Asthma
Conditions
Brief summary
The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium compared to placebo over 12 week treatment period. Tiotropium inhalation solution will be delivered via Respimat inhaler and will be examined on top of maintenance inhaled corticosteroid treatment in patients with mild persistent asthma. Efficacy and safety will be assessed by measuring the effects on lung functions, effects on lung exacerbations, effects on asthma control and numbers of adverse events.
Interventions
DRUGplacebo
To evaluate efficacy and safety of 2.5 and 5 mcg tiotropium versus placebo delivered via Respimat inhaler
DRUGtiotropium 2.5 mcg
To evaluate efficacy and safety of 2.5 and 5 mcg tiotropium versus placebo delivered via Respimat inhaler
DRUGtiotropium 5 mcg
To evaluate efficacy and safety of 2.5 and 5 mcg tiotropium versus placebo delivered via Respimat inhaler
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation -Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1). 2. Male or female patients aged 18 years or more at Visit 0 and 75 years or less at Visit 0. All patients must have 3. at least a 3 months history of asthma at the time of enrolment into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40; 4. a pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)= 60% predicted and = 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%. 5. Patient's diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (within 10 minutes pre and 15-30 minutes after 400 µg salbutamol/albuterol) resulting in a FEV1 increase of = 12% and = 200mL. If this is not achieved the reversibility test may be repeated once within two weeks. 6. All patients must be symptomatic despite their current maintenance treatment with low doses of inhaled corticosteroids. 7. All patients must be symptomatic at Visit 1 (screening) and Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of = 1.5. 8. All patients must have been on maintenance treatment with a low, stable dose of inhaled corticosteroids for at least 4 weeks prior to Visit 1. 9. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years ((see Appendix 10.3 for calculation). 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 pulmonary function tests and use of the e-Diary/peak flow meter (e-Diary-compliance of at least 80% is required; refer to Section 6.2.1 for instructions). 12. Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).
Exclusion criteria
1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the Investigator, may (i) put the patient at risk because of participation in the trial, or (ii) cause concern regarding the patient's ability to participate in the trial. 2. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion number 1. 3. Patients requiring more than 10 puffs of rescue medication (salbutamol/albuterol MDI) per 24 hours on 2 consecutive days during the screening period. 4. Patients with a recent history (i.e. six months or less) of Acute Coronary Syndrome (STEMI, Non-STEMI and Unstable Angina Pectoris). 5. Patients who have been hospitalised for cardiac failure during the past year. 6. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 7. Patients with lung diseases other than asthma (e.g. COPD). 8. Patients with known active tuberculosis. 9. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed. 10. 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. 11. Patients with significant alcohol or drug abuse on Investigator's assessment within the past two years. 12. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening). 13. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. 14. Pregnant or nursing woman, including female patients with positive beta-HCG test at Visit 1. 15. Female patients of child-bearing potential not using highly effective method of birth control As defined in ICH (M3). 16. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period.Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed. 17. Patients who have been treated with oral or patch beta-adrenergics, systemic, i.e. oral or intravenous corticosteroids, long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 and/or during the screening period. 18. Patients who have been treated with depot corticosteroids within six months prior to Visit 1 and/or during the screening period. 19. Patients who have ever been treated with anti-IgE antibodies. 20. Patients who have been treated with leukotriene modifiers, systemic anticholinergics, cromolyn sodium or nedocromil sodium and methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period. 21. Patients who have been treated with inhaled long acting beta adrenergics and long acting beta adrenergics combination products within four weeks prior to Visit 0 and/or during the screening period. 22. Patients who have taken an investigational drug within four weeks or six half lives whichever is greater prior to Visit 1. 23. Patients who have been treated with other non-approved and according to international guidelines not recommended, experimental drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). 24. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). 25. Current participation in another trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 Weeks. | Baseline and 12 weeks | Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit and baseline\*visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-week Treatment Period. | Baseline and 12 weeks | Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit and baseline\*visit. |
| FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-week Treatment Period. | Baseline and 12 weeks | The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit baseline\*visit. |
| FVC (AUC0-3h) Response at the End of the 12-week Treatment Period. | Baseline and 12 weeks | The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit baseline\*visit. |
| Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | 12 weeks | For the ACQ, the total score was calculated as the mean of the responses to 6 self administered questions and one question which was completed by clinical staff based upon pre-bronchodilator FEV1. The score ranges from 0 (no impairment) to 6 (maximum impairment). Response was categorised as: responder (change from baseline \<= -0.5), no change (-0.5 \<change from baseline \< 0.5) and worsening (change from baseline \>= 0.5). |
| Trough FEV1 Response Determined After a Treatment Period of 12 Weeks. | Baseline and 12 weeks | The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 12 weeks and the trough FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Time to First Asthma Exacerbation During the 12-week Treatment. | 12 weeks | An asthma exacerbation was defined as an episode of progressive increase in 1 or more asthma symptom that were outside the patient's usual range of day-to-day asthma symptoms and lasted for at least 2 consecutive days or as a decrease in a patient's best morning PEF of 30% or more from a patient's mean morning PEF for at least 2 consecutive days that may or may not have been accompanied by symptoms. |
| Use of Rescue Medication During 24h Period | Baseline and 12 weeks | Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during 24 h period), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment\*week and baseline\*week. |
| Use of Rescue Medication During Daytime | Baseline and 12 weeks | Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during daytime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment\*week and baseline\*week. |
| Use of Rescue Medication During Nighttime | Baseline and 12 weeks | Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during nighttime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment\*week and baseline\*week. |
| Time to First Severe Asthma Exacerbation During the 12-week Treatment. | 12 weeks | Severe asthma exacerbations are defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days. |
Countries
Argentina, Austria, Croatia, Estonia, Guatemala, Hungary, India, Italy, Latvia, Poland, Slovakia, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients treated with matching placebo | 155 |
| Tio R2.5 Patients treated with tiotropium inhalation solution 2.5 microgram qd | 154 |
| Tio R5 Patients treated with tiotropium inhalation solution 5 microgram qd | 155 |
| Total | 464 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 1 |
| Overall Study | Not treated | 1 | 0 | 0 |
| Overall Study | Other | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Tio R2.5 | Tio R5 | Total |
|---|---|---|---|---|
| Age, Continuous | 42.8 Years STANDARD_DEVIATION 12.1 | 43.8 Years STANDARD_DEVIATION 14 | 41.9 Years STANDARD_DEVIATION 13 | 42.9 Years STANDARD_DEVIATION 13 |
| Sex: Female, Male Female | 103 Participants | 82 Participants | 96 Participants | 281 Participants |
| Sex: Female, Male Male | 52 Participants | 72 Participants | 59 Participants | 183 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 | 25 / 155 | 30 / 154 | 21 / 155 |
| serious Total, serious adverse events | 1 / 155 | 0 / 154 | 1 / 155 |
Outcome results
Primary
Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 Weeks.
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 12 weeks
Population: All patients from Full Analysis Set (FAS) FAS is defined as all patients in the treated set who received at least one dose of randomized trial medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 Weeks. | 0.134 Liter | Standard Error 0.026 |
| Tio R2.5 | Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 Weeks. | 0.293 Liter | Standard Error 0.026 |
| Tio R5 | Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 Weeks. | 0.262 Liter | Standard Error 0.026 |
p-value: 0.000595% CI: [0.057, 0.199]Mixed Models Analysis
p-value: <0.000195% CI: [0.088, 0.23]Mixed Models Analysis
Secondary
Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment
For the ACQ, the total score was calculated as the mean of the responses to 6 self administered questions and one question which was completed by clinical staff based upon pre-bronchodilator FEV1. The score ranges from 0 (no impairment) to 6 (maximum impairment). Response was categorised as: responder (change from baseline \<= -0.5), no change (-0.5 \<change from baseline \< 0.5) and worsening (change from baseline \>= 0.5).
Time frame: 12 weeks
Population: All patients from FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | No change | 61 Number of patients |
| Placebo | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | Responder | 91 Number of patients |
| Placebo | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | Worsening | 2 Number of patients |
| Tio R2.5 | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | No change | 48 Number of patients |
| Tio R2.5 | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | Responder | 91 Number of patients |
| Tio R2.5 | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | Worsening | 10 Number of patients |
| Tio R5 | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | Responder | 90 Number of patients |
| Tio R5 | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | Worsening | 5 Number of patients |
| Tio R5 | Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | No change | 57 Number of patients |
Secondary
FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-week Treatment Period.
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit baseline\*visit.
Time frame: Baseline and 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-week Treatment Period. | 0.048 Liter | Standard Error 0.024 |
| Tio R2.5 | FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-week Treatment Period. | 0.198 Liter | Standard Error 0.024 |
| Tio R5 | FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-week Treatment Period. | 0.174 Liter | Standard Error 0.025 |
p-value: 0.000395% CI: [0.058, 0.192]Mixed Models Analysis
p-value: <0.000195% CI: [0.082, 0.216]Mixed Models Analysis
Secondary
FVC (AUC0-3h) Response at the End of the 12-week Treatment Period.
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit baseline\*visit.
Time frame: Baseline and 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC (AUC0-3h) Response at the End of the 12-week Treatment Period. | -0.000 Liter | Standard Error 0.028 |
| Tio R2.5 | FVC (AUC0-3h) Response at the End of the 12-week Treatment Period. | 0.101 Liter | Standard Error 0.028 |
| Tio R5 | FVC (AUC0-3h) Response at the End of the 12-week Treatment Period. | 0.061 Liter | Standard Error 0.028 |
p-value: 0.118295% CI: [-0.016, 0.138]Mixed Models Analysis
p-value: 0.010295% CI: [0.024, 0.178]Mixed Models Analysis
Secondary
Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-week Treatment Period.
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-week Treatment Period. | 0.126 Liter | Standard Error 0.03 |
| Tio R2.5 | Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-week Treatment Period. | 0.231 Liter | Standard Error 0.03 |
| Tio R5 | Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-week Treatment Period. | 0.183 Liter | Standard Error 0.03 |
p-value: 0.171495% CI: [-0.025, 0.14]Mixed Models Analysis
p-value: 0.011995% CI: [0.023, 0.188]Mixed Models Analysis
Secondary
Time to First Asthma Exacerbation During the 12-week Treatment.
An asthma exacerbation was defined as an episode of progressive increase in 1 or more asthma symptom that were outside the patient's usual range of day-to-day asthma symptoms and lasted for at least 2 consecutive days or as a decrease in a patient's best morning PEF of 30% or more from a patient's mean morning PEF for at least 2 consecutive days that may or may not have been accompanied by symptoms.
Time frame: 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Asthma Exacerbation During the 12-week Treatment. | NA Days |
| Tio R2.5 | Time to First Asthma Exacerbation During the 12-week Treatment. | NA Days |
| Tio R5 | Time to First Asthma Exacerbation During the 12-week Treatment. | NA Days |
Comparison: Since only 22 of the 155 patients in the placebo group, 21 of the 154 patients in the Tio R2.5 group and 13 of the 155 patients in the Tio R5 group had asthma exacerbations, the median times were not calculable (nc).p-value: 0.121795% CI: [0.29, 1.16]Regression, Cox
Comparison: Since only 22 of the 155 patients in the placebo group, 21 of the 154 patients in the Tio R2.5 group and 13 of the 155 patients in the Tio R5 group had asthma exacerbations, the median times were not calculable (nc). The Hazard Ratio is still estimable from the Cox model.p-value: 0.897495% CI: [0.53, 1.75]Regression, Cox
Secondary
Time to First Severe Asthma Exacerbation During the 12-week Treatment.
Severe asthma exacerbations are defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days.
Time frame: 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Severe Asthma Exacerbation During the 12-week Treatment. | NA Days |
| Tio R2.5 | Time to First Severe Asthma Exacerbation During the 12-week Treatment. | NA Days |
| Tio R5 | Time to First Severe Asthma Exacerbation During the 12-week Treatment. | NA Days |
Comparison: Since the percent patients with event is less than 50% the median is not calculable, but Hazard Ratio is still estimable from the Cox model.p-value: 0.215595% CI: [0.03, 2.24]Regression, Cox
Comparison: Since the percent patients with event is less than 50% the median is not calculable, but Hazard Ratio is still estimable from the Cox model.p-value: 0.507195% CI: [0.43, 5.44]Regression, Cox
Secondary
Trough FEV1 Response Determined After a Treatment Period of 12 Weeks.
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 12 weeks and the trough FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response Determined After a Treatment Period of 12 Weeks. | 0.015 Liter | Standard Error 0.026 |
| Tio R2.5 | Trough FEV1 Response Determined After a Treatment Period of 12 Weeks. | 0.125 Liter | Standard Error 0.026 |
| Tio R5 | Trough FEV1 Response Determined After a Treatment Period of 12 Weeks. | 0.137 Liter | Standard Error 0.027 |
p-value: 0.00195% CI: [0.049, 0.194]Mixed Models Analysis
p-value: 0.002895% CI: [0.038, 0.182]Mixed Models Analysis
Secondary
Use of Rescue Medication During 24h Period
Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during 24 h period), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment\*week and baseline\*week.
Time frame: Baseline and 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Use of Rescue Medication During 24h Period | -0.815 puffs of rescue medication | Standard Error 0.093 |
| Tio R2.5 | Use of Rescue Medication During 24h Period | -0.594 puffs of rescue medication | Standard Error 0.093 |
| Tio R5 | Use of Rescue Medication During 24h Period | -0.848 puffs of rescue medication | Standard Error 0.093 |
Comparison: Restricted maximum likelihood (REML)- based repeated measures model was used.p-value: 0.087295% CI: [-0.032, 0.476]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)- based repeated measures model was used.p-value: 0.799595% CI: [-0.287, 0.221]Mixed Models Analysis
Secondary
Use of Rescue Medication During Daytime
Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during daytime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment\*week and baseline\*week.
Time frame: Baseline and 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Use of Rescue Medication During Daytime | -0.428 puffs of rescue medication | Standard Error 0.055 |
| Tio R2.5 | Use of Rescue Medication During Daytime | -0.331 puffs of rescue medication | Standard Error 0.055 |
| Tio R5 | Use of Rescue Medication During Daytime | -0.436 puffs of rescue medication | Standard Error 0.055 |
Comparison: Restricted maximum likelihood (REML)- based repeated measures model was used. Means are adjusted for treatment, centre, week, baseline, treatment\*week and baseline\*week.p-value: 0.203895% CI: [-0.053, 0.247]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)- based repeated measures model was used.p-value: 0.910495% CI: [-0.158, 0.141]Mixed Models Analysis
Secondary
Use of Rescue Medication During Nighttime
Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during nighttime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment\*week and baseline\*week.
Time frame: Baseline and 12 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Use of Rescue Medication During Nighttime | -0.376 puffs of rescue medication | Standard Error 0.049 |
| Tio R2.5 | Use of Rescue Medication During Nighttime | -0.245 puffs of rescue medication | Standard Error 0.049 |
| Tio R5 | Use of Rescue Medication During Nighttime | -0.386 puffs of rescue medication | Standard Error 0.049 |
Comparison: Restricted maximum likelihood (REML)- based repeated measures model was used.p-value: 0.055995% CI: [-0.003, 0.265]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)- based repeated measures model was used.p-value: 0.879595% CI: [-0.144, 0.123]Mixed Models Analysis