Asthma
Conditions
Brief summary
The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution (2.5 mcg and 5 mcg) delivered via Respimat® inhaler once daily in the evening over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in children (6 to 11 years old) with severe persistent asthma.
Interventions
DRUGPlacebo
2 actuations once daily in the evening
DRUGTiotropium low dose mcg
2 actuations once daily in the evening
2 actuations once daily in the evening
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
Inclusion criteria are: 1. All patients' parent(s) (or legal guardian) must sign and date an informed consent prior to participation in the trial. In addition, an informed assent suitable for this age group has to be obtained from patients. A separate informed consent/assent is required for pharmacogenomic sampling. 2. Male or female patients between 6 and 11 years of age. 3. All patients must have at least a 6-month history of asthma. 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 (partly controlled) at Visit 1 and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ-IA) mean score \>= 1.5. 6. All patients must have a pre-bronchodilator forced expiratory volume in one 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% 15 to 30 minutes after 200 mcg salbutamol/albuterol. 9. Patients must be able to use the Respimat inhaler correctly. 10. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Peak(0-3h) 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 peak(0-3h)) measured at week 12. Measured values presented are actually adjusted means. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| FVC Peak(0-3h) 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 peak(0-3h)) 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 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. |
| FEV1 Change From Baseline at Each Individual Timepoint | Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks | Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint. The measured values presented are actually adjusted means. |
| FVC Change From Baseline at Each Individual Timepoint | Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks | FVC change from baseline at each individual timepoint. The measured values presented are actually adjusted means. |
| Control of Asthma as Assessed by ACQ-IA Total Score | Baseline and 12 weeks | Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12. The ACQ-IA 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-IA total score is calculated as the mean of the responses to all 7 questions. The measured values presented are actually adjusted means. |
| ACQ-IA Total Score Responders | 12 weeks | Responder categories based on the ACQ-IA 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-IA total score responders. The ACQ-IA 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. |
| Use of PRN Rescue Medication Per Day | Baseline and 12 weeks | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per 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 |
| Trough FVC Change From Baseline | Baseline and 12 weeks | Change from baseline in Trough (pre-dose) FVC measured at week 12. Measured values presented are actually adjusted means. |
| Peak Expiratory Flow (PEF) p.m. Change From Baseline | Baseline and 12 weeks | Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at week 12. Measured values presented are actually adjusted means. |
| Peak Expiratory Flow (PEF) Variability Change From Baseline | Baseline and 12 weeks | Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12. Measured values presented are actually adjusted means. |
| FEV1 a.m. Change From Baseline | Baseline and 12 weeks | Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 12. Measured values presented are actually adjusted means. |
| FEV1 p.m. Change From Baseline | Baseline and 12 weeks | Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 12. Measured values presented are actually adjusted means. |
| Change From Baseline in Nighttime Awakenings | Baseline and 12 weeks | Change from baseline in nighttime awakenings based on the weekly mean at week 12. Nighttime awakenings was assessed by the question Did you wake up during the night due to your asthma? from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night). Measured values presented are actually adjusted means. |
| Change From Baseline in Morning Asthma Symptoms | Baseline and 12 weeks | Change from baseline in morning asthma symptoms based on the weekly mean at week 12. Morning asthma symptoms was assessed by the question how were your asthma symptoms this morning? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means. |
| Change From Baseline in Daytime Asthma Symptoms | Baseline and 12 weeks | Change from baseline in daytime asthma symptoms based on the weekly mean at week 12. Daytime asthma symptoms was assessed by the question how were your asthma symptoms during the day? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means. |
| Change From Baseline in Daytime Activity Limitations | Baseline and 12 weeks | Change from baseline in daytime activity limitations based on the weekly mean at week 12. Daytime activity limitations was assessed by the question how limited were you in your activities today because of your asthma? from the e-diary. Scores range from 1 (not limited) to 5 (totally limited). Measured values presented are actually adjusted means. |
| Change From Baseline in Daytime Experiences of Shortness of Breath | Baseline and 12 weeks | Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12. Daytime experiences of shortness of breath was assessed by the question how much shortness of breath did you experience during the day from the e-diary. Scores range from 1 (none) to 5 (a very great deal). Measured values presented are actually adjusted means. |
| Change From Baseline in Daytime Experiences of Wheeze or Cough | Baseline and 12 weeks | Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12. Daytime experiences of wheeze or cough was assessed by the question did you experience wheeze or cough during the day? from the e-diary. Scores range from 1 (not at all) to 5 (all the time). Measured values presented are actually adjusted means. |
| Change From Baseline in Asthma Symptom-free Days | Baseline and 12 weeks | Change from baseline in asthma symptom-free days based on the weekly mean at week 12. A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day. Measured values presented are actually adjusted means. |
| Peak Expiratory Flow (PEF) a.m. Change From Baseline | Baseline and 12 weeks | Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at week 12. Measured values presented are actually adjusted means. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Czechia, Germany, Guatemala, Hungary, Latvia, Lithuania, Poland, Romania, Russia, Slovakia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Respimat Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care. | 134 |
| Tio R2.5 Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care. | 136 |
| Tio R5 Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care. | 130 |
| Total | 400 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 2 |
| Overall Study | Consent withdrawn not due to AE | 1 | 0 | 1 |
| Overall Study | Not treated | 0 | 1 | 0 |
| Overall Study | Other reason not defined above | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Respimat | Tio R2.5 | Tio R5 | Total |
|---|---|---|---|---|
| Age, Continuous | 9.1 Years STANDARD_DEVIATION 1.6 | 8.8 Years STANDARD_DEVIATION 1.7 | 9.2 Years STANDARD_DEVIATION 1.6 | 9.0 Years STANDARD_DEVIATION 1.6 |
| Sex: Female, Male Female | 41 Participants | 40 Participants | 40 Participants | 121 Participants |
| Sex: Female, Male Male | 93 Participants | 96 Participants | 90 Participants | 279 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 | 49 / 134 | 36 / 136 | 35 / 130 |
| serious Total, serious adverse events | 2 / 134 | 2 / 136 | 4 / 130 |
Outcome results
Primary
FEV1 Peak(0-3h) Change From Baseline
Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak(0-3h)) 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 Peak(0-3h) Change From Baseline | 0.252 Litres | Standard Error 0.025 |
| Tio R2.5 | FEV1 Peak(0-3h) Change From Baseline | 0.287 Litres | Standard Error 0.025 |
| Tio R5 | FEV1 Peak(0-3h) Change From Baseline | 0.391 Litres | Standard Error 0.026 |
Comparison: Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis was performed in a stepwise manner, firstly for this endpoint, then Trough FEV1. Each step was only considered confirmatory if all previous steps were successful.p-value: 0.272495% CI: [-0.028, 0.099]Mixed Models Analysis
Comparison: Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis was performed in a stepwise manner, firstly for this endpoint, then Trough FEV1. Each step was only considered confirmatory if all previous steps were successful.p-value: <0.000195% CI: [0.075, 0.203]Mixed Models Analysis
Secondary
ACQ-IA Total Score Responders
Responder categories based on the ACQ-IA 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-IA total score responders. The ACQ-IA 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: FAS, 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-IA Total Score Responders | No change | 20.9 Percentage of participants |
| Placebo Respimat | ACQ-IA Total Score Responders | Responder | 76.9 Percentage of participants |
| Placebo Respimat | ACQ-IA Total Score Responders | Worsening | 2.2 Percentage of participants |
| Tio R2.5 | ACQ-IA Total Score Responders | No change | 18.4 Percentage of participants |
| Tio R2.5 | ACQ-IA Total Score Responders | Responder | 79.4 Percentage of participants |
| Tio R2.5 | ACQ-IA Total Score Responders | Worsening | 2.2 Percentage of participants |
| Tio R5 | ACQ-IA Total Score Responders | Responder | 80.8 Percentage of participants |
| Tio R5 | ACQ-IA Total Score Responders | Worsening | 3.1 Percentage of participants |
| Tio R5 | ACQ-IA Total Score Responders | No change | 16.2 Percentage of participants |
Secondary
Change From Baseline in Asthma Symptom-free Days
Change from baseline in asthma symptom-free days based on the weekly mean at week 12. A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Change From Baseline in Asthma Symptom-free Days | 0.147 Days | Standard Error 0.031 |
| Tio R2.5 | Change From Baseline in Asthma Symptom-free Days | 0.130 Days | Standard Error 0.03 |
| Tio R5 | Change From Baseline in Asthma Symptom-free Days | 0.172 Days | Standard Error 0.031 |
p-value: 0.674895% CI: [-0.097, 0.063]Mixed Models Analysis
p-value: 0.549795% CI: [-0.056, 0.105]Mixed Models Analysis
Secondary
Change From Baseline in Daytime Activity Limitations
Change from baseline in daytime activity limitations based on the weekly mean at week 12. Daytime activity limitations was assessed by the question how limited were you in your activities today because of your asthma? from the e-diary. Scores range from 1 (not limited) to 5 (totally limited). Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Change From Baseline in Daytime Activity Limitations | -0.210 Units on a scale | Standard Error 0.039 |
| Tio R2.5 | Change From Baseline in Daytime Activity Limitations | -0.203 Units on a scale | Standard Error 0.038 |
| Tio R5 | Change From Baseline in Daytime Activity Limitations | -0.222 Units on a scale | Standard Error 0.039 |
p-value: 0.888495% CI: [-0.092, 0.106]Mixed Models Analysis
p-value: 0.811595% CI: [-0.112, 0.088]Mixed Models Analysis
Secondary
Change From Baseline in Daytime Asthma Symptoms
Change from baseline in daytime asthma symptoms based on the weekly mean at week 12. Daytime asthma symptoms was assessed by the question how were your asthma symptoms during the day? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Change From Baseline in Daytime Asthma Symptoms | -0.226 Units on a scale | Standard Error 0.04 |
| Tio R2.5 | Change From Baseline in Daytime Asthma Symptoms | -0.262 Units on a scale | Standard Error 0.039 |
| Tio R5 | Change From Baseline in Daytime Asthma Symptoms | -0.239 Units on a scale | Standard Error 0.041 |
p-value: 0.486495% CI: [-0.139, 0.066]Mixed Models Analysis
p-value: 0.799195% CI: [-0.117, 0.09]Mixed Models Analysis
Secondary
Change From Baseline in Daytime Experiences of Shortness of Breath
Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12. Daytime experiences of shortness of breath was assessed by the question how much shortness of breath did you experience during the day from the e-diary. Scores range from 1 (none) to 5 (a very great deal). Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Change From Baseline in Daytime Experiences of Shortness of Breath | -0.204 Units on a scale | Standard Error 0.039 |
| Tio R2.5 | Change From Baseline in Daytime Experiences of Shortness of Breath | -0.187 Units on a scale | Standard Error 0.038 |
| Tio R5 | Change From Baseline in Daytime Experiences of Shortness of Breath | -0.287 Units on a scale | Standard Error 0.04 |
p-value: 0.749895% CI: [-0.084, 0.117]Mixed Models Analysis
p-value: 0.110895% CI: [-0.185, 0.019]Mixed Models Analysis
Secondary
Change From Baseline in Daytime Experiences of Wheeze or Cough
Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12. Daytime experiences of wheeze or cough was assessed by the question did you experience wheeze or cough during the day? from the e-diary. Scores range from 1 (not at all) to 5 (all the time). Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Change From Baseline in Daytime Experiences of Wheeze or Cough | -0.249 Units on a scale | Standard Error 0.045 |
| Tio R2.5 | Change From Baseline in Daytime Experiences of Wheeze or Cough | -0.263 Units on a scale | Standard Error 0.044 |
| Tio R5 | Change From Baseline in Daytime Experiences of Wheeze or Cough | -0.320 Units on a scale | Standard Error 0.046 |
p-value: 0.805595% CI: [-0.131, 0.102]Mixed Models Analysis
p-value: 0.23695% CI: [-0.189, 0.047]Mixed Models Analysis
Secondary
Change From Baseline in Morning Asthma Symptoms
Change from baseline in morning asthma symptoms based on the weekly mean at week 12. Morning asthma symptoms was assessed by the question how were your asthma symptoms this morning? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Change From Baseline in Morning Asthma Symptoms | -0.207 Units on a scale | Standard Error 0.038 |
| Tio R2.5 | Change From Baseline in Morning Asthma Symptoms | -0.213 Units on a scale | Standard Error 0.037 |
| Tio R5 | Change From Baseline in Morning Asthma Symptoms | -0.221 Units on a scale | Standard Error 0.038 |
p-value: 0.904395% CI: [-0.103, 0.091]Mixed Models Analysis
p-value: 0.770895% CI: [-0.112, 0.083]Mixed Models Analysis
Secondary
Change From Baseline in Nighttime Awakenings
Change from baseline in nighttime awakenings based on the weekly mean at week 12. Nighttime awakenings was assessed by the question Did you wake up during the night due to your asthma? from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night). Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Change From Baseline in Nighttime Awakenings | -0.165 Units on a scale | Standard Error 0.032 |
| Tio R2.5 | Change From Baseline in Nighttime Awakenings | -0.166 Units on a scale | Standard Error 0.031 |
| Tio R5 | Change From Baseline in Nighttime Awakenings | -0.159 Units on a scale | Standard Error 0.033 |
p-value: 0.986995% CI: [-0.083, 0.082]Mixed Models Analysis
p-value: 0.87395% CI: [-0.077, 0.09]Mixed Models Analysis
Secondary
Control of Asthma as Assessed by ACQ-IA Total Score
Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12. The ACQ-IA 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-IA 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: FAS, 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-IA Total Score | 1.026 Units on a scale | Standard Error 0.06 |
| Tio R2.5 | Control of Asthma as Assessed by ACQ-IA Total Score | 1.046 Units on a scale | Standard Error 0.059 |
| Tio R5 | Control of Asthma as Assessed by ACQ-IA Total Score | 0.948 Units on a scale | Standard Error 0.061 |
p-value: 0.79895% CI: [-0.133, 0.173]Mixed Models Analysis
p-value: 0.316695% CI: [-0.233, 0.076]Mixed Models Analysis
Secondary
FEV1 a.m. Change From Baseline
Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 a.m. Change From Baseline | 0.174 Litres | Standard Error 0.03 |
| Tio R2.5 | FEV1 a.m. Change From Baseline | 0.142 Litres | Standard Error 0.029 |
| Tio R5 | FEV1 a.m. Change From Baseline | 0.125 Litres | Standard Error 0.03 |
p-value: 0.406695% CI: [-0.107, 0.043]Mixed Models Analysis
p-value: 0.203295% CI: [-0.125, 0.027]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: FAS, 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 | 0.175 Litres | Standard Error 0.023 |
| Tio R2.5 | FEV1 AUC (0-3h) Change From Baseline | 0.206 Litres | Standard Error 0.022 |
| Tio R5 | FEV1 AUC (0-3h) Change From Baseline | 0.301 Litres | Standard Error 0.023 |
p-value: 0.290795% CI: [-0.026, 0.088]Mixed Models Analysis
p-value: <0.000195% CI: [0.068, 0.184]Mixed Models Analysis
Secondary
FEV1 Change From Baseline at Each Individual Timepoint
Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint. The 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: FAS, 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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Respimat | FEV1 Change From Baseline at Each Individual Timepoint | 2 hours post-dose | 0.191 Litres | Standard Error 0.025 |
| Placebo Respimat | FEV1 Change From Baseline at Each Individual Timepoint | 1 hour post-dose | 0.177 Litres | Standard Error 0.025 |
| Placebo Respimat | FEV1 Change From Baseline at Each Individual Timepoint | 10 minutes pre-dose | 0.136 Litres | Standard Error 0.027 |
| Placebo Respimat | FEV1 Change From Baseline at Each Individual Timepoint | 30 minutes post-dose | 0.166 Litres | Standard Error 0.024 |
| Placebo Respimat | FEV1 Change From Baseline at Each Individual Timepoint | 3 hours post-dose | 0.168 Litres | Standard Error 0.026 |
| Tio R2.5 | FEV1 Change From Baseline at Each Individual Timepoint | 1 hour post-dose | 0.203 Litres | Standard Error 0.024 |
| Tio R2.5 | FEV1 Change From Baseline at Each Individual Timepoint | 10 minutes pre-dose | 0.154 Litres | Standard Error 0.026 |
| Tio R2.5 | FEV1 Change From Baseline at Each Individual Timepoint | 30 minutes post-dose | 0.202 Litres | Standard Error 0.023 |
| Tio R2.5 | FEV1 Change From Baseline at Each Individual Timepoint | 2 hours post-dose | 0.216 Litres | Standard Error 0.025 |
| Tio R2.5 | FEV1 Change From Baseline at Each Individual Timepoint | 3 hours post-dose | 0.215 Litres | Standard Error 0.026 |
| Tio R5 | FEV1 Change From Baseline at Each Individual Timepoint | 3 hours post-dose | 0.308 Litres | Standard Error 0.026 |
| Tio R5 | FEV1 Change From Baseline at Each Individual Timepoint | 2 hours post-dose | 0.324 Litres | Standard Error 0.026 |
| Tio R5 | FEV1 Change From Baseline at Each Individual Timepoint | 10 minutes pre-dose | 0.223 Litres | Standard Error 0.027 |
| Tio R5 | FEV1 Change From Baseline at Each Individual Timepoint | 1 hour post-dose | 0.300 Litres | Standard Error 0.025 |
| Tio R5 | FEV1 Change From Baseline at Each Individual Timepoint | 30 minutes post-dose | 0.285 Litres | Standard Error 0.024 |
Secondary
FEV1 p.m. Change From Baseline
Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 p.m. Change From Baseline | 0.155 Litres | Standard Error 0.031 |
| Tio R2.5 | FEV1 p.m. Change From Baseline | 0.104 Litres | Standard Error 0.03 |
| Tio R5 | FEV1 p.m. Change From Baseline | 0.094 Litres | Standard Error 0.032 |
p-value: 0.206495% CI: [-0.131, 0.028]Mixed Models Analysis
p-value: 0.14195% CI: [-0.142, 0.02]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 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: FAS, 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 | 0.145 Litres | Standard Error 0.025 |
| Tio R2.5 | FVC AUC (0-3h) Change From Baseline | 0.105 Litres | Standard Error 0.024 |
| Tio R5 | FVC AUC (0-3h) Change From Baseline | 0.182 Litres | Standard Error 0.025 |
p-value: 0.200895% CI: [-0.103, 0.022]Mixed Models Analysis
p-value: 0.254595% CI: [-0.026, 0.1]Mixed Models Analysis
Secondary
FVC Change From Baseline at Each Individual Timepoint
FVC change from baseline at each individual timepoint. The 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: FAS, 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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Respimat | FVC Change From Baseline at Each Individual Timepoint | 2 hours post-dose | 0.159 Litres | Standard Error 0.028 |
| Placebo Respimat | FVC Change From Baseline at Each Individual Timepoint | 1 hour post-dose | 0.146 Litres | Standard Error 0.027 |
| Placebo Respimat | FVC Change From Baseline at Each Individual Timepoint | 10 minutes pre-dose | 0.141 Litres | Standard Error 0.029 |
| Placebo Respimat | FVC Change From Baseline at Each Individual Timepoint | 30 minutes post-dose | 0.130 Litres | Standard Error 0.026 |
| Placebo Respimat | FVC Change From Baseline at Each Individual Timepoint | 3 hours post-dose | 0.132 Litres | Standard Error 0.028 |
| Tio R2.5 | FVC Change From Baseline at Each Individual Timepoint | 1 hour post-dose | 0.097 Litres | Standard Error 0.026 |
| Tio R2.5 | FVC Change From Baseline at Each Individual Timepoint | 10 minutes pre-dose | 0.094 Litres | Standard Error 0.029 |
| Tio R2.5 | FVC Change From Baseline at Each Individual Timepoint | 30 minutes post-dose | 0.096 Litres | Standard Error 0.026 |
| Tio R2.5 | FVC Change From Baseline at Each Individual Timepoint | 2 hours post-dose | 0.113 Litres | Standard Error 0.027 |
| Tio R2.5 | FVC Change From Baseline at Each Individual Timepoint | 3 hours post-dose | 0.110 Litres | Standard Error 0.028 |
| Tio R5 | FVC Change From Baseline at Each Individual Timepoint | 3 hours post-dose | 0.176 Litres | Standard Error 0.029 |
| Tio R5 | FVC Change From Baseline at Each Individual Timepoint | 2 hours post-dose | 0.199 Litres | Standard Error 0.028 |
| Tio R5 | FVC Change From Baseline at Each Individual Timepoint | 10 minutes pre-dose | 0.150 Litres | Standard Error 0.03 |
| Tio R5 | FVC Change From Baseline at Each Individual Timepoint | 1 hour post-dose | 0.181 Litres | Standard Error 0.027 |
| Tio R5 | FVC Change From Baseline at Each Individual Timepoint | 30 minutes post-dose | 0.164 Litres | Standard Error 0.027 |
Secondary
FVC Peak(0-3h) Change From Baseline
Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak(0-3h)) after 12 weeks of treatment. The measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 Peak(0-3h) Change From Baseline | 0.244 Litres | Standard Error 0.028 |
| Tio R2.5 | FVC Peak(0-3h) Change From Baseline | 0.201 Litres | Standard Error 0.027 |
| Tio R5 | FVC Peak(0-3h) Change From Baseline | 0.275 Litres | Standard Error 0.028 |
p-value: 0.227795% CI: [-0.113, 0.027]Mixed Models Analysis
p-value: 0.399895% CI: [-0.04, 0.101]Mixed Models Analysis
Secondary
Peak Expiratory Flow (PEF) a.m. Change From Baseline
Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Peak Expiratory Flow (PEF) a.m. Change From Baseline | 8.343 L/min | Standard Error 3.613 |
| Tio R2.5 | Peak Expiratory Flow (PEF) a.m. Change From Baseline | 13.119 L/min | Standard Error 3.5 |
| Tio R5 | Peak Expiratory Flow (PEF) a.m. Change From Baseline | 13.086 L/min | Standard Error 3.63 |
p-value: 0.308395% CI: [-4.419, 13.97]Mixed Models Analysis
p-value: 0.317995% CI: [-4.571, 14.057]Mixed Models Analysis
Secondary
Peak Expiratory Flow (PEF) p.m. Change From Baseline
Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Peak Expiratory Flow (PEF) p.m. Change From Baseline | 7.892 L/min | Standard Error 3.717 |
| Tio R2.5 | Peak Expiratory Flow (PEF) p.m. Change From Baseline | 8.459 L/min | Standard Error 3.599 |
| Tio R5 | Peak Expiratory Flow (PEF) p.m. Change From Baseline | 3.785 L/min | Standard Error 3.731 |
p-value: 0.906195% CI: [-8.866, 10.001]Mixed Models Analysis
p-value: 0.39995% CI: [-13.658, 5.444]Mixed Models Analysis
Secondary
Peak Expiratory Flow (PEF) Variability Change From Baseline
Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 | Peak Expiratory Flow (PEF) Variability Change From Baseline | 0.150 Percentage of PEF | Standard Error 0.777 |
| Tio R2.5 | Peak Expiratory Flow (PEF) Variability Change From Baseline | -0.800 Percentage of PEF | Standard Error 0.749 |
| Tio R5 | Peak Expiratory Flow (PEF) Variability Change From Baseline | -0.352 Percentage of PEF | Standard Error 0.78 |
p-value: 0.354295% CI: [-2.959, 1.06]Mixed Models Analysis
p-value: 0.629895% CI: [-2.545, 1.541]Mixed Models Analysis
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: FAS, 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 | 0.136 Litres | Standard Error 0.027 |
| Tio R2.5 | Trough FEV1 Change From Baseline | 0.154 Litres | Standard Error 0.026 |
| Tio R5 | Trough FEV1 Change From Baseline | 0.223 Litres | Standard Error 0.027 |
Comparison: Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis for this endpoint was performed in a stepwise manner after the analysis of the primary endpoint was performed. Each step was only considered confirmatory if all previous steps were successful.p-value: 0.589895% CI: [-0.048, 0.085]Mixed Models Analysis
Comparison: Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis for this endpoint was performed in a stepwise manner after the analysis of the primary endpoint was performed. Each step was only considered confirmatory if all previous steps were successful.p-value: 0.011795% CI: [0.019, 0.154]Mixed Models Analysis
Secondary
Trough FVC Change From Baseline
Change from baseline in Trough (pre-dose) FVC measured at week 12. Measured values presented are actually adjusted means.
Time frame: Baseline and 12 weeks
Population: FAS, 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 FVC Change From Baseline | 0.141 Litres | Standard Error 0.029 |
| Tio R2.5 | Trough FVC Change From Baseline | 0.094 Litres | Standard Error 0.029 |
| Tio R5 | Trough FVC Change From Baseline | 0.150 Litres | Standard Error 0.03 |
p-value: 0.20395% CI: [-0.121, 0.026]Mixed Models Analysis
p-value: 0.819495% CI: [-0.066, 0.083]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: FAS, 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 | Use of PRN Rescue Medication During the Daytime | -0.279 Number of puffs of rescue medication | Standard Error 0.057 |
| Tio R2.5 | Use of PRN Rescue Medication During the Daytime | -0.294 Number of puffs of rescue medication | Standard Error 0.055 |
| Tio R5 | Use of PRN Rescue Medication During the Daytime | -0.365 Number of puffs of rescue medication | Standard Error 0.057 |
p-value: 0.836195% CI: [-0.16, 0.129]Mixed Models Analysis
p-value: 0.246195% CI: [-0.233, 0.06]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: FAS, 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 | Use of PRN Rescue Medication During the Night-time | -0.285 Number of puffs of rescue medication | Standard Error 0.051 |
| Tio R2.5 | Use of PRN Rescue Medication During the Night-time | -0.250 Number of puffs of rescue medication | Standard Error 0.05 |
| Tio R5 | Use of PRN Rescue Medication During the Night-time | -0.310 Number of puffs of rescue medication | Standard Error 0.052 |
p-value: 0.602995% CI: [-0.096, 0.165]Mixed Models Analysis
p-value: 0.703495% CI: [-0.158, 0.107]Mixed Models Analysis
Secondary
Use of PRN Rescue Medication Per Day
Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per 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: FAS, 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 | Use of PRN Rescue Medication Per Day | -0.570 Number of puffs of rescue medication | Standard Error 0.096 |
| Tio R2.5 | Use of PRN Rescue Medication Per Day | -0.553 Number of puffs of rescue medication | Standard Error 0.094 |
| Tio R5 | Use of PRN Rescue Medication Per Day | -0.660 Number of puffs of rescue medication | Standard Error 0.097 |
p-value: 0.891695% CI: [-0.227, 0.261]Mixed Models Analysis
p-value: 0.478995% CI: [-0.336, 0.158]Mixed Models Analysis