Asthma
Conditions
Brief summary
Rationale for the current trial is to demonstrate 24 hour bronchodilator efficacy and safety of tiotropium 5 µg administered once daily (in the evening) which is regarded beneficial for the compliance and convenience of the patient in comparison to placebo. Further the rationale is to evaluate efficacy and safety of tiotropium 2.5 µg administered twice daily delivered by the Respimat® inhaler in comparison to placebo and tiotropium 5 µg administered once daily (in the evening) delivered by the Respimat® inhaler in patients with moderate persistent asthma. Rationale for the pharmacokinetic subinvestigation is to evaluate the 24 hours exposure to tiotropium in patients with moderate persistent asthma when administered 5 µg tiotropium once daily (in the evening) or 2.5 µg tiotropium twice daily.
Interventions
DRUGTiotropium 2.5 µg b.i.d
2.5 µg (two actuations of 1.25 µg) delivered via Respimat® inhaler
DRUGPlacebo
N/A (two actuations of placebo) delivered via Respimat® inhaler
DRUGTiotropium 5 µg q.d.
5 µg (two actuations of 2.5 µg) delivered via Respimat® inhaler
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 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 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 months history of asthma at the time of enrolment into the trial. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility resulting in a Forced Expiratory Volume in 1 Second (FEV1) increase of equal above 12% and equal above 200mL. 4. The initial diagnosis of asthma must have been made before the patient's age of 40. 5. All patients must have a diagnosis of moderate persistent asthma and must be symptomatic despite their current maintenance treatment with medium doses of inhaled corticosteroids. 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 Betaadrenergic (LABA) or Short Acting Betaadrenergic (SABA)) for at least 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and Visit 2 as defined by an Asthma Control Questionnaire (ACQ) Score 8. All patients must have a pre-bronchodilator FEV1 above equal 60% predicted and below equal 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to the European Coal and Steel Community Guidelines (ECSC). 9. All patients must have an increase in FEV1 of equal above 12% and equal above 200 mL 15 minutes after 400 µg salbutamol at Visit 1. 10. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30% . 11. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years. 12. Patients must be able to use the Respimat® inhaler correctly. 13. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the e-Diary/peak flow meter. 14. Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).
Exclusion criteria
1. Patients with a significant disease other than asthma.A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) 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 hematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion no. 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 Lung 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. 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 V 1. 12. Patients with known hypersensitivity to anticholinergic drugs, Benzalconiumchloride (BAC), Ethylenediaminetetraacetate (EDTA) or any other components of the study medication delivery systems. 13. Pregnant or nursing women. 14. Women of childbearing potential not using a highly effective method of birth control. 15. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 or during the screening period. Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed. 16. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 or during the screening period. 17. Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 or during the screening period. 18. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 or during the screening period. 19. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), within 6 months prior to Visit 1 or during the screening period.20. Patients who have been treated with cromolyn sodium or nedocromil sodium within two weeks prior to Visit 1 or during the screening period. 21\. Patients who have been treated with methylxanthines within two weeks prior to Visit 1 or during the screening period. 22\. Patients who have taken an investigational drug within four weeks prior to Visit 1. 23\. Patients who have been treated with other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 or during the screening period. 24\. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period. Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection. 25\. Patients who have previously been randomised in this trial or are currently participating in another trial. 26.Patients who have been treated with depot corticosteroids within six months prior to Visit 1 or during the screening period. 27.Patients who have been treated with leukotriene modifiers within two weeks prior to Visit 1 or during the screening period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response | 10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 | Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment | Baseline and during week 4 of each treatment period | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device. |
| FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response | 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4 | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. |
| FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response | 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. |
| Peak FEV1 Within 24 Hours Post-dose Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment. |
| Trough FEV1 Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment. |
| Trough Forced Vital Capacity (FVC) Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FVC is defined as FVC value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment. |
| FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response | 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4 | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. |
| FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response | 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. |
| Peak FVC Within 24 Hours Post-dose Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. |
| Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment | Baseline and during week 4 of each treatment period | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device. |
| Individual FVC Over Time (at Each Timepoint at Visits) Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline. 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. Means are adjusted for treatment, period, patient and study baseline. |
| FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response | 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres. |
| PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response | 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4 | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres/min. |
| PEF Variability Response (Last Week on Treatment) | Baseline and during week 4 | MMRM results. Response was defined as change from baseline. 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 during week 4 | MMRM results. Response was defined as change from baseline. 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. |
| Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | Baseline and during week 4 | MMRM results. Response was defined as change from baseline. 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. |
| Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | Baseline and during week 4 | MMRM results. Response was defined as change from baseline. 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. |
| Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | Baseline and during week 4 | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Assessed by the patient's electronic diary (eDiary incorporated in the AM2+ device), obtained during the last week of each period of randomised treatment. |
| Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Baseline and 4 weeks | MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. |
Countries
Austria, Czechia, Estonia, Germany, Latvia
Participant flow
Recruitment details
A total of 94 patients entered the study and was treated whilst 89 patients completed the trial.
Pre-assignment details
Randomised, double-blind, placebo controlled, cross-over design without washout phase between the three periods. Patients were randomized equally to one of the six sequences (ABC, ACB, BAC, BCA, CAB, CBA).
Participants by arm
| Arm | Count |
|---|---|
| Baseline Total Total number of patients randomised and treated in the study. | 94 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 (4 Weeks) | Adverse Event | 0 | 0 | 0 | 0 | 1 | 1 |
| Period 1 (4 Weeks) | Lost to Follow-up | 0 | 1 | 1 | 0 | 0 | 0 |
| Period 1 (4 Weeks) | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Baseline Total |
|---|---|
| Age, Continuous | 44.3 Years STANDARD_DEVIATION 13.2 |
| Sex: Female, Male Female | 55 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 92 | 7 / 90 | 5 / 90 |
| serious Total, serious adverse events | 1 / 92 | 0 / 90 | 2 / 90 |
Outcome results
Primary
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response
Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
Time frame: 10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Population: Full Analysis Set (FAS) defined as all treated patients who had baseline data and at least 1 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) Area Under the Curve 0-24 Hours (AUC0-24h) Response | 0.091 L | Standard Error 0.043 |
| Tio R2.5 Bid | Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response | 0.241 L | Standard Error 0.044 |
| Tio R5 qd | Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response | 0.250 L | Standard Error 0.044 |
p-value: <0.000195% CI: [0.102, 0.196]Mixed Models Analysis
p-value: <0.000195% CI: [0.111, 0.205]Mixed Models Analysis
95% CI: [-0.038, 0.056]Mixed Models Analysis
Secondary
FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response | 0.048 L | Standard Error 0.044 |
| Tio R2.5 Bid | FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response | 0.217 L | Standard Error 0.044 |
| Tio R5 qd | FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response | 0.233 L | Standard Error 0.044 |
p-value: <0.000195% CI: [0.12, 0.218]Mixed Models Analysis
p-value: <0.000195% CI: [0.136, 0.234]Mixed Models Analysis
95% CI: [-0.033, 0.065]Mixed Models Analysis
Secondary
FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time frame: 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response | 0.135 L | Standard Error 0.044 |
| Tio R2.5 Bid | FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response | 0.264 L | Standard Error 0.045 |
| Tio R5 qd | FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response | 0.266 L | Standard Error 0.044 |
p-value: <0.000195% CI: [0.077, 0.181]Mixed Models Analysis
p-value: <0.000195% CI: [0.079, 0.183]Mixed Models Analysis
95% CI: [-0.05, 0.054]Mixed Models Analysis
Secondary
FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response | -0.026 L | Standard Error 0.046 |
| Tio R2.5 Bid | FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response | 0.099 L | Standard Error 0.046 |
| Tio R5 qd | FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response | 0.074 L | Standard Error 0.046 |
p-value: <0.000195% CI: [0.073, 0.177]Mixed Models Analysis
p-value: 0.000295% CI: [0.048, 0.152]Mixed Models Analysis
95% CI: [-0.077, 0.027]Mixed Models Analysis
Secondary
FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
Time frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response | 0.003 L | Standard Error 0.044 |
| Tio R2.5 Bid | FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response | 0.104 L | Standard Error 0.044 |
| Tio R5 qd | FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response | 0.087 L | Standard Error 0.044 |
p-value: <0.000195% CI: [0.055, 0.147]Mixed Models Analysis
p-value: 0.000495% CI: [0.038, 0.13]Mixed Models Analysis
95% CI: [-0.063, 0.03]Mixed Models Analysis
Secondary
FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time frame: 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response | 0.032 L | Standard Error 0.045 |
| Tio R2.5 Bid | FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response | 0.108 L | Standard Error 0.045 |
| Tio R5 qd | FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response | 0.100 L | Standard Error 0.045 |
p-value: 0.005195% CI: [0.023, 0.129]Mixed Models Analysis
p-value: 0.012395% CI: [0.015, 0.12]Mixed Models Analysis
95% CI: [-0.061, 0.045]Mixed Models Analysis
Secondary
Individual FEV1 Over Time (at Each Timepoint at Visits) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time frame: Baseline and 4 weeks
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 0.161 L | Standard Error 0.046 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | -0.021 L | Standard Error 0.049 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 0.143 L | Standard Error 0.044 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 0.163 L | Standard Error 0.046 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 0.075 L | Standard Error 0.047 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 0.132 L | Standard Error 0.044 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 0.138 L | Standard Error 0.045 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 0.101 L | Standard Error 0.047 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 0.117 L | Standard Error 0.047 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 0.103 L | Standard Error 0.044 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 0.125 L | Standard Error 0.047 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 0.127 L | Standard Error 0.045 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 0.082 L | Standard Error 0.044 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 0.124 L | Standard Error 0.045 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 0.177 L | Standard Error 0.047 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 0.062 L | Standard Error 0.045 |
| Placebo | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 0.123 L | Standard Error 0.044 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | 0.134 L | Standard Error 0.049 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 0.254 L | Standard Error 0.044 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 0.281 L | Standard Error 0.044 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 0.274 L | Standard Error 0.044 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 0.270 L | Standard Error 0.044 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 0.264 L | Standard Error 0.044 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 0.248 L | Standard Error 0.045 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 0.198 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 0.250 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 0.288 L | Standard Error 0.045 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 0.299 L | Standard Error 0.046 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 0.306 L | Standard Error 0.046 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 0.300 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 0.256 L | Standard Error 0.046 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 0.221 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 0.243 L | Standard Error 0.045 |
| Tio R2.5 Bid | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 0.232 L | Standard Error 0.047 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 0.263 L | Standard Error 0.045 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 0.304 L | Standard Error 0.044 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 0.313 L | Standard Error 0.046 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 0.268 L | Standard Error 0.044 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 0.224 L | Standard Error 0.047 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 0.297 L | Standard Error 0.044 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 0.223 L | Standard Error 0.045 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 0.245 L | Standard Error 0.045 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 0.289 L | Standard Error 0.044 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 0.237 L | Standard Error 0.047 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 0.217 L | Standard Error 0.047 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 0.275 L | Standard Error 0.044 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 0.282 L | Standard Error 0.045 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | 0.150 L | Standard Error 0.049 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 0.308 L | Standard Error 0.047 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 0.244 L | Standard Error 0.047 |
| Tio R5 qd | Individual FEV1 Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 0.308 L | Standard Error 0.046 |
Secondary
Individual FVC Over Time (at Each Timepoint at Visits) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time frame: Baseline and 4 weeks
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 0.018 L | Standard Error 0.048 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | -0.064 L | Standard Error 0.049 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 0.053 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 0.050 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 0.004 L | Standard Error 0.046 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 0.036 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 0.034 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 0.010 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 0.033 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 0.038 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | -0.015 L | Standard Error 0.049 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 0.112 L | Standard Error 0.046 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | -0.003 L | Standard Error 0.047 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 0.028 L | Standard Error 0.048 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 0.062 L | Standard Error 0.046 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | -0.040 L | Standard Error 0.049 |
| Placebo | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 0.055 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 0.123 L | Standard Error 0.046 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 0.179 L | Standard Error 0.046 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 0.158 L | Standard Error 0.048 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 0.152 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 0.131 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 0.100 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 0.096 L | Standard Error 0.049 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | 0.070 L | Standard Error 0.049 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 0.133 L | Standard Error 0.046 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 0.114 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 0.106 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 0.109 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 0.111 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 0.125 L | Standard Error 0.047 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 0.077 L | Standard Error 0.048 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 0.094 L | Standard Error 0.048 |
| Tio R2.5 Bid | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 0.078 L | Standard Error 0.049 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 0.065 L | Standard Error 0.049 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 0.052 L | Standard Error 0.049 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 0.116 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 0.057 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 0.093 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 0.113 L | Standard Error 0.046 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 0.124 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 0.062 L | Standard Error 0.048 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 0.088 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 0.130 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 0.102 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 0.168 L | Standard Error 0.046 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 0.120 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 0.103 L | Standard Error 0.046 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 0.096 L | Standard Error 0.048 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 0.124 L | Standard Error 0.047 |
| Tio R5 qd | Individual FVC Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | 0.060 L | Standard Error 0.049 |
Secondary
Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time frame: Baseline and 4 weeks
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 19.616 L/min | Standard Error 7.304 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | -11.219 L/min | Standard Error 7.747 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 12.994 L/min | Standard Error 7.275 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 19.770 L/min | Standard Error 7.357 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 4.345 L/min | Standard Error 7.314 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 14.275 L/min | Standard Error 7.317 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 16.125 L/min | Standard Error 6.992 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 6.820 L/min | Standard Error 7.479 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 11.366 L/min | Standard Error 7.246 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 13.879 L/min | Standard Error 7.323 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 15.169 L/min | Standard Error 7.67 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 13.348 L/min | Standard Error 7.213 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 9.769 L/min | Standard Error 7.457 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 13.590 L/min | Standard Error 7.36 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 20.084 L/min | Standard Error 7.303 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 7.499 L/min | Standard Error 7.242 |
| Placebo | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 13.783 L/min | Standard Error 7.027 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 47.991 L/min | Standard Error 7.012 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 42.428 L/min | Standard Error 7.378 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 46.272 L/min | Standard Error 7.295 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 43.049 L/min | Standard Error 7.043 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 48.328 L/min | Standard Error 7.263 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 48.723 L/min | Standard Error 7.474 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 42.599 L/min | Standard Error 7.26 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | 20.011 L/min | Standard Error 7.765 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 27.436 L/min | Standard Error 7.335 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 33.810 L/min | Standard Error 7.499 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 44.786 L/min | Standard Error 7.348 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 47.697 L/min | Standard Error 7.33 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 47.795 L/min | Standard Error 7.326 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 42.240 L/min | Standard Error 7.232 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 33.567 L/min | Standard Error 7.339 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 36.712 L/min | Standard Error 7.384 |
| Tio R2.5 Bid | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 36.837 L/min | Standard Error 7.697 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 0:30 (hours:minutes) | 58.436 L/min | Standard Error 7.277 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 16:00 (hours:minutes) | 46.441 L/min | Standard Error 7.306 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 3:00 (hours:minutes) | 50.747 L/min | Standard Error 7.458 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 23:50 (hours:minutes) | 37.595 L/min | Standard Error 7.673 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 18:00 (hours:minutes) | 48.790 L/min | Standard Error 7.306 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 2:00 (hours:minutes) | 55.826 L/min | Standard Error 7.248 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 23:00 (hours:minutes) | 38.384 L/min | Standard Error 7.362 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 20:00 (hours:minutes) | 40.888 L/min | Standard Error 7.215 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 1:00 (hours:minutes) | 53.138 L/min | Standard Error 7.028 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint -0:10 (hours:minutes) | 57.897 L/min | Standard Error 7.359 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 13:00 (hours:minutes) | 34.582 L/min | Standard Error 7.481 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 22:00 (hours:minutes) | 41.635 L/min | Standard Error 7.319 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 14:00 (hours:minutes) | 43.371 L/min | Standard Error 7.325 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 12:30 (hours:minutes) | 33.887 L/min | Standard Error 7.316 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 11:50 (hours:minutes) | 26.201 L/min | Standard Error 7.749 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 15:00 (hours:minutes) | 45.699 L/min | Standard Error 6.994 |
| Tio R5 qd | Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | Timepoint 4:00 (hours:minutes) | 50.077 L/min | Standard Error 7.244 |
Secondary
Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values)
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Assessed by the patient's electronic diary (eDiary incorporated in the AM2+ device), obtained during the last week of each period of randomised treatment.
Time frame: Baseline and during week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | -0.106 Night awakenings | Standard Error 0.028 |
| Tio R2.5 Bid | Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | -0.104 Night awakenings | Standard Error 0.029 |
| Tio R5 qd | Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | -0.102 Night awakenings | Standard Error 0.029 |
p-value: 0.962695% CI: [-0.059, 0.062]Mixed Models Analysis
p-value: 0.910295% CI: [-0.058, 0.065]Mixed Models Analysis
95% CI: [-0.059, 0.063]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. 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.
Time frame: Baseline and during week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | -0.562 Puffs | Standard Error 0.106 |
| Tio R2.5 Bid | Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | -0.564 Puffs | Standard Error 0.106 |
| Tio R5 qd | Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | -0.624 Puffs | Standard Error 0.106 |
p-value: 0.979795% CI: [-0.163, 0.159]Mixed Models Analysis
p-value: 0.451895% CI: [-0.223, 0.1]Mixed Models Analysis
95% CI: [-0.222, 0.102]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. 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.
Time frame: Baseline and during week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | -0.358 Puffs | Standard Error 0.092 |
| Tio R2.5 Bid | Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | -0.419 Puffs | Standard Error 0.093 |
| Tio R5 qd | Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | -0.432 Puffs | Standard Error 0.093 |
p-value: 0.408995% CI: [-0.207, 0.085]Mixed Models Analysis
p-value: 0.318595% CI: [-0.221, 0.072]Mixed Models Analysis
95% CI: [-0.16, 0.134]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. 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.
Time frame: Baseline and during week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | -0.841 Puffs | Standard Error 0.189 |
| Tio R2.5 Bid | Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | -0.917 Puffs | Standard Error 0.19 |
| Tio R5 qd | Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | -1.016 Puffs | Standard Error 0.19 |
p-value: 0.590695% CI: [-0.358, 0.204]Mixed Models Analysis
p-value: 0.220895% CI: [-0.458, 0.106]Mixed Models Analysis
95% CI: [-0.382, 0.184]Mixed Models Analysis
Secondary
Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
Time frame: Baseline and during week 4 of each treatment period
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment | -1.560 L/min | Standard Error 5.891 |
| Tio R2.5 Bid | Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment | 28.360 L/min | Standard Error 5.932 |
| Tio R5 qd | Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment | 27.096 L/min | Standard Error 5.931 |
p-value: <0.000195% CI: [20.001, 39.839]Mixed Models Analysis
p-value: <0.000195% CI: [18.707, 38.606]Mixed Models Analysis
95% CI: [-11.243, 8.716]Mixed Models Analysis
Secondary
Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
Time frame: Baseline and during week 4 of each treatment period
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment | 1.953 L/min | Standard Error 5.864 |
| Tio R2.5 Bid | Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment | 23.281 L/min | Standard Error 5.907 |
| Tio R5 qd | Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment | 24.310 L/min | Standard Error 5.924 |
p-value: <0.000195% CI: [11.084, 31.573]Mixed Models Analysis
p-value: <0.000195% CI: [12.044, 32.67]Mixed Models Analysis
95% CI: [-9.318, 11.376]Mixed Models Analysis
Secondary
Peak FEV1 Within 24 Hours Post-dose Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment.
Time frame: Baseline and 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 Within 24 Hours Post-dose Response | 0.337 L | Standard Error 0.045 |
| Tio R2.5 Bid | Peak FEV1 Within 24 Hours Post-dose Response | 0.469 L | Standard Error 0.045 |
| Tio R5 qd | Peak FEV1 Within 24 Hours Post-dose Response | 0.468 L | Standard Error 0.045 |
p-value: <0.000195% CI: [0.084, 0.179]Mixed Models Analysis
p-value: <0.000195% CI: [0.084, 0.179]Mixed Models Analysis
95% CI: [-0.048, 0.047]Mixed Models Analysis
Secondary
Peak FVC Within 24 Hours Post-dose Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period.
Time frame: Baseline and 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FVC Within 24 Hours Post-dose Response | 0.302 L | Standard Error 0.045 |
| Tio R2.5 Bid | Peak FVC Within 24 Hours Post-dose Response | 0.380 L | Standard Error 0.045 |
| Tio R5 qd | Peak FVC Within 24 Hours Post-dose Response | 0.350 L | Standard Error 0.045 |
p-value: 0.004295% CI: [0.025, 0.13]Mixed Models Analysis
p-value: 0.074795% CI: [-0.005, 0.1]Mixed Models Analysis
95% CI: [-0.082, 0.023]Mixed Models Analysis
Secondary
PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres/min.
Time frame: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response | 8.589 L/min | Standard Error 6.87 |
| Tio R2.5 Bid | PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response | 38.831 L/min | Standard Error 6.883 |
| Tio R5 qd | PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response | 42.899 L/min | Standard Error 6.871 |
p-value: <0.000195% CI: [22.167, 38.317]Mixed Models Analysis
p-value: <0.000195% CI: [26.24, 42.38]Mixed Models Analysis
95% CI: [-4.012, 12.148]Mixed Models Analysis
Secondary
PEF Variability Response (Last Week on Treatment)
MMRM results. Response was defined as change from baseline. 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 during week 4
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PEF Variability Response (Last Week on Treatment) | 0.296 Percent | Standard Error 0.711 |
| Tio R2.5 Bid | PEF Variability Response (Last Week on Treatment) | 0.619 Percent | Standard Error 0.718 |
| Tio R5 qd | PEF Variability Response (Last Week on Treatment) | 0.685 Percent | Standard Error 0.721 |
p-value: 0.674795% CI: [-1.195, 1.841]Mixed Models Analysis
p-value: 0.615995% CI: [-1.138, 1.916]Mixed Models Analysis
95% CI: [-1.468, 1.599]Mixed Models Analysis
Secondary
Trough FEV1 Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
Time frame: Baseline and 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | 0.143 L | Standard Error 0.044 |
| Tio R2.5 Bid | Trough FEV1 Response | 0.254 L | Standard Error 0.044 |
| Tio R5 qd | Trough FEV1 Response | 0.275 L | Standard Error 0.044 |
p-value: 0.000295% CI: [0.053, 0.17]Mixed Models Analysis
p-value: <0.000195% CI: [0.074, 0.191]Mixed Models Analysis
95% CI: [-0.037, 0.08]Mixed Models Analysis
Secondary
Trough Forced Vital Capacity (FVC) Response
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FVC is defined as FVC value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
Time frame: Baseline and 4 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough Forced Vital Capacity (FVC) Response | 0.112 L | Standard Error 0.046 |
| Tio R2.5 Bid | Trough Forced Vital Capacity (FVC) Response | 0.179 L | Standard Error 0.046 |
| Tio R5 qd | Trough Forced Vital Capacity (FVC) Response | 0.168 L | Standard Error 0.046 |
p-value: 0.051595% CI: [0, 0.136]Mixed Models Analysis
p-value: 0.105895% CI: [-0.012, 0.124]Mixed Models Analysis
95% CI: [-0.08, 0.057]Mixed Models Analysis