Asthma
Conditions
Brief summary
The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 mcg and 5 mcg once daily) over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in adolescents (12 to 17 years old) with severe persistent asthma. The primary objective of the trial is to demonstrate superiority of tiotropium (5 mcg and possibly 2.5 mcg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment. Secondary objectives are to evaluate efficacy of tiotropium with regard to other endpoints, and to evaluate the safety of tiotropium, compared to placebo, as add-on controller therapy on top of usual care in this patient population.
Interventions
2 actuations once daily
DRUGplacebo
2 actuations once daily
2 actuations once daily
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. All patients and their parent(s) (or legally accepted representative) must sign and date respectively an informed assent and an informed consent consistent with International Conference on Harmonisation - Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to the patient's participation in the trial. A separate informed consent/assent is required for pharmacogenomic sampling. 2. Male or female patients between 12 and 17 years of age (at date of informed consent/assent). 3. All patients must have at least a 3-month history of asthma at the time of enrolment into the trial. 4. All patients must have been on maintenance treatment with an inhaled corticosteroid either at stable high dose in combination with another controller medication, OR at stable medium dose in combination with two other controller medications, for at least 4 weeks before Visit 1. 5. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of = 1.5. 6. All patients must have a pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) = 60% and = 90% of predicted normal at Visit 1. 7. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator, considered as 100%) as compared to Visit 2 (pre-dose) must be within ± 30%. 8. All patients must confirm the diagnosis of asthma by bronchodilator reversibility at Visit 1, resulting in an increase in FEV1 of = 12% and = 200 mL 15 to 30 minutes after 400 µg salbutamol (albuterol). If patients in the lower age range (e.g. 12 to 14 year old patients) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (=12%) post-bronchodilator response. 9. All patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment. 10. Patients must be able to use the Respimat® inhaler correctly. 11. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres according to American Thoracic Society/ European Respiratory Society (ATS/ERS) standards and use of the electronic diary/peak flow meter (diary compliance of at least 80% is required).
Exclusion criteria
1. Significant disease other than asthma. 2. Abnormal haematology or blood chemistry. 3. History of heart disease, and/or hospitalised for cardiac syncope or failure. 4. Any unstable or life-threatening or requiring intervention or cardiac arrhythmia. 5. Malignancy for which the patient has undergone resection, radiation therapy or chemotherapy. 6. Active tuberculosis. 7. Alcohol or drug abuse. 8. Thoracotomy with pulmonary resection. 9. Pulmonary rehabilitation program. 10. Hypersensitivity to anticholinergic drugs, or any components of the study medication delivery system. 11. Pregnant or nursing adolescent female patients. 12. Female patients of child-bearing potential not using a highly effective method of birth control. 13. Investigational drug within four weeks or six half lives prior to Visit 1. 14. Long-acting anticholinergics within four weeks prior to Visit 1. 15. Systemic corticosteroids at a high dose or at a not stable low dose within four weeks prior to Visit 1. 16. Leukotriene modifiers if not stabilised for at least four weeks prior to Visit 1. 17. Long-acting theophylline preparations if not stabilised for at least two weeks prior to Visit 1. 18. Anti Immunoglobulin E (Anti-IgE) treatment if not stabilised for at least six months prior to Visit 1. 19. Cromones if not stabilised within four weeks prior to Visit 1. 20. Oral beta-blocker medication within four weeks prior to Visit 1. 21. Systemic oral or i.v. or s.c. beta-adrenergics within four weeks prior to Visit 1. 22. Other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1. 23. Any acute asthma exacerbation or respiratory tract infection in the four weeks prior to Visit 1and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed. 24. Randomised in this trial or currently participating in another trial. 25. Narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated. 26. Moderate to severe renal impairment. 27. Patients requiring 10 or more puffs of rescue medication per day on more than 2 consecutive days in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 peak0-3 Change From Baseline | Baseline and 12 weeks | Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 12. Measured values presented are actually adjusted means. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FVC peak0-3 Change From Baseline | Baseline and 12 weeks | Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak0-3h) after 12 weeks of treatment. The measured values presented are actually adjusted means. |
| FEV1 AUC (0-3h) Change From Baseline | Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks | Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). Measured values presented are actually adjusted means. |
| FVC AUC (0-3h) Change From Baseline | Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks | Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). Measured values presented are actually adjusted means. |
| Control of Asthma as Assessed by ACQ6 Score. | Baseline and 12 weeks | Change from baseline in Asthma Control Questionnaire (ACQ) 6 score measured at week 12 The ACQ is a scale containing 7 questions, each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ6. The measured values presented are actually adjusted means. |
| ACQ6 Score Responders | 12 weeks | Responder rates based on the ACQ6 score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline \<= -0.5), no change (-0.5 \< change from trial baseline \<0.5) and worsening (change from trial baseline \>= 0.5). The ACQ is a scale containing 7 questions, each question has a 7- point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 is calculated as the mean of the responses to the first 6 questions of the ACQ6. No statistical testing was performed on ACQ6 responders. |
| Control of Asthma as Assessed by ACQ Total Score | Baseline and 12 weeks | Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 12. The ACQ is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ total score is calculated as the mean of the responses to all 7 questions. The measured values presented are actually adjusted means. |
| Trough FEV1 Change From Baseline | Baseline and 12 weeks | Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12. Measured values presented are actually adjusted means. |
| Use of PRN Rescue Medication During the Day | Baseline and 12 weeks | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 12. The measured values presented are actually adjusted means. |
| Use of PRN Rescue Medication During the Daytime | Baseline and 12 weeks | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12. Measured values presented are actually adjusted means. |
| Use of PRN Rescue Medication During the Night-time | Baseline and 12 weeks | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12. Measured values presented are actually adjusted means |
| Time to First Severe Asthma Exacerbation During the 12-week Treatment Period. | 12 weeks | Time in days to first severe asthma exacerbation during the 12 week treatment period. The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values. A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required an initiation of treatment with systemic corticosteroids for at least 3 days or, in case of ongoing and pre-existing systemic corticosteroid therapy, requiring at least doubling of previous daily doses of systemic corticosteroids for at least 3 days. |
| Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period. | 12 weeks | Time in days to first asthma exacerbation during the 12 week treatment period. The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values. |
| Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | From first drug administration until 30 days after last drug intake, up to 142 days | Clinically relevant abnormalities for physical examination, ECG, vital signs and laboratory tests. New abnormal findings or worsening of baseline conditions were reported as adverse events. |
| ACQ Total Score Responders | 12 weeks | Responder rates based on the ACQ total score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 \<change from trial baseline \<0.5) and worsening (change from trial baseline ≥0.5) No statistical testing was performed for ACQ total score responders. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. |
Countries
Argentina, Australia, Bulgaria, Germany, Guatemala, Hungary, Israel, Latvia, Mexico, Philippines, Portugal, South Africa, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Respimat Inhalation of placebo solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. | 135 |
| Tio R2.5 Inhalation of 2.5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. | 127 |
| Tio R5 Inhalation of 5mcg tiotropium bromide solution once daily for 12 weeks delivered by the Respimat Inhaler, as add on therapy on top of usual care. | 130 |
| Total | 392 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Other Reason not Defined | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo Respimat | Tio R2.5 | Tio R5 | Total |
|---|---|---|---|---|
| Age, Continuous | 14.1 years STANDARD_DEVIATION 1.7 | 14.4 years STANDARD_DEVIATION 1.8 | 14.3 years STANDARD_DEVIATION 1.6 | 14.2 years STANDARD_DEVIATION 1.7 |
| Sex: Female, Male Female | 56 Participants | 47 Participants | 47 Participants | 150 Participants |
| Sex: Female, Male Male | 79 Participants | 80 Participants | 83 Participants | 242 Participants |
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 | 23 / 135 | 23 / 127 | 16 / 130 |
| serious Total, serious adverse events | 0 / 135 | 1 / 127 | 2 / 130 |
Outcome results
Primary
FEV1 peak0-3 Change From Baseline
Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | FEV1 peak0-3 Change From Baseline | 0.438 litres | Standard Error 0.045 |
| Tio R2.5 | FEV1 peak0-3 Change From Baseline | 0.550 litres | Standard Error 0.046 |
| Tio R5 | FEV1 peak0-3 Change From Baseline | 0.528 litres | Standard Error 0.045 |
p-value: 0.045795% CI: [0.002, 0.22]Mixed Models Analysis
p-value: 0.103995% CI: [-0.019, 0.198]Mixed Models Analysis
Secondary
ACQ6 Score Responders
Responder rates based on the ACQ6 score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline \<= -0.5), no change (-0.5 \< change from trial baseline \<0.5) and worsening (change from trial baseline \>= 0.5). The ACQ is a scale containing 7 questions, each question has a 7- point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 is calculated as the mean of the responses to the first 6 questions of the ACQ6. No statistical testing was performed on ACQ6 responders.
Time frame: 12 weeks
Population: Full Analysis Set which included all randomised patients who were dispensed and received at least one documented dose of trial medication.~Missing data for patients not withdrawn from the study were either categorised as no change or based on available data, withdrawn patients were imputed based upon discontinuation reason.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Respimat | ACQ6 Score Responders | No Change | 23.7 percentage of participants |
| Placebo Respimat | ACQ6 Score Responders | Responder | 74.1 percentage of participants |
| Placebo Respimat | ACQ6 Score Responders | Worsening | 2.2 percentage of participants |
| Tio R2.5 | ACQ6 Score Responders | No Change | 19.7 percentage of participants |
| Tio R2.5 | ACQ6 Score Responders | Responder | 74.0 percentage of participants |
| Tio R2.5 | ACQ6 Score Responders | Worsening | 6.3 percentage of participants |
| Tio R5 | ACQ6 Score Responders | Responder | 74.6 percentage of participants |
| Tio R5 | ACQ6 Score Responders | Worsening | 2.3 percentage of participants |
| Tio R5 | ACQ6 Score Responders | No Change | 23.1 percentage of participants |
Secondary
ACQ Total Score Responders
Responder rates based on the ACQ total score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 \<change from trial baseline \<0.5) and worsening (change from trial baseline ≥0.5) No statistical testing was performed for ACQ total score responders. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment.
Time frame: 12 weeks
Population: Full Analysis Set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data for patients not withdrawn from the study were either categorised as no change or based on available data. Withdrawn patients were imputed based upon discontinuation reason.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Respimat | ACQ Total Score Responders | No Change | 23.7 percentage of participants |
| Placebo Respimat | ACQ Total Score Responders | Responder | 73.3 percentage of participants |
| Placebo Respimat | ACQ Total Score Responders | Worsening | 3.0 percentage of participants |
| Tio R2.5 | ACQ Total Score Responders | No Change | 22.0 percentage of participants |
| Tio R2.5 | ACQ Total Score Responders | Responder | 74.8 percentage of participants |
| Tio R2.5 | ACQ Total Score Responders | Worsening | 3.1 percentage of participants |
| Tio R5 | ACQ Total Score Responders | Responder | 73.1 percentage of participants |
| Tio R5 | ACQ Total Score Responders | Worsening | 0.8 percentage of participants |
| Tio R5 | ACQ Total Score Responders | No Change | 26.2 percentage of participants |
Secondary
Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period.
Time in days to first asthma exacerbation during the 12 week treatment period. The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values.
Time frame: 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Respimat | Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period. | 25 participants |
| Tio R2.5 | Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period. | 18 participants |
| Tio R5 | Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period. | 15 participants |
p-value: 0.356795% CI: [0.41, 1.38]Regression, Cox
p-value: 0.116895% CI: [0.32, 1.14]Regression, Cox
Secondary
Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests
Clinically relevant abnormalities for physical examination, ECG, vital signs and laboratory tests. New abnormal findings or worsening of baseline conditions were reported as adverse events.
Time frame: From first drug administration until 30 days after last drug intake, up to 142 days
Population: Treated set which included all randomised patients who were dispensed and received, at least one documented dose of trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Respimat | Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | Peak expiratory flow rate decreased | 9.6 percentage of participants |
| Placebo Respimat | Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | Blood glucose decreased | 0.0 percentage of participants |
| Tio R2.5 | Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | Peak expiratory flow rate decreased | 7.1 percentage of participants |
| Tio R2.5 | Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | Blood glucose decreased | 0.8 percentage of participants |
| Tio R5 | Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | Peak expiratory flow rate decreased | 3.8 percentage of participants |
| Tio R5 | Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | Blood glucose decreased | 0.0 percentage of participants |
Secondary
Control of Asthma as Assessed by ACQ6 Score.
Change from baseline in Asthma Control Questionnaire (ACQ) 6 score measured at week 12 The ACQ is a scale containing 7 questions, each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ6. The measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Control of Asthma as Assessed by ACQ6 Score. | 1.144 units on a scale | Standard Error 0.069 |
| Tio R2.5 | Control of Asthma as Assessed by ACQ6 Score. | 1.262 units on a scale | Standard Error 0.071 |
| Tio R5 | Control of Asthma as Assessed by ACQ6 Score. | 1.197 units on a scale | Standard Error 0.07 |
p-value: 0.181995% CI: [-0.055, 0.292]Mixed Models Analysis
p-value: 0.544895% CI: [-0.119, 0.226]Mixed Models Analysis
Secondary
Control of Asthma as Assessed by ACQ Total Score
Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 12. The ACQ is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ total score is calculated as the mean of the responses to all 7 questions. The measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Control of Asthma as Assessed by ACQ Total Score | 1.234 units on a scale | Standard Error 0.064 |
| Tio R2.5 | Control of Asthma as Assessed by ACQ Total Score | 1.292 units on a scale | Standard Error 0.066 |
| Tio R5 | Control of Asthma as Assessed by ACQ Total Score | 1.270 units on a scale | Standard Error 0.065 |
p-value: 0.476295% CI: [-0.102, 0.219]Mixed Models Analysis
p-value: 0.655895% CI: [-0.123, 0.196]Mixed Models Analysis
Secondary
FEV1 AUC (0-3h) Change From Baseline
Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). Measured values presented are actually adjusted means.
Time frame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | FEV1 AUC (0-3h) Change From Baseline | 0.336 Litres | Standard Error 0.043 |
| Tio R2.5 | FEV1 AUC (0-3h) Change From Baseline | 0.449 Litres | Standard Error 0.043 |
| Tio R5 | FEV1 AUC (0-3h) Change From Baseline | 0.423 Litres | Standard Error 0.043 |
p-value: 0.033895% CI: [0.009, 0.217]Mixed Models Analysis
p-value: 0.099995% CI: [-0.017, 0.191]Mixed Models Analysis
Secondary
FVC AUC (0-3h) Change From Baseline
Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). Measured values presented are actually adjusted means.
Time frame: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | FVC AUC (0-3h) Change From Baseline | 0.175 litres | Standard Error 0.045 |
| Tio R2.5 | FVC AUC (0-3h) Change From Baseline | 0.262 litres | Standard Error 0.047 |
| Tio R5 | FVC AUC (0-3h) Change From Baseline | 0.227 litres | Standard Error 0.046 |
p-value: 0.125295% CI: [-0.024, 0.198]Mixed Models Analysis
p-value: 0.354995% CI: [-0.058, 0.163]Mixed Models Analysis
Secondary
FVC peak0-3 Change From Baseline
Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak0-3h) after 12 weeks of treatment. The measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | FVC peak0-3 Change From Baseline | 0.279 Litres | Standard Error 0.048 |
| Tio R2.5 | FVC peak0-3 Change From Baseline | 0.370 Litres | Standard Error 0.049 |
| Tio R5 | FVC peak0-3 Change From Baseline | 0.342 Litres | Standard Error 0.048 |
p-value: 0.126495% CI: [-0.026, 0.207]Mixed Models Analysis
p-value: 0.284595% CI: [-0.053, 0.179]Mixed Models Analysis
Secondary
Time to First Severe Asthma Exacerbation During the 12-week Treatment Period.
Time in days to first severe asthma exacerbation during the 12 week treatment period. The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values. A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required an initiation of treatment with systemic corticosteroids for at least 3 days or, in case of ongoing and pre-existing systemic corticosteroid therapy, requiring at least doubling of previous daily doses of systemic corticosteroids for at least 3 days.
Time frame: 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Respimat | Time to First Severe Asthma Exacerbation During the 12-week Treatment Period. | 1 participants |
| Tio R2.5 | Time to First Severe Asthma Exacerbation During the 12-week Treatment Period. | 1 participants |
| Tio R5 | Time to First Severe Asthma Exacerbation During the 12-week Treatment Period. | 2 participants |
p-value: 0.967195% CI: [0.07, 16.95]Regression, Cox
p-value: 0.555795% CI: [0.19, 22.7]Regression, Cox
Secondary
Trough FEV1 Change From Baseline
Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Trough FEV1 Change From Baseline | 0.230 litres | Standard Error 0.048 |
| Tio R2.5 | Trough FEV1 Change From Baseline | 0.345 litres | Standard Error 0.048 |
| Tio R5 | Trough FEV1 Change From Baseline | 0.284 litres | Standard Error 0.048 |
p-value: 0.050995% CI: [0, 0.231]Mixed Models Analysis
p-value: 0.360595% CI: [-0.061, 0.168]Mixed Models Analysis
Secondary
Use of PRN Rescue Medication During the Day
Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 12. The measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data was imputed by the available data from the patient. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Use of PRN Rescue Medication During the Day | -0.482 Number of puffs of rescue medication | Standard Error 0.118 |
| Tio R2.5 | Use of PRN Rescue Medication During the Day | -0.483 Number of puffs of rescue medication | Standard Error 0.122 |
| Tio R5 | Use of PRN Rescue Medication During the Day | -0.540 Number of puffs of rescue medication | Standard Error 0.12 |
p-value: 0.99695% CI: [-0.301, 0.3]Mixed Models Analysis
p-value: 0.70395% CI: [-0.355, 0.239]Mixed Models Analysis
Secondary
Use of PRN Rescue Medication During the Daytime
Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data was imputed by the available data from the patient. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Use of PRN Rescue Medication During the Daytime | -0.262 Number of puffs of rescue medication | Standard Error 0.073 |
| Tio R2.5 | Use of PRN Rescue Medication During the Daytime | -0.295 Number of puffs of rescue medication | Standard Error 0.075 |
| Tio R5 | Use of PRN Rescue Medication During the Daytime | -0.312 Number of puffs of rescue medication | Standard Error 0.073 |
p-value: 0.730995% CI: [-0.217, 0.153]Mixed Models Analysis
p-value: 0.595495% CI: [-0.232, 0.133]Mixed Models Analysis
Secondary
Use of PRN Rescue Medication During the Night-time
Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12. Measured values presented are actually adjusted means
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data was imputed by the available data from the patient. Completely missing data were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Use of PRN Rescue Medication During the Night-time | -0.180 Number of puffs of rescue medication | Standard Error 0.064 |
| Tio R2.5 | Use of PRN Rescue Medication During the Night-time | -0.092 Number of puffs of rescue medication | Standard Error 0.066 |
| Tio R5 | Use of PRN Rescue Medication During the Night-time | -0.159 Number of puffs of rescue medication | Standard Error 0.065 |
p-value: 0.284195% CI: [-0.074, 0.252]Mixed Models Analysis
p-value: 0.79595% CI: [-0.14, 0.182]Mixed Models Analysis