Asthma
Conditions
Brief summary
The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium over a 24-week treatment period as compared to placebo and salmeterol (50 mcg twice daily). Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined on top of maintenance treatment with inhaled corticosteroid controller medication in patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on quality of life, effects on asthma control, effects on health care resource utilisation, and number of adverse events.
Interventions
DRUGplacebo
Placebo that represents BI drug
Active comparator
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 at least 18 years but not more than 75 years. 3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5. 4. The initial diagnosis of asthma must have been made before the patient's age of 40. 5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 minutes after 400 mcg salbutamol (albuterol)) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200mL. 6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids for at least for 4 weeks prior to Visit 1. 7. 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 at least 1.5. 8\. All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1. 9\. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%. 10\. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years. 11\. Patients must be able to use the Respimat® inhaler and metered dose inhaler correctly. 12\. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter.
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) influence the results of the trial, or (iii) 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 1. 3. Patients with a recent history (i.e. six months or less) of myocardial infarction. 4. Patients who have been hospitalised for cardiac failure during the past year. 5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 6. Patients with lung diseases other than asthma (e.g. Chronic Obstructive Pulmonary Disease (COPD)). 7. Patients with known active tuberculosis. 8. 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. 9. 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. 10. Patients with significant alcohol or drug abuse within the past two years. 11. 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). 12. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediamineteraacetic acid (EDTA), salmeterol xinafoate or any other components of the study medication delivery systems. 13. Pregnant or nursing woman. 14. Women of childbearing potential not using a highly effective method of birth control. 15. Patients who have taken an investigational drug within four weeks prior to Visit 1. 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 the 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 oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period. 19. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period. 20. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), within 6 months prior to Visit 1 and/or during the screening period. 21. Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period. 22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period. 23. Patients who have been treated with other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period. 24. Patients with any asthma exacerbation or any respiratory tract infection iin the four weeks prior to Visit 1 and/or during the screening period. 25. Patients who have previously been randomised in this trial or in the respective twin trial (205.418) or are currently participating in another trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak FEV1 Within 3 Hours Post-dose Response | 24 weeks | Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. |
| Trough FEV1 Response | 24 weeks | Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. |
| The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | 24 weeks | The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FVC Area Under Curve 0-3 Hours (AUC0-3h) Response | 24 weeks | Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres. |
| Trough PEF Response | 24 weeks | Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. |
| Total Asthma Quality of Life Questionnaire (AQLQs)) Score | 24 weeks | Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items and ranges from from 1 (highest intensity) till 7 (no symptoms). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. |
| Total Asthma Control Questionnaire (ACQ) Score | 24 weeks | Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items and ranges from from 0 (no symptoms) till 6 (highest intensity). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. |
| The Responder Rate as Assessed by the ACQ | 24 weeks | The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points.The score ranges from 0 (no impairment) to 6 (maximum impairment). |
| Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week |
| Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. |
| Peak FVC Within 3 Hours Post-dose Response | 24 weeks | Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. |
| Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. |
| Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. |
| Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 | Baseline and last 7 days before week 24 visit | Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. |
| Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication. |
| Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | 24 weeks | Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) |
| Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | 24 weeks | Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) |
| PEF Variability | Last 7 days before week 24 visit | PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. |
| Trough FVC Response | 24 weeks | Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. |
| FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response | 24 weeks | Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres. |
Countries
Brazil, China, Colombia, Germany, India, Japan, Mexico, Peru, Poland, Romania, United States
Participant flow
Pre-assignment details
There was 1 patient in the TIO R2.5 and 1 patient in the TIO R5 group randomized but not treated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler). | 254 |
| Tio R2.5 Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler. | 257 |
| Tio R5 Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler. | 253 |
| Salmeterol Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler). | 266 |
| Total | 1,030 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 | 2 | 7 |
| Overall Study | Lost to Follow-up | 4 | 1 | 2 | 2 |
| Overall Study | Other | 3 | 4 | 5 | 3 |
| Overall Study | Protocol Violation | 0 | 2 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 3 | 3 |
Baseline characteristics
| Characteristic | Placebo | Tio R2.5 | Tio R5 | Salmeterol | Total |
|---|---|---|---|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 13 | 43.0 years STANDARD_DEVIATION 12.6 | 44.3 years STANDARD_DEVIATION 12.7 | 41.5 years STANDARD_DEVIATION 13.1 | 42.9 years STANDARD_DEVIATION 12.9 |
| Sex: Female, Male Female | 145 Participants | 160 Participants | 146 Participants | 153 Participants | 604 Participants |
| Sex: Female, Male Male | 109 Participants | 97 Participants | 107 Participants | 113 Participants | 426 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 102 / 254 | 89 / 257 | 87 / 253 | 90 / 266 |
| serious Total, serious adverse events | 4 / 254 | 7 / 257 | 7 / 253 | 4 / 266 |
Outcome results
Primary
Peak FEV1 Within 3 Hours Post-dose Response
Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time frame: 24 weeks
Population: Full Analysis Set (FAS) - all treated patients who had baseline data and at least 1 on-treatment efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 Within 3 Hours Post-dose Response | 0.075 Litre | Standard Error 0.02 |
| Tio R2.5 | Peak FEV1 Within 3 Hours Post-dose Response | 0.287 Litre | Standard Error 0.02 |
| Tio R5 | Peak FEV1 Within 3 Hours Post-dose Response | 0.244 Litre | Standard Error 0.02 |
| Salmeterol | Peak FEV1 Within 3 Hours Post-dose Response | 0.252 Litre | Standard Error 0.019 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [0.159, 0.264]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [0.116, 0.222]Mixed Models Analysis
Primary
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.
Time frame: 24 weeks
Population: FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | 57.7 Percentage of participants |
| Tio R2.5 | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | 64.5 Percentage of participants |
| Tio R5 | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | 64.3 Percentage of participants |
| Salmeterol | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | 66.5 Percentage of participants |
p-value: 0.030895% CI: [1.03, 1.72]Fisher Exact
p-value: 0.034895% CI: [1.02, 1.71]Fisher Exact
Primary
Trough FEV1 Response
Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | -0.012 Litre | Standard Error 0.021 |
| Tio R2.5 | Trough FEV1 Response | 0.164 Litre | Standard Error 0.021 |
| Tio R5 | Trough FEV1 Response | 0.121 Litre | Standard Error 0.021 |
| Salmeterol | Trough FEV1 Response | 0.094 Litre | Standard Error 0.021 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [0.12, 0.233]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [0.076, 0.19]Mixed Models Analysis
Secondary
Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication.
Time frame: Baseline and last 7 days before week 24 visit
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 | 0.189 Days | Standard Error 0.023 |
| Tio R2.5 | Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 | 0.164 Days | Standard Error 0.023 |
| Tio R5 | Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 | 0.196 Days | Standard Error 0.023 |
| Salmeterol | Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 | 0.195 Days | Standard Error 0.022 |
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.350195% CI: [-0.079, 0.028]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.804595% CI: [-0.047, 0.061]Mixed Models Analysis
Secondary
FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response
Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response | -0.005 Litre | Standard Error 0.019 |
| Tio R2.5 | FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response | 0.196 Litre | Standard Error 0.019 |
| Tio R5 | FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response | 0.158 Litre | Standard Error 0.019 |
| Salmeterol | FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response | 0.173 Litre | Standard Error 0.019 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [0.15, 0.252]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [0.112, 0.215]Mixed Models Analysis
Secondary
FVC Area Under Curve 0-3 Hours (AUC0-3h) Response
Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-3 Hours (AUC0-3h) Response | -0.065 Litre | Standard Error 0.024 |
| Tio R2.5 | FVC Area Under Curve 0-3 Hours (AUC0-3h) Response | 0.043 Litre | Standard Error 0.024 |
| Tio R5 | FVC Area Under Curve 0-3 Hours (AUC0-3h) Response | 0.024 Litre | Standard Error 0.025 |
| Salmeterol | FVC Area Under Curve 0-3 Hours (AUC0-3h) Response | 0.066 Litre | Standard Error 0.024 |
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.000295% CI: [0.052, 0.164]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.001995% CI: [0.033, 0.145]Mixed Models Analysis
Secondary
Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24
Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time frame: Baseline and last 7 days before week 24 visit
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 | -0.952 Number of Puffs | Standard Error 0.093 |
| Tio R2.5 | Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 | -1.123 Number of Puffs | Standard Error 0.092 |
| Tio R5 | Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 | -0.843 Number of Puffs | Standard Error 0.093 |
| Salmeterol | Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 | -1.078 Number of Puffs | Standard Error 0.091 |
Comparison: Analyses included the fixed, categorical effects of treatment, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.192795% CI: [-0.427, 0.086]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.405395% CI: [-0.148, 0.367]Mixed Models Analysis
Secondary
Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time frame: Baseline and last 7 days before week 24 visit
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 | -0.002 Litre | Standard Error 0.024 |
| Tio R2.5 | Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 | 0.066 Litre | Standard Error 0.023 |
| Tio R5 | Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 | 0.064 Litre | Standard Error 0.024 |
| Salmeterol | Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 | 0.048 Litre | Standard Error 0.023 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.035795% CI: [0.005, 0.131]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.042295% CI: [0.002, 0.129]Mixed Models Analysis
Secondary
Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time frame: Baseline and last 7 days before week 24 visit
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 | -0.072 Litre/min | Standard Error 3.328 |
| Tio R2.5 | Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 | 15.919 Litre/min | Standard Error 3.303 |
| Tio R5 | Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 | 21.175 Litre/min | Standard Error 3.33 |
| Salmeterol | Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 | 11.617 Litre/min | Standard Error 3.256 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.000495% CI: [7.074, 24.908]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [12.302, 30.193]Mixed Models Analysis
Secondary
Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time frame: Baseline and last 7 days before week 24 visit
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 | 0.020 Litre | Standard Error 0.023 |
| Tio R2.5 | Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 | 0.099 Litre | Standard Error 0.023 |
| Tio R5 | Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 | 0.084 Litre | Standard Error 0.023 |
| Salmeterol | Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 | 0.103 Litre | Standard Error 0.022 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.011195% CI: [0.018, 0.14]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.039595% CI: [0.003, 0.126]Mixed Models Analysis
Secondary
Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week
Time frame: Baseline and last 7 days before week 24 visit
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 | 2.764 Litre/min | Standard Error 3.292 |
| Tio R2.5 | Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 | 23.377 Litre/min | Standard Error 3.267 |
| Tio R5 | Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 | 27.521 Litre/min | Standard Error 3.294 |
| Salmeterol | Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 | 19.779 Litre/min | Standard Error 3.219 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [11.795, 29.431]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [15.907, 33.607]Mixed Models Analysis
Secondary
Peak FVC Within 3 Hours Post-dose Response
Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FVC Within 3 Hours Post-dose Response | 0.071 Litre | Standard Error 0.022 |
| Tio R2.5 | Peak FVC Within 3 Hours Post-dose Response | 0.181 Litre | Standard Error 0.022 |
| Tio R5 | Peak FVC Within 3 Hours Post-dose Response | 0.160 Litre | Standard Error 0.022 |
| Salmeterol | Peak FVC Within 3 Hours Post-dose Response | 0.188 Litre | Standard Error 0.021 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.000295% CI: [0.052, 0.168]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.003195% CI: [0.03, 0.147]Mixed Models Analysis
Secondary
PEF Variability
PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time frame: Last 7 days before week 24 visit
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PEF Variability | -0.448 Percentage of Mean PEF | Standard Error 0.484 |
| Tio R2.5 | PEF Variability | -1.401 Percentage of Mean PEF | Standard Error 0.48 |
| Tio R5 | PEF Variability | -0.627 Percentage of Mean PEF | Standard Error 0.487 |
| Salmeterol | PEF Variability | -1.518 Percentage of Mean PEF | Standard Error 0.472 |
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.111495% CI: [-2.125, 0.22]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.766595% CI: [-1.355, 0.999]Mixed Models Analysis
Secondary
The Responder Rate as Assessed by the ACQ
The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points.The score ranges from 0 (no impairment) to 6 (maximum impairment).
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Responder Rate as Assessed by the ACQ | 62.5 Percentage of participants |
| Tio R2.5 | The Responder Rate as Assessed by the ACQ | 66.4 Percentage of participants |
| Tio R5 | The Responder Rate as Assessed by the ACQ | 61.9 Percentage of participants |
| Salmeterol | The Responder Rate as Assessed by the ACQ | 64.4 Percentage of participants |
p-value: 0.401295% CI: [0.81, 1.74]Fisher Exact
p-value: 1.172795% CI: [0.67, 1.42]Fisher Exact
Secondary
Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)
Time frame: 24 weeks
Population: FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
| Tio R2.5 | Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
| Tio R5 | Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
| Salmeterol | Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
Secondary
Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)
Time frame: 24 weeks
Population: FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
| Tio R2.5 | Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
| Tio R5 | Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
| Salmeterol | Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) | NA weeks |
Secondary
Total Asthma Control Questionnaire (ACQ) Score
Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items and ranges from from 0 (no symptoms) till 6 (highest intensity). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Asthma Control Questionnaire (ACQ) Score | 1.442 units on a scale | Standard Error 0.043 |
| Tio R2.5 | Total Asthma Control Questionnaire (ACQ) Score | 1.315 units on a scale | Standard Error 0.042 |
| Tio R5 | Total Asthma Control Questionnaire (ACQ) Score | 1.359 units on a scale | Standard Error 0.043 |
| Salmeterol | Total Asthma Control Questionnaire (ACQ) Score | 1.318 units on a scale | Standard Error 0.042 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.030595% CI: [-0.241, -0.012]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.160295% CI: [-0.198, 0.033]Mixed Models Analysis
Secondary
Total Asthma Quality of Life Questionnaire (AQLQs)) Score
Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items and ranges from from 1 (highest intensity) till 7 (no symptoms). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Asthma Quality of Life Questionnaire (AQLQs)) Score | 5.551 units on a scale | Standard Error 0.05 |
| Tio R2.5 | Total Asthma Quality of Life Questionnaire (AQLQs)) Score | 5.562 units on a scale | Standard Error 0.049 |
| Tio R5 | Total Asthma Quality of Life Questionnaire (AQLQs)) Score | 5.548 units on a scale | Standard Error 0.05 |
| Salmeterol | Total Asthma Quality of Life Questionnaire (AQLQs)) Score | 5.634 units on a scale | Standard Error 0.048 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.8795% CI: [-0.122, 0.144]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.961295% CI: [-0.137, 0.13]Mixed Models Analysis
Secondary
Trough FVC Response
Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response | -0.048 Litre | Standard Error 0.027 |
| Tio R2.5 | Trough FVC Response | 0.039 Litre | Standard Error 0.027 |
| Tio R5 | Trough FVC Response | 0.035 Litre | Standard Error 0.027 |
| Salmeterol | Trough FVC Response | 0.020 Litre | Standard Error 0.027 |
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.006195% CI: [0.025, 0.149]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: 0.009395% CI: [0.021, 0.146]Mixed Models Analysis
Secondary
Trough PEF Response
Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough PEF Response | 7.938 Litre/min | Standard Error 3.659 |
| Tio R2.5 | Trough PEF Response | 36.698 Litre/min | Standard Error 3.614 |
| Tio R5 | Trough PEF Response | 36.117 Litre/min | Standard Error 3.646 |
| Salmeterol | Trough PEF Response | 29.352 Litre/min | Standard Error 3.572 |
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [19.025, 38.494]Mixed Models Analysis
Comparison: Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.p-value: <0.000195% CI: [18.401, 37.956]Mixed Models Analysis