deviation 23.1 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Respirat (N=45, 43, 50) | -2.2 units on a scale | Standard Deviation 18.8 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Digest (N=46, 43, 50) | -1.8 units on a scale | Standard Deviation 17 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Weight (N=45, 45, 49) | 1.5 units on a scale | Standard Deviation 30.1 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Digest (N=46, 43, 50) | 1.1 units on a scale | Standard Deviation 16.8 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Health (N=46, 45, 52) | -3.0 units on a scale | Standard Deviation 20.7 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Vitality (N=46, 44, 53) | -1.5 units on a scale | Standard Deviation 14.9 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Physical (N=46, 45, 53) | 0.2 units on a scale | Standard Deviation 12.7 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Respirat (N=45, 43, 50) | -6.0 units on a scale | Standard Deviation 14.2 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Emotion (N=46, 45, 52) | -0.1 units on a scale | Standard Deviation 15.7 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Body (N=46, 45, 52) | -3.2 units on a scale | Standard Deviation 22.6 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Eat (N=46, 43, 49) | 3.4 units on a scale | Standard Deviation 15.9 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Weight (N=45, 45, 49) | 4.1 units on a scale | Standard Deviation 31.6 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | Treat (N=46, 45, 52) | -0.2 units on a scale | Standard Deviation 21.4 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in CFQ Scores - Parent Questionnaire | School (N=46, 45, 52) | 0.4 units on a scale | Standard Deviation 17 |
Secondary
Change From Baseline in Residual Volume/Total Lung Capacity (RV/TLC) at the End of Week 12
Change from baseline in static lung hyperinflation as measured by RV/TLC. Calculated as percent predicted at week 12 minus percent predicted at baseline.
Time frame: Baseline, Week 12
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Residual Volume/Total Lung Capacity (RV/TLC) at the End of Week 12 | -0.01 Percentage change | Standard Error 0.03 |
| Tiotropium Respimat 2.5 Micrograms | Change From Baseline in Residual Volume/Total Lung Capacity (RV/TLC) at the End of Week 12 | 0.00 Percentage change | Standard Error 0.03 |
| Tiotropium Respimat 5 Micrograms | Change From Baseline in Residual Volume/Total Lung Capacity (RV/TLC) at the End of Week 12 | 0.04 Percentage change | Standard Error 0.03 |
Comparison: Comparison of Tiotropium 2.5 microgram dose versus placebop-value: 0.741495% CI: [-0.06, 0.08]Mixed Models Analysis
Comparison: Comparison of Tiotropium 5.0 microgram dose versus placebop-value: 0.141895% CI: [-0.02, 0.12]Mixed Models Analysis
Secondary
Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation
Clinical Relevant Abnormalities for Vital Signs and Laboratory evaluation. Any new or clinically relevant worsening of baseline conditions was reported as Adverse Event.
Time frame: From first drug administration until 30 days after last drug administration (up to 121 days)
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood sodium decreased | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | White blood cell count increased | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Hepatic enzyme increased | 2 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Eosinophil count increased | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood chloride decreased | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Vitamin K decreased | 1 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood pressure increased | 2 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood glucose increased | 1 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Oxygen saturation decreased | 0 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Eosinophil count increased | 1 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood chloride decreased | 0 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood glucose increased | 1 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood pressure increased | 1 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood sodium decreased | 0 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Hepatic enzyme increased | 0 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Oxygen saturation decreased | 0 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Vitamin K decreased | 0 participants |
| Tiotropium Respimat 2.5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | White blood cell count increased | 1 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood pressure increased | 0 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood chloride decreased | 1 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Oxygen saturation decreased | 1 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood glucose increased | 0 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | White blood cell count increased | 0 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Eosinophil count increased | 0 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Blood sodium decreased | 1 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Vitamin K decreased | 0 participants |
| Tiotropium Respimat 5 Micrograms | Clinical Relevant Abnormalities for Vital Signs and Laboratory Evaluation | Hepatic enzyme increased | 0 participants |
Secondary
Maximum Measured Concentration at Steady State (Cmax,ss)
Cmax,ss represents the maximum measured concentration of tiotropium in plasma at steady state.
Time frame: pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement - patients \>= 12 years
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Concentration at Steady State (Cmax,ss) | 6.49 pg/mL | Geometric Coefficient of Variation 58.5 |
| Tiotropium Respimat 2.5 Micrograms | Maximum Measured Concentration at Steady State (Cmax,ss) | 9.95 pg/mL | Geometric Coefficient of Variation 66.6 |
Secondary
Percent Predicted FVC AUC0-4 Response at the End of Week 12
Change from baseline in percent predicted Forced Vital Capacity (FVC) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline.
Time frame: Baseline, Week 12
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Predicted FVC AUC0-4 Response at the End of Week 12 | -1.30 Percentage change | Standard Error 0.74 |
| Tiotropium Respimat 2.5 Micrograms | Percent Predicted FVC AUC0-4 Response at the End of Week 12 | 0.53 Percentage change | Standard Error 0.74 |
| Tiotropium Respimat 5 Micrograms | Percent Predicted FVC AUC0-4 Response at the End of Week 12 | 1.81 Percentage change | Standard Error 0.72 |
Comparison: Comparison of Tiotropium 2.5 microgram dose versus placebop-value: 0.075695% CI: [-0.19, 3.86]Mixed Models Analysis
Comparison: Comparison of Tiotropium 5.0 microgram dose versus placebop-value: 0.002395% CI: [1.12, 5.12]Mixed Models Analysis
Secondary
Percent Predicted FVC Trough Response at the End of Week 12
Change from baseline in percent predicted trough Forced Vital Capacity (FVC). Calculated as percent predicted at week 12 minus percent predicted at baseline.
Time frame: Baseline, Week 12
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Predicted FVC Trough Response at the End of Week 12 | -0.39 Percentage change | Standard Error 0.73 |
| Tiotropium Respimat 2.5 Micrograms | Percent Predicted FVC Trough Response at the End of Week 12 | 0.47 Percentage change | Standard Error 0.72 |
| Tiotropium Respimat 5 Micrograms | Percent Predicted FVC Trough Response at the End of Week 12 | 0.81 Percentage change | Standard Error 0.7 |
Comparison: Comparison of Tiotropium 2.5 microgram dose versus placebop-value: 0.385795% CI: [-1.08, 2.79]Mixed Models Analysis
Comparison: Comparison of Tiotropium 5.0 microgram dose versus placebop-value: 0.219995% CI: [-0.72, 3.11]Mixed Models Analysis
Secondary
Pre-bronchodilator FEF25-75 Percent Predicted at the End of Week 12
Forced Expiratory Flow at 25-75% of vital capacity (FEF25-75). Calculated as percent predicted at week 12 minus percent predicted at baseline.
Time frame: Baseline, Week 12
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pre-bronchodilator FEF25-75 Percent Predicted at the End of Week 12 | -1.40 Percentage change | Standard Error 1.57 |
| Tiotropium Respimat 2.5 Micrograms | Pre-bronchodilator FEF25-75 Percent Predicted at the End of Week 12 | 2.78 Percentage change | Standard Error 1.55 |
| Tiotropium Respimat 5 Micrograms | Pre-bronchodilator FEF25-75 Percent Predicted at the End of Week 12 | 3.94 Percentage change | Standard Error 1.52 |
Comparison: Comparison of Tiotropium 5.0 microgram dose versus placebop-value: 0.007395% CI: [1.45, 9.23]Mixed Models Analysis
Comparison: Comparison of Tiotropium 2.5 microgram dose versus placebop-value: 0.036395% CI: [0.27, 8.11]Mixed Models Analysis
Secondary
Respiratory and Systemic Symptoms Questionnaire (RSSQ)
Outcome measure description: The RSSQ questionnaire is used to determine the presence or absence of an exacerbation during the recall period.
Time frame: 12 weeks
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Respiratory and Systemic Symptoms Questionnaire (RSSQ) | At least one pulmonary exacerbation | 16 Participants |
| Placebo | Respiratory and Systemic Symptoms Questionnaire (RSSQ) | No pulmonary exacerbation | 151 Participants |
| Tiotropium Respimat 2.5 Micrograms | Respiratory and Systemic Symptoms Questionnaire (RSSQ) | At least one pulmonary exacerbation | 13 Participants |
| Tiotropium Respimat 2.5 Micrograms | Respiratory and Systemic Symptoms Questionnaire (RSSQ) | No pulmonary exacerbation | 153 Participants |
| Tiotropium Respimat 5 Micrograms | Respiratory and Systemic Symptoms Questionnaire (RSSQ) | At least one pulmonary exacerbation | 12 Participants |
| Tiotropium Respimat 5 Micrograms | Respiratory and Systemic Symptoms Questionnaire (RSSQ) | No pulmonary exacerbation | 163 Participants |
Comparison: Comparison of Tiotropium 2.5 microgram dose versus placebop-value: 0.851595% CI: [0.37, 1.72]Regression, Logistic
Comparison: Comparison of Tiotropium 5.0 microgram dose versus placebop-value: 0.556595% CI: [0.33, 1.59]Regression, Logistic
Secondary
Time From Dosing to the Maximum Concentration (Tmax,ss)
Tmax,ss represents the time from dosing to the maximum concentration of tiotropium in plasma
Time frame: pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
Population: Full Analysis Set (FAS) includes all participants having a baseline measurement and at least one post-dose measurement - patients \>= 12 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Dosing to the Maximum Concentration (Tmax,ss) | 0.0830 h |
| Tiotropium Respimat 2.5 Micrograms | Time From Dosing to the Maximum Concentration (Tmax,ss) | 0.0830 h |