Asthma
Conditions
Brief summary
The aim of this trial is to select an optimum dose may be selected based on bronchodilator efficacy, safety evaluations and pharmacokinetics of tiotropium bromide.
Interventions
DRUGTiotropium bromide
inhalation solution administered via Respimat in 3 different doses
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into this study: 1. All patients' parents (or legally accepted caregivers) must sign and date an informed consent prior to any study procedures including medication washout and restrictions. In addition, an informed assent suitable for this age group has to be obtained from patients. 2. Male or female patients between 6 and 11 years of age (up to 1 day prior to their 12th birthday at Visit 1). 3. All patients must have at least a 6-month history of asthma at the time of enrolment into the trial. 4. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose - a patient is eligible on =200 µg to =400 µg Budesonide DPI or equivalent. 5. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ mean score of =1.5. 6. All patients must have a pre-bronchodilator FEV1 =60% and =90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 2 (pre-dose) as compared to values at Visit 2 (pre-bronchodilator) must be within ± 30%. 7. All patients must demonstrate an increase in FEV1 of =12% 15 to 30 min. after 200 µg salbutamol (albuterol) at Visit 1. 8. Patients must be able to inhale from the Respimat® inhaler correctly. 9. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres according to current ATS/ERS standards and the use of the electronic diary/peak flow meter.
Exclusion criteria
Patients with any of the following characteristics will not be eligible for entry into this study: 1. Patients with a significant disease other than asthma. 2. Patients with clinically relevant abnormal screening haematology or blood chemistry will be excluded if the abnormality defines a significant disease as defined in exclusion criterion 1. For participation in PK sampling, a haemoglobin of less than 11.3 g/dL will be regarded as exclusion criterion. 3. Patients with a history of congenital or acquired heart disease, or patients who have been hospitalised for cardiac syncope or failure during the past year. 4. Patients with any unstable or life-threatening cardiac arrhythmia, including cardiac arrhythmia requiring intervention (e.g. pacemaker implantation, catheter ablation etc.) or a change in drug therapy within the past year. 5. Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. 6. Patients with clinically significant lung diseases other than asthma, such as CF, or bronchopulmonary dysplasia. 7. Patients with known active tuberculosis. 8. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1. 9. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1). 10. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. 11. Patients with known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated. 12. Patients with moderate to severe renal impairment, as defined by a creatinine clearance \<50 mL/min./1.73 m2 BSA, as tiotropium is a predominantly renally excreted drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume (FEV1) Peak (0-3h) Response | Baseline and 4 weeks | The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Forced Vital Capacity (FVC) Peak (0-3h) Response | Baseline and 4 weeks | The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| FVC Trough Response | Baseline and 4 weeks | The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | Baseline and 4 weeks | FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | Baseline and 4 weeks | FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Trough FEV1 Response | Baseline and 4 weeks | The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Mean Evening PEF Response | Baseline and 4 weeks | Mean Evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Baseline and 4 weeks | Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day (24 h, daytime and night-time use). Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 4 weeks | ACQ is a questionnaire consisting of seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Change From Baseline in Mean Number of Nighttime Awakenings | Baseline and last week of treatment (week 4) | Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. The scores for this question used the following scale where: 1='Did not wake up', 2='Woke up once', 3='Woke up 2-5 times', 4='Woke up more than 5 times' and 5='Was awake all night'. |
| Mean Morning Peak Expiratory Flow (PEF) Response | Baseline and 4 weeks | Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
Countries
Germany, Hungary, Latvia, Lithuania, Russia, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Total. Total number of patients randomised and treated at all in the study. | 101 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 (4 Weeks) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total. |
|---|---|
| Age, Continuous | 8.8 years STANDARD_DEVIATION 1.7 |
| Forced expiratory volume in 1s (FEV1) | 1.640 Litre STANDARD_DEVIATION 0.386 |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 76 | 0 / 75 | 0 / 74 | 0 / 76 |
| serious Total, serious adverse events | 0 / 76 | 0 / 75 | 0 / 74 | 0 / 76 |
Outcome results
Primary
Forced Expiratory Volume (FEV1) Peak (0-3h) Response
The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: The Full analysis set (FAS) is defined as patients randomised, treated, with baseline data and at least one on-treatment efficacy measurement after 4 weeks on treatment within a period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.185 Litre | Standard Error 0.025 |
| Tio R1.25 | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.261 Litre | Standard Error 0.026 |
| Tio R2.5 | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.290 Litre | Standard Error 0.026 |
| Tio R5 | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.272 Litre | Standard Error 0.026 |
Comparison: Tio R5 minus Placebop-value: 0.000295% CI: [0.042, 0.132]Mixed model repeated measures (MMRM)
Comparison: Tio R2.5 minus Placebop-value: <0.000195% CI: [0.059, 0.149]Mixed model repeated measures (MMRM)
Comparison: Tio R1.25 minus Placebop-value: 0.001195% CI: [0.03, 0.12]Mixed model repeated measures (MMRM)
Comparison: Tio R5 minus Tio R1.2595% CI: [-0.034, 0.057]Mixed model repeated measures (MMRM)
Comparison: Tio R5 minus Tio R2.595% CI: [-0.063, 0.028]Mixed model repeated measures (MMRM)
Comparison: Tio R2.5 minus Tio R1.2595% CI: [-0.016, 0.074]Mixed models repeated measures (MMRM)
Secondary
Change From Baseline in Mean Number of Nighttime Awakenings
Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. The scores for this question used the following scale where: 1='Did not wake up', 2='Woke up once', 3='Woke up 2-5 times', 4='Woke up more than 5 times' and 5='Was awake all night'.
Time frame: Baseline and last week of treatment (week 4)
Population: FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the TioR2.5 group had no on-treatment data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Number of Nighttime Awakenings | -0.135 scores on a scale | Standard Error 0.034 |
| Tio R1.25 | Change From Baseline in Mean Number of Nighttime Awakenings | -0.104 scores on a scale | Standard Error 0.034 |
| Tio R2.5 | Change From Baseline in Mean Number of Nighttime Awakenings | -0.080 scores on a scale | Standard Error 0.034 |
| Tio R5 | Change From Baseline in Mean Number of Nighttime Awakenings | -0.099 scores on a scale | Standard Error 0.034 |
Secondary
Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use)
Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day (24 h, daytime and night-time use). Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the TioR2.5 group had no on-treatment data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | 24 h | -0.664 Puffs | Standard Error 0.105 |
| Placebo | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Night-time | -0.354 Puffs | Standard Error 0.06 |
| Placebo | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Daytime | -0.338 Puffs | Standard Error 0.061 |
| Tio R1.25 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | 24 h | -0.691 Puffs | Standard Error 0.105 |
| Tio R1.25 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Night-time | -0.355 Puffs | Standard Error 0.06 |
| Tio R1.25 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Daytime | -0.348 Puffs | Standard Error 0.062 |
| Tio R2.5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | 24 h | -0.314 Puffs | Standard Error 0.106 |
| Tio R2.5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Daytime | -0.130 Puffs | Standard Error 0.062 |
| Tio R2.5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Night-time | -0.180 Puffs | Standard Error 0.06 |
| Tio R5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | 24 h | -0.550 Puffs | Standard Error 0.105 |
| Tio R5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Night-time | -0.272 Puffs | Standard Error 0.06 |
| Tio R5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use) | Daytime | -0.258 Puffs | Standard Error 0.062 |
Secondary
Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ)
ACQ is a questionnaire consisting of seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: 4 weeks
Population: FAS with at least one on-treatment value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 0.966 Score | Standard Error 0.066 |
| Tio R1.25 | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 0.909 Score | Standard Error 0.066 |
| Tio R2.5 | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 0.846 Score | Standard Error 0.066 |
| Tio R5 | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 0.879 Score | Standard Error 0.066 |
Secondary
FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response
FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.110 Litre | Standard Error 0.025 |
| Tio R1.25 | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.178 Litre | Standard Error 0.025 |
| Tio R2.5 | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.208 Litre | Standard Error 0.025 |
| Tio R5 | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.201 Litre | Standard Error 0.025 |
Secondary
Forced Vital Capacity (FVC) Peak (0-3h) Response
The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.202 Litre | Standard Error 0.029 |
| Tio R1.25 | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.208 Litre | Standard Error 0.029 |
| Tio R2.5 | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.253 Litre | Standard Error 0.029 |
| Tio R5 | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.239 Litre | Standard Error 0.029 |
Secondary
FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response
FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.087 Litre | Standard Error 0.027 |
| Tio R1.25 | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.097 Litre | Standard Error 0.027 |
| Tio R2.5 | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.134 Litre | Standard Error 0.027 |
| Tio R5 | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.110 Litre | Standard Error 0.027 |
Secondary
FVC Trough Response
The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Trough Response | 0.060 Litre | Standard Error 0.03 |
| Tio R1.25 | FVC Trough Response | 0.109 Litre | Standard Error 0.03 |
| Tio R2.5 | FVC Trough Response | 0.107 Litre | Standard Error 0.03 |
| Tio R5 | FVC Trough Response | 0.113 Litre | Standard Error 0.03 |
Secondary
Mean Evening PEF Response
Mean Evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the TioR2.5 group had no on-treatment data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Evening PEF Response | -0.568 Litre/min | Standard Error 5.081 |
| Tio R1.25 | Mean Evening PEF Response | 9.910 Litre/min | Standard Error 5.103 |
| Tio R2.5 | Mean Evening PEF Response | 6.991 Litre/min | Standard Error 5.15 |
| Tio R5 | Mean Evening PEF Response | 15.910 Litre/min | Standard Error 5.103 |
Secondary
Mean Morning Peak Expiratory Flow (PEF) Response
Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the TioR2.5 group had no on-treatment data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Morning Peak Expiratory Flow (PEF) Response | -0.928 Litre/min | Standard Error 5.103 |
| Tio R1.25 | Mean Morning Peak Expiratory Flow (PEF) Response | 14.474 Litre/min | Standard Error 5.127 |
| Tio R2.5 | Mean Morning Peak Expiratory Flow (PEF) Response | 12.045 Litre/min | Standard Error 5.177 |
| Tio R5 | Mean Morning Peak Expiratory Flow (PEF) Response | 15.439 Litre/min | Standard Error 5.127 |
Secondary
Trough FEV1 Response
The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with at least one on-treatment value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | 0.085 Litre | Standard Error 0.026 |
| Tio R1.25 | Trough FEV1 Response | 0.160 Litre | Standard Error 0.026 |
| Tio R2.5 | Trough FEV1 Response | 0.190 Litre | Standard Error 0.026 |
| Tio R5 | Trough FEV1 Response | 0.183 Litre | Standard Error 0.026 |