Asthma
Conditions
Brief summary
Rationale for the current trial is to evaluate the efficacy and safety of three doses (1.25 µg, 2.5 µg and 5.0 µg ex mouthpiece) of tiotropium inhalation solution in patients with moderate persistent asthma who are still symptomatic despite regular maintenance therapy with inhaled corticosteroids (ICS). The data collected in the present trial will provide useful information to health care providers and patients regarding the efficacy and safety of a once daily inhalation of three different doses of tiotropium solution delivered by the Respimat® inhaler in addition to inhaled corticosteroids in the treatment of not fully controlled moderate asthma in comparison to placebo. The Pharmacokinetics (PK) of tiotropium is well established in COPD patients. However, there is currently no PK data available for the 3 doses of tiotropium being tested in this trial in patients with moderate persistent asthma. Tiotropium is a once daily drug. Hence, the rationale for blood and urine sampling for PK analysis over 24 hours in a subset of patients is to confirm the PK of the 3 doses in moderate asthma patients. Rationale for the 24-hour pulmonary function test sub-investigation is to demonstrate that a once daily dosing of tiotropium inhalation solution is effective and safe in the treatment of moderate persistent asthma.
Interventions
DRUGtiotropium bromide 2.5µg once daily
Efficacy and safety comparison of 3 doses of inhaled tiotropium (1.25µg, 2.5µg and 5µg) versus placebo
DRUGTiotropium matching Placebo once daily
Efficacy and safety comparison of 3 doses of inhaled tiotropium (1.25µg, 2.5µg and 5µg) versus placebo
DRUGtiotropium bromide high dose once daily
Efficacy and safety comparison of 3 doses of inhaled tiotropium (1.25µg, 2.5µg and 5µg) versus placebo
DRUGtiotropium bromide 1.25µg once daily
IMP
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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 the Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) 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 between 18 and 75 years (at date of informed consent). 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 no. 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 to 30 minutes after 4 puffs of 100 µg salbutamol) resulting in a Forced Expiratory Volume in one second (FEV1) increase of = 12% and = 200mL. 6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (alone or in a fixed combination with a long acting or short acting beta agonist \[LABA or SABA\]) for at least 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 = 1.5. 8. All patients must have a pre-bronchodilator FEV1 = 60% and = 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to the European Community for Steel and Coal (ECSC). 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 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 (diary compliance of at least 80% is required).
Exclusion criteria
1. Patients with a significant disease other than asthma. 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. 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. 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 known moderate to severe renal impairment. 11. Patients with known narrow angle glaucoma or any other disease where anticholinergic treatment is contraindicated. 12. Patients with significant symptomatic prostatic hyperplasia or bladder-neck obstruction. Patients whose symptoms are controlled on treatment may be included. 13. Patients with significant alcohol or drug abuse within the past two years (to the discretion of the investigator). 14. Patients who are currently in a pulmonary rehabilitation program or have completed pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening) or who will start a rehabilitation program during the study. 15. Patients with known hypersensitivity to anticholinergic drugs, Benzalkonium chloride (BAC), Ethylenediaminetetraacetate (EDTA) or any other components of the study medication delivery system (Respimat®/ tiotropium inhalation solution). 16. Pregnant or nursing woman. 17. Women of childbearing potential not using a highly effective method of birth control. 18. Patients who have taken an investigational drug within four weeks prior to Visit 1. 19. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed. 20. 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 (period between Visit 1 and Visit 2). 21. Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period (period between Visit 1 and Visit 2) 22. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period. 23. Patients who have been treated with anti-Immunoglobuline E (anti-IgE) antibodies, e.g. omalizumab, within 6 months prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). 24. Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). 25. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). 26. Patients who have been treated with other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy (e.g. Tumor Necrosis Factor (TNF)-alpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). 27. Patient with any asthma exacerbation or respiratory tract infection in the 4 weeks prior to visit 1 and/or during the screening period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | Mixed model repeated measurement (MMRM) results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres. |
| Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. |
| Trough FVC Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FVC was measured just prior to the last administration of randomised treatment. |
| FVC AUC0-3h Response | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres. |
| Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. |
| Individual FVC Over Time (at Each Timepoint at Visits) Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. |
| Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. |
| Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). |
| Trough FEV1 Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 was measured just prior to the last administration of randomised treatment. |
| PEF Variability Response (Last Week on Treatment) | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent . Weekly means obtained during the last week of each period of randomised treatment will be compared. |
| Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). |
| Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). |
| Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). |
| Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). |
| FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-12, FEV1 AUC12-24 and FEV1 AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres. |
| FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-12, FVC AUC12-24 and FVC AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres. |
| Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). |
Countries
Austria, Germany, Ukraine
Participant flow
Recruitment details
A total of 149 patients were randomised and treated, 141 patients completed the trial.
Pre-assignment details
Randomised, double-blind, placebo controlled, cross-over design without washout phase between the four periods. Patients were randomized to one of the 4 sequences (ABCD, DCBA, BDAC, CADB). For one patient treatment 2 and treatment 3 were interchanged (resulting sequence DBCA).
Participants by arm
| Arm | Count |
|---|---|
| Baseline Total Total number of patients randomised and treated in the study. | 149 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 1 (4 Weeks) | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Period 1 (4 Weeks) | Other | 0 | 0 | 1 | 0 | 0 |
| Period 1 (4 Weeks) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 |
| Period 2 (4 Weeks) | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
| Period 3 (4 Weeks) | Other | 0 | 0 | 0 | 1 | 0 |
| Period 3 (4 Weeks) | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
| Period 4 (4 Weeks) | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Period 4 (4 Weeks) | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Baseline Total |
|---|---|
| Age, Continuous | 49.3 years STANDARD_DEVIATION 13.3 |
| Sex: Female, Male Female | 82 Participants |
| Sex: Female, Male Male | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 144 | 0 / 146 | 0 / 147 | 0 / 146 |
| serious Total, serious adverse events | 0 / 144 | 0 / 146 | 0 / 147 | 2 / 146 |
Outcome results
Primary
Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response
Mixed model repeated measurement (MMRM) results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
Population: Full analysis set (FAS) reduced to patients with non-missing FEV1 data. The FAS is defined as patients randomised, treated, with baseline data and at least one on-treatment efficacy measurement after 4 weeks on treatment within a period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response | 0.116 Litre | Standard Error 0.027 |
| Tio R1.25 qd | Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response | 0.255 Litre | Standard Error 0.027 |
| Tio R2.5 qd | Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response | 0.244 Litre | Standard Error 0.027 |
| Tio R5 qd | Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response | 0.304 Litre | Standard Error 0.028 |
p-value: <0.000195% CI: [0.09, 0.186]Mixed Models Analysis
p-value: <0.000195% CI: [0.08, 0.176]Mixed Models Analysis
p-value: <0.000195% CI: [0.14, 0.236]Mixed Models Analysis
Secondary
FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres.
Time frame: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
Population: FAS reduced to patients with non-missing FEV1 data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response | 0.025 Litre | Standard Error 0.027 |
| Tio R1.25 qd | FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response | 0.154 Litre | Standard Error 0.027 |
| Tio R2.5 qd | FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response | 0.152 Litre | Standard Error 0.027 |
| Tio R5 qd | FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response | 0.203 Litre | Standard Error 0.027 |
p-value: <0.000195% CI: [0.083, 0.175]Mixed Models Analysis
p-value: <0.000195% CI: [0.081, 0.172]Mixed Models Analysis
p-value: <0.000195% CI: [0.132, 0.224]Mixed Models Analysis
Secondary
FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h)
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-12, FEV1 AUC12-24 and FEV1 AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres.
Time frame: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration
Population: FAS24 was defined as all patients in the FAS who gave informed consent for the 24-h PFT and who participated in this optional PFT.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-24h | -0.001 Litres | Standard Error 0.057 |
| Placebo | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-12h | -0.013 Litres | Standard Error 0.058 |
| Placebo | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC12-24h | 0.012 Litres | Standard Error 0.061 |
| Tio R1.25 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-24h | 0.099 Litres | Standard Error 0.054 |
| Tio R1.25 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC12-24h | 0.093 Litres | Standard Error 0.058 |
| Tio R1.25 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-12h | 0.105 Litres | Standard Error 0.055 |
| Tio R2.5 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-12h | 0.134 Litres | Standard Error 0.054 |
| Tio R2.5 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC12-24h | 0.148 Litres | Standard Error 0.058 |
| Tio R2.5 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-24h | 0.141 Litres | Standard Error 0.054 |
| Tio R5 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-24h | 0.168 Litres | Standard Error 0.053 |
| Tio R5 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC0-12h | 0.128 Litres | Standard Error 0.054 |
| Tio R5 qd | FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | FEV1 AUC12-24h | 0.208 Litres | Standard Error 0.057 |
Comparison: Comparison vs. Placebo for AUC0-24hp-value: 0.073195% CI: [-0.014, 0.297]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-12hp-value: 0.140295% CI: [-0.04, 0.276]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-12hp-value: 0.065695% CI: [-0.01, 0.305]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-12hp-value: 0.076695% CI: [-0.015, 0.299]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC12-24hp-value: 0.337195% CI: [-0.086, 0.249]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC12-24hp-value: 0.109795% CI: [-0.031, 0.303]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC12-24hp-value: 0.02295% CI: [0.029, 0.363]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-24hp-value: 0.206295% CI: [-0.056, 0.256]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-24hp-value: 0.033395% CI: [0.014, 0.324]Mixed Models Analysis
Secondary
Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.
Time frame: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
Population: FAS reduced to patients with non-missing FVC data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response | 0.092 Litre | Standard Error 0.034 |
| Tio R1.25 qd | Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response | 0.171 Litre | Standard Error 0.034 |
| Tio R2.5 qd | Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response | 0.163 Litre | Standard Error 0.034 |
| Tio R5 qd | Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response | 0.229 Litre | Standard Error 0.034 |
p-value: 0.003495% CI: [0.026, 0.132]Mixed Models Analysis
p-value: 0.008795% CI: [0.018, 0.124]Mixed Models Analysis
p-value: <0.000195% CI: [0.085, 0.19]Mixed Models Analysis
Secondary
FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h)
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-12, FVC AUC12-24 and FVC AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres.
Time frame: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration
Population: FAS24 was defined as all patients in the FAS who gave informed consent for the 24-h PFT and who participated in this optional PFT.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-12h | -0.052 Litres | Standard Error 0.072 |
| Placebo | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-24h | -0.036 Litres | Standard Error 0.072 |
| Placebo | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC12-24h | -0.021 Litres | Standard Error 0.076 |
| Tio R1.25 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-12h | 0.064 Litres | Standard Error 0.068 |
| Tio R1.25 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-24h | 0.055 Litres | Standard Error 0.067 |
| Tio R1.25 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC12-24h | 0.046 Litres | Standard Error 0.071 |
| Tio R2.5 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC12-24h | 0.177 Litres | Standard Error 0.071 |
| Tio R2.5 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-12h | 0.157 Litres | Standard Error 0.068 |
| Tio R2.5 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-24h | 0.167 Litres | Standard Error 0.067 |
| Tio R5 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-12h | 0.115 Litres | Standard Error 0.068 |
| Tio R5 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC0-24h | 0.137 Litres | Standard Error 0.067 |
| Tio R5 qd | FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | FVC AUC12-24h | 0.160 Litres | Standard Error 0.071 |
Comparison: Comparison vs. Placebo for AUC0-12hp-value: 0.245195% CI: [-0.081, 0.312]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-12hp-value: 0.037995% CI: [0.012, 0.405]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-12hp-value: 0.095795% CI: [-0.03, 0.363]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC12-24hp-value: 0.520795% CI: [-0.139, 0.273]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC12-24hp-value: 0.060695% CI: [-0.009, 0.404]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC12-24hp-value: 0.085595% CI: [-0.026, 0.387]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-24hp-value: 0.356495% CI: [-0.104, 0.287]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-24hp-value: 0.042495% CI: [0.007, 0.399]Mixed Models Analysis
Comparison: Comparison vs. Placebo for AUC0-24hp-value: 0.081595% CI: [-0.022, 0.37]Mixed Models Analysis
Secondary
FVC AUC0-3h Response
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres.
Time frame: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
Population: FAS reduced to patients with non-missing FVC data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC0-3h Response | -0.028 Litre | Standard Error 0.034 |
| Tio R1.25 qd | FVC AUC0-3h Response | 0.036 Litre | Standard Error 0.034 |
| Tio R2.5 qd | FVC AUC0-3h Response | 0.047 Litre | Standard Error 0.034 |
| Tio R5 qd | FVC AUC0-3h Response | 0.110 Litre | Standard Error 0.034 |
p-value: 0.014995% CI: [0.013, 0.115]Mixed Models Analysis
p-value: 0.004395% CI: [0.024, 0.126]Mixed Models Analysis
p-value: <0.000195% CI: [0.086, 0.189]Mixed Models Analysis
Secondary
Individual FEV1 Over Time (at Each Timepoint at Visits) Response
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing FEV1 data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 0.026 Litre | Standard Error 0.029 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 0.033 Litre | Standard Error 0.029 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.006 Litre | Standard Error 0.027 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 0.029 Litre | Standard Error 0.028 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 0.013 Litre | Standard Error 0.029 |
| Tio R1.25 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 0.148 Litre | Standard Error 0.029 |
| Tio R1.25 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 0.158 Litre | Standard Error 0.029 |
| Tio R1.25 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 0.160 Litre | Standard Error 0.028 |
| Tio R1.25 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.131 Litre | Standard Error 0.027 |
| Tio R1.25 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 0.160 Litre | Standard Error 0.029 |
| Tio R2.5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 0.156 Litre | Standard Error 0.029 |
| Tio R2.5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.138 Litre | Standard Error 0.027 |
| Tio R2.5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 0.163 Litre | Standard Error 0.028 |
| Tio R2.5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 0.149 Litre | Standard Error 0.029 |
| Tio R2.5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 0.148 Litre | Standard Error 0.029 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 0.218 Litre | Standard Error 0.029 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 0.209 Litre | Standard Error 0.028 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.149 Litre | Standard Error 0.027 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 0.205 Litre | Standard Error 0.029 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 0.191 Litre | Standard Error 0.029 |
Secondary
Individual FVC Over Time (at Each Timepoint at Visits) Response
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing FVC data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | -0.022 Litre | Standard Error 0.036 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | -0.028 Litre | Standard Error 0.035 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | -0.050 Litre | Standard Error 0.036 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | -0.031 Litre | Standard Error 0.036 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.004 Litre | Standard Error 0.035 |
| Tio R1.25 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 0.024 Litre | Standard Error 0.036 |
| Tio R1.25 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 0.037 Litre | Standard Error 0.036 |
| Tio R1.25 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 0.036 Litre | Standard Error 0.036 |
| Tio R1.25 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 0.042 Litre | Standard Error 0.035 |
| Tio R1.25 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.058 Litre | Standard Error 0.035 |
| Tio R2.5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 0.041 Litre | Standard Error 0.036 |
| Tio R2.5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.076 Litre | Standard Error 0.035 |
| Tio R2.5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 0.060 Litre | Standard Error 0.035 |
| Tio R2.5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 0.045 Litre | Standard Error 0.036 |
| Tio R2.5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 0.033 Litre | Standard Error 0.036 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 0.119 Litre | Standard Error 0.036 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 0.124 Litre | Standard Error 0.035 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 0.102 Litre | Standard Error 0.035 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 0.112 Litre | Standard Error 0.036 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 0.078 Litre | Standard Error 0.036 |
Secondary
Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing PEF data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 6.095 Litre/min | Standard Error 5.074 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 11.038 Litre/min | Standard Error 4.804 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 7.237 Litre/min | Standard Error 5.039 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 8.235 Litre/min | Standard Error 4.949 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 5.046 Litre/min | Standard Error 5.024 |
| Tio R1.25 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 34.070 Litre/min | Standard Error 5.072 |
| Tio R1.25 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 32.163 Litre/min | Standard Error 4.947 |
| Tio R1.25 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 34.544 Litre/min | Standard Error 5.037 |
| Tio R1.25 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 30.567 Litre/min | Standard Error 4.802 |
| Tio R1.25 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 34.620 Litre/min | Standard Error 5.022 |
| Tio R2.5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 36.972 Litre/min | Standard Error 5.039 |
| Tio R2.5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 33.903 Litre/min | Standard Error 4.804 |
| Tio R2.5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 37.149 Litre/min | Standard Error 4.949 |
| Tio R2.5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 36.851 Litre/min | Standard Error 5.074 |
| Tio R2.5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 37.283 Litre/min | Standard Error 5.024 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 | 42.694 Litre/min | Standard Error 5.047 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 | 39.325 Litre/min | Standard Error 4.957 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 | 34.787 Litre/min | Standard Error 4.812 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 | 40.624 Litre/min | Standard Error 5.033 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 | 41.260 Litre/min | Standard Error 5.082 |
Secondary
Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values)
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing data for nighttime awakenings
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | -0.156 Night awakenings | Standard Error 0.034 |
| Tio R1.25 qd | Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | -0.166 Night awakenings | Standard Error 0.034 |
| Tio R2.5 qd | Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | -0.162 Night awakenings | Standard Error 0.034 |
| Tio R5 qd | Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | -0.187 Night awakenings | Standard Error 0.034 |
p-value: 0.750195% CI: [-0.073, 0.052]Mixed Models Analysis
p-value: 0.840195% CI: [-0.069, 0.056]Mixed Models Analysis
p-value: 0.323795% CI: [-0.094, 0.031]Mixed Models Analysis
Secondary
Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values)
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing data for rescue medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | -0.314 Puffs | Standard Error 0.071 |
| Tio R1.25 qd | Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | -0.463 Puffs | Standard Error 0.071 |
| Tio R2.5 qd | Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | -0.452 Puffs | Standard Error 0.071 |
| Tio R5 qd | Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | -0.425 Puffs | Standard Error 0.071 |
p-value: 0.018395% CI: [-0.273, -0.025]Mixed Models Analysis
p-value: 0.028895% CI: [-0.262, -0.014]Mixed Models Analysis
p-value: 0.078195% CI: [-0.235, 0.013]Mixed Models Analysis
Secondary
Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values)
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing data for rescue medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | -0.273 Puffs | Standard Error 0.064 |
| Tio R1.25 qd | Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | -0.357 Puffs | Standard Error 0.063 |
| Tio R2.5 qd | Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | -0.341 Puffs | Standard Error 0.063 |
| Tio R5 qd | Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | -0.360 Puffs | Standard Error 0.064 |
p-value: 0.130395% CI: [-0.193, 0.025]Mixed Models Analysis
p-value: 0.219195% CI: [-0.177, 0.041]Mixed Models Analysis
p-value: 0.116395% CI: [-0.196, 0.022]Mixed Models Analysis
Secondary
Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values)
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing data for rescue medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | -0.569 Puffs | Standard Error 0.122 |
| Tio R1.25 qd | Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | -0.802 Puffs | Standard Error 0.121 |
| Tio R2.5 qd | Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | -0.783 Puffs | Standard Error 0.121 |
| Tio R5 qd | Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | -0.769 Puffs | Standard Error 0.122 |
p-value: 0.029695% CI: [-0.443, -0.023]Mixed Models Analysis
p-value: 0.045495% CI: [-0.424, -0.004]Mixed Models Analysis
p-value: 0.06195% CI: [-0.41, 0.009]Mixed Models Analysis
Secondary
Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing evening PEF data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment | 3.833 Litre/min | Standard Error 4.363 |
| Tio R1.25 qd | Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment | 25.084 Litre/min | Standard Error 4.331 |
| Tio R2.5 qd | Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment | 18.410 Litre/min | Standard Error 4.331 |
| Tio R5 qd | Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment | 25.414 Litre/min | Standard Error 4.348 |
p-value: <0.000195% CI: [14.166, 28.997]Mixed Models Analysis
p-value: <0.000195% CI: [13.84, 28.662]Mixed Models Analysis
p-value: 0.000195% CI: [7.166, 21.988]Mixed Models Analysis
Secondary
Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing morning PEF data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment | 4.395 Litre/min | Standard Error 4.573 |
| Tio R1.25 qd | Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment | 22.944 Litre/min | Standard Error 4.543 |
| Tio R2.5 qd | Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment | 22.290 Litre/min | Standard Error 4.543 |
| Tio R5 qd | Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment | 25.241 Litre/min | Standard Error 4.559 |
p-value: <0.000195% CI: [11.204, 25.895]Mixed Models Analysis
p-value: <0.000195% CI: [10.55, 25.24]Mixed Models Analysis
p-value: <0.000195% CI: [13.497, 28.195]Mixed Models Analysis
Secondary
PEF Variability Response (Last Week on Treatment)
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent . Weekly means obtained during the last week of each period of randomised treatment will be compared.
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing morning and evening PEF data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PEF Variability Response (Last Week on Treatment) | -0.171 Percentage of the mean daily PEF | Standard Error 0.615 |
| Tio R1.25 qd | PEF Variability Response (Last Week on Treatment) | -0.285 Percentage of the mean daily PEF | Standard Error 0.609 |
| Tio R2.5 qd | PEF Variability Response (Last Week on Treatment) | -0.711 Percentage of the mean daily PEF | Standard Error 0.609 |
| Tio R5 qd | PEF Variability Response (Last Week on Treatment) | -0.248 Percentage of the mean daily PEF | Standard Error 0.612 |
p-value: 0.857495% CI: [-1.363, 1.134]Mixed Models Analysis
p-value: 0.395495% CI: [-1.789, 0.708]Mixed Models Analysis
p-value: 0.903495% CI: [-1.327, 1.173]Mixed Models Analysis
Secondary
Trough FEV1 Response
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 was measured just prior to the last administration of randomised treatment.
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing FEV1 data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | 0.006 Litre | Standard Error 0.027 |
| Tio R1.25 qd | Trough FEV1 Response | 0.131 Litre | Standard Error 0.027 |
| Tio R2.5 qd | Trough FEV1 Response | 0.138 Litre | Standard Error 0.027 |
| Tio R5 qd | Trough FEV1 Response | 0.149 Litre | Standard Error 0.027 |
p-value: <0.000195% CI: [0.078, 0.173]Mixed Models Analysis
p-value: <0.000195% CI: [0.084, 0.179]Mixed Models Analysis
p-value: <0.000195% CI: [0.096, 0.191]Mixed Models Analysis
Secondary
Trough FVC Response
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FVC was measured just prior to the last administration of randomised treatment.
Time frame: Baseline and 4 weeks
Population: FAS reduced to patients with non-missing FVC data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response | 0.004 Litre | Standard Error 0.035 |
| Tio R1.25 qd | Trough FVC Response | 0.058 Litre | Standard Error 0.035 |
| Tio R2.5 qd | Trough FVC Response | 0.076 Litre | Standard Error 0.035 |
| Tio R5 qd | Trough FVC Response | 0.102 Litre | Standard Error 0.035 |
p-value: 0.073295% CI: [-0.005, 0.113]Mixed Models Analysis
p-value: 0.017795% CI: [0.012, 0.131]Mixed Models Analysis
p-value: 0.001295% CI: [0.039, 0.157]Mixed Models Analysis