Asthma
Conditions
Brief summary
The primary objective of this trial is to evaluate the efficacy and safety of tiotropium 1.25 mcg (2 actuations of 0.625 mcg), tiotropium 2.5 mcg (2 actuations of 1.25 mcg) and tiotropium 5 mcg (2 actuations of 2.5 mcg) once daily in the evening delivered by the Respimat inhaler in adolescents (12 to 17 yrs) with moderate persistent asthma, compared to placebo and on top of maintenance therapy with an inhaled corticosteroid controller medication. It is a randomised, double-blind, placebo-controlled Phase II trial with incomplete cross-over design. Patients need to be still symptomatic, i. e. not fully controlled with their maintenance treatment.
Interventions
DRUGTiotropium bromide
inhalation solution, dose of 1.25 mcg (2 puffs of 0.625 mcg)
DRUGtiotropium bromide
inhalation solution, dose of 2.5 mcg (2 puffs of 1.25 mcg)
DRUGPlacebo
placebo inhalation solution
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. All patients and legally accepted caregiver(s) must sign and date an Informed Consent form consistent with Good Clinical Practice (GCP) guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and local legislation prior to participation in the trial. 2. Male or female patients between 12 and 17 years of age. 3. All patients must have at least a 3 months history of asthma and fulfill the diagnostic criteria of moderate persistent asthma, according to the current Global Initiative for Asthma (GINA) guidelines at the time of enrolment into the trial. 4. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose for at least 4 weeks before Visit 1. 5. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of equal or above 1.5. 6. All patients must have a pre-bronchodilator FEV1 above 60% and less than or equal 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%. 7. All patients must have an increase in FEV1 of equal or above 12% and 200 mL 15 min. after 400 mcg salbutamol (albuterol) at Visit 1. If patients in the lower age range (e.g., 12 to 14 year olds) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (12%) post-bronchodilator response. 8. All patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment. 9. Patients should be able to use the Respimat® inhaler correctly. 10. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres, according to American Thoracic Society (ATS) standards and the use of the electronic diary/peak flow meter.
Exclusion criteria
1. Patients with a significant disease other than asthma. 2. Patients with a history of congenital or acquired heart disease, and/or have been hospitalised for cardiac syncope or failure during the past year. 3. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention (e. g. pacemaker implantation) or a change in drug therapy within the past year. 4. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. 5. Patients with lung diseases other than asthma, e.g. cystic fibrosis (CF). In case of ex-premature infants, a history of significant bronchopulmonary dysplasia (BPD) will be regarded as exclusion criterion 6. Patients with significant alcohol or drug abuse within the past two years. 7. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA) or any other components of the tiotropium inhalation solution. 8. Pregnant or nursing adolescent female patients, including female patients with a positive Beta HCG (serum pregnancy) testing at screening (visit 1). 9. Sexually active female patients of child-bearing potential not using a highly effective method of birth control. 10. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated. 11. Patients with renal impairment, as defined by a creatinine clearance less than 50 mL/min/1.73 m2 body surface area (BSA) as calculated by Schwartz Formula.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume (FEV1) Peak (0-3h) Response | Baseline and 4 weeks | The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | Baseline and 4 weeks | FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| FEV1 Individual Measurements Response at Each Time-point | Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) | Individual FEV1 measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Change From Baseline in the Number of Puffs of Rescue Medication Per Day | Baseline and 4 weeks | Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Forced Vital Capacity (FVC) Peak (0-3h) Response | Baseline and 4 weeks | The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| FVC Trough Response | Baseline and 4 weeks | The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | Baseline and 4 weeks | FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Trough FEV1 Response | Baseline and 4 weeks | The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) | FEF 25-75% is the mean forced expiratory flow between 25% and 75% of the FVC determined at the end of the 4-week treatment period. This is often referred to as the maximum midexpiratory flow. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Mean Morning Peak Expiratory Flow (PEF) Response | Baseline and 4 weeks | Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Mean Evening PEF Response | Baseline and 4 weeks | Mean evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 4 weeks | ACQ is a questionnaire consisting of a seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| Change From Baseline in Mean Number of Nighttime Awakenings | Baseline and last week of treatment (week 4) | Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
| FVC Individual Measurements at Each Time-point | Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) | Individual FVC measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. |
Countries
Germany, Latvia, Lithuania, Slovenia, United States
Participant flow
Recruitment details
In this incomplete crossover design, 105 patients were randomised to one of four sequences (in general terms, ABC, BDA, CAD or DCB). Whilst there were 4 possible treatments, A, B, C and D, each patient would receive a maximum of 3 different treatments. Hence, approximately 75 patients would receive each of A, B, C and D at any timepoint.
Participants by arm
| Arm | Count |
|---|---|
| Total. Total number of patients randomised and treated at all in the study. | 105 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 (4 Weeks) | Adverse Event | 1 | 0 | 0 | 0 |
| Period 1 (4 Weeks) | Other | 1 | 1 | 0 | 0 |
| Period 1 (4 Weeks) | Protocol Violation | 1 | 0 | 0 | 0 |
| Period 2 (4 Weeks) | Other | 1 | 0 | 0 | 0 |
| Period 2 (4 Weeks) | Protocol Violation | 0 | 0 | 0 | 1 |
| Period 3 (4 Weeks) | Adverse Event | 1 | 0 | 0 | 0 |
| Period 3 (4 Weeks) | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total. |
|---|---|
| Age, Continuous | 14.0 Years STANDARD_DEVIATION 1.5 |
| Forced expiratory volume in 1s (FEV1) | 2.742 Litre STANDARD_DEVIATION 0.697 |
| Sex: Female, Male Female | 38 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 / 75 | 0 / 75 | 0 / 75 | 0 / 80 |
| serious Total, serious adverse events | 0 / 75 | 1 / 75 | 0 / 75 | 1 / 80 |
Outcome results
Primary
Forced Expiratory Volume (FEV1) Peak (0-3h) Response
The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: The Full analysis set (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. This patient set is therefore FAS reduced to patients with non-missing FEV1 data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.489 Litre | Standard Error 0.047 |
| Tio R1.25 | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.556 Litre | Standard Error 0.047 |
| Tio R2.5 | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.546 Litre | Standard Error 0.047 |
| Tio R5 | Forced Expiratory Volume (FEV1) Peak (0-3h) Response | 0.602 Litre | Standard Error 0.046 |
Comparison: Tio R5 minus Placebop-value: 0.004395% CI: [0.036, 0.19]Mixed model repeated measures (MMRM)
Comparison: Tio R2.5 minus Placebop-value: 0.148495% CI: [-0.021, 0.135]Mixed effect repeated measures (MMRM)
Comparison: Tio R1.25 minus Placebop-value: 0.066495% CI: [-0.005, 0.138]Mixed effect repeated measures (MMRM)
Comparison: Tio R5 minus Tio R1.2595% CI: [-0.031, 0.124]Mixed effect repeated measures (MMRM)
Comparison: Tio R5 minus Tio R2.595% CI: [-0.014, 0.126]Mixed effect repeated measures (MMRM)
Comparison: Tio R2.5 minus Tio R1.2595% CI: [-0.088, 0.069]Mixed effect repeated measures (MMRM)
Secondary
Change From Baseline in Mean Number of Nighttime Awakenings
Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and last week of treatment (week 4)
Population: FAS with non-missing data for nighttime awakenings
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Number of Nighttime Awakenings | -0.086 Night awakenings per week | Standard Error 0.03 |
| Tio R1.25 | Change From Baseline in Mean Number of Nighttime Awakenings | -0.027 Night awakenings per week | Standard Error 0.03 |
| Tio R2.5 | Change From Baseline in Mean Number of Nighttime Awakenings | -0.074 Night awakenings per week | Standard Error 0.03 |
| Tio R5 | Change From Baseline in Mean Number of Nighttime Awakenings | -0.066 Night awakenings per week | Standard Error 0.029 |
Secondary
Change From Baseline in the Number of Puffs of Rescue Medication Per Day
Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing data for rescue medication
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Puffs of Rescue Medication Per Day | -0.412 Puffs/day | Standard Error 0.155 |
| Tio R1.25 | Change From Baseline in the Number of Puffs of Rescue Medication Per Day | -0.635 Puffs/day | Standard Error 0.156 |
| Tio R2.5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Day | -0.521 Puffs/day | Standard Error 0.154 |
| Tio R5 | Change From Baseline in the Number of Puffs of Rescue Medication Per Day | -0.528 Puffs/day | Standard Error 0.151 |
Secondary
Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ)
ACQ is a questionnaire consisting of a seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: 4 weeks
Population: FAS with non-missing ACQ data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 1.371 Units on a scale | Standard Error 0.078 |
| Tio R1.25 | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 1.189 Units on a scale | Standard Error 0.079 |
| Tio R2.5 | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 1.366 Units on a scale | Standard Error 0.078 |
| Tio R5 | Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | 1.287 Units on a scale | Standard Error 0.078 |
Secondary
FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response
FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing FEV1 data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.363 Litre | Standard Error 0.045 |
| Tio R1.25 | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.455 Litre | Standard Error 0.045 |
| Tio R2.5 | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.434 Litre | Standard Error 0.045 |
| Tio R5 | FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.497 Litre | Standard Error 0.045 |
Secondary
FEV1 Individual Measurements Response at Each Time-point
Individual FEV1 measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
Population: FAS with non-missing FEV1 data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | FEV1 Individual Measurements Response at Each Time-point | Timepoint 2:00 hr response | 0.394 Litre | Standard Error 0.047 |
| Placebo | FEV1 Individual Measurements Response at Each Time-point | Timepoint 0:30 hr response | 0.337 Litre | Standard Error 0.047 |
| Placebo | FEV1 Individual Measurements Response at Each Time-point | Timepoint 3:00 hr response | 0.396 Litre | Standard Error 0.048 |
| Placebo | FEV1 Individual Measurements Response at Each Time-point | Timepoint 1:00 hr response | 0.353 Litre | Standard Error 0.048 |
| Placebo | FEV1 Individual Measurements Response at Each Time-point | Timepoint -0:10 hr response | 0.292 Litre | Standard Error 0.045 |
| Tio R1.25 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 1:00 hr response | 0.456 Litre | Standard Error 0.048 |
| Tio R1.25 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 2:00 hr response | 0.467 Litre | Standard Error 0.048 |
| Tio R1.25 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 3:00 hr response | 0.467 Litre | Standard Error 0.048 |
| Tio R1.25 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 0:30 hr response | 0.456 Litre | Standard Error 0.047 |
| Tio R1.25 | FEV1 Individual Measurements Response at Each Time-point | Timepoint -0:10 hr response | 0.384 Litre | Standard Error 0.045 |
| Tio R2.5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 1:00 hr response | 0.416 Litre | Standard Error 0.048 |
| Tio R2.5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint -0:10 hr response | 0.353 Litre | Standard Error 0.045 |
| Tio R2.5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 0:30 hr response | 0.407 Litre | Standard Error 0.047 |
| Tio R2.5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 2:00 hr response | 0.453 Litre | Standard Error 0.047 |
| Tio R2.5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 3:00 hr response | 0.489 Litre | Standard Error 0.048 |
| Tio R5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 2:00 hr response | 0.501 Litre | Standard Error 0.047 |
| Tio R5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 0:30 hr response | 0.486 Litre | Standard Error 0.047 |
| Tio R5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint -0:10 hr response | 0.442 Litre | Standard Error 0.045 |
| Tio R5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 1:00 hr response | 0.505 Litre | Standard Error 0.047 |
| Tio R5 | FEV1 Individual Measurements Response at Each Time-point | Timepoint 3:00 hr response | 0.497 Litre | Standard Error 0.047 |
Secondary
Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point
FEF 25-75% is the mean forced expiratory flow between 25% and 75% of the FVC determined at the end of the 4-week treatment period. This is often referred to as the maximum midexpiratory flow. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
Population: FAS with non-missing FEF data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 2:00 hr response | 0.357 Litre | Standard Error 0.088 |
| Placebo | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 0:30 hr response | 0.268 Litre | Standard Error 0.083 |
| Placebo | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 3:00 hr response | 0.329 Litre | Standard Error 0.083 |
| Placebo | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 1:00 hr response | 0.321 Litre | Standard Error 0.087 |
| Placebo | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint -0:10 hr response | 0.242 Litre | Standard Error 0.081 |
| Tio R1.25 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 1:00 hr response | 0.655 Litre | Standard Error 0.087 |
| Tio R1.25 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 2:00 hr response | 0.678 Litre | Standard Error 0.089 |
| Tio R1.25 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 3:00 hr response | 0.662 Litre | Standard Error 0.084 |
| Tio R1.25 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 0:30 hr response | 0.643 Litre | Standard Error 0.084 |
| Tio R1.25 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint -0:10 hr response | 0.533 Litre | Standard Error 0.082 |
| Tio R2.5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 1:00 hr response | 0.569 Litre | Standard Error 0.087 |
| Tio R2.5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint -0:10 hr response | 0.380 Litre | Standard Error 0.082 |
| Tio R2.5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 0:30 hr response | 0.513 Litre | Standard Error 0.084 |
| Tio R2.5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 2:00 hr response | 0.607 Litre | Standard Error 0.089 |
| Tio R2.5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 3:00 hr response | 0.616 Litre | Standard Error 0.084 |
| Tio R5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 2:00 hr response | 0.622 Litre | Standard Error 0.087 |
| Tio R5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 0:30 hr response | 0.647 Litre | Standard Error 0.082 |
| Tio R5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint -0:10 hr response | 0.566 Litre | Standard Error 0.08 |
| Tio R5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 1:00 hr response | 0.641 Litre | Standard Error 0.086 |
| Tio R5 | Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | Timepoint 3:00 hr response | 0.620 Litre | Standard Error 0.083 |
Secondary
Forced Vital Capacity (FVC) Peak (0-3h) Response
The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing FVC data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.546 Litre | Standard Error 0.049 |
| Tio R1.25 | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.554 Litre | Standard Error 0.049 |
| Tio R2.5 | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.554 Litre | Standard Error 0.048 |
| Tio R5 | Forced Vital Capacity (FVC) Peak (0-3h) Response | 0.548 Litre | Standard Error 0.048 |
Secondary
FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response
FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing FVC data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.413 Litre | Standard Error 0.046 |
| Tio R1.25 | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.441 Litre | Standard Error 0.046 |
| Tio R2.5 | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.417 Litre | Standard Error 0.045 |
| Tio R5 | FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | 0.429 Litre | Standard Error 0.045 |
Secondary
FVC Individual Measurements at Each Time-point
Individual FVC measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
Population: FAS with non-missing FVC data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | FVC Individual Measurements at Each Time-point | Timepoint 2:00 hr response | 0.429 Litre | Standard Error 0.048 |
| Placebo | FVC Individual Measurements at Each Time-point | Timepoint 0:30 hr response | 0.397 Litre | Standard Error 0.049 |
| Placebo | FVC Individual Measurements at Each Time-point | Timepoint 3:00 hr response | 0.430 Litre | Standard Error 0.048 |
| Placebo | FVC Individual Measurements at Each Time-point | Timepoint 1:00 hr response | 0.417 Litre | Standard Error 0.049 |
| Placebo | FVC Individual Measurements at Each Time-point | Timepoint -0:10 hr response | 0.357 Litre | Standard Error 0.047 |
| Tio R1.25 | FVC Individual Measurements at Each Time-point | Timepoint 1:00 hr response | 0.443 Litre | Standard Error 0.05 |
| Tio R1.25 | FVC Individual Measurements at Each Time-point | Timepoint 2:00 hr response | 0.438 Litre | Standard Error 0.048 |
| Tio R1.25 | FVC Individual Measurements at Each Time-point | Timepoint 3:00 hr response | 0.461 Litre | Standard Error 0.048 |
| Tio R1.25 | FVC Individual Measurements at Each Time-point | Timepoint 0:30 hr response | 0.434 Litre | Standard Error 0.049 |
| Tio R1.25 | FVC Individual Measurements at Each Time-point | Timepoint -0:10 hr response | 0.375 Litre | Standard Error 0.047 |
| Tio R2.5 | FVC Individual Measurements at Each Time-point | Timepoint 1:00 hr response | 0.387 Litre | Standard Error 0.049 |
| Tio R2.5 | FVC Individual Measurements at Each Time-point | Timepoint -0:10 hr response | 0.381 Litre | Standard Error 0.047 |
| Tio R2.5 | FVC Individual Measurements at Each Time-point | Timepoint 0:30 hr response | 0.394 Litre | Standard Error 0.049 |
| Tio R2.5 | FVC Individual Measurements at Each Time-point | Timepoint 2:00 hr response | 0.444 Litre | Standard Error 0.048 |
| Tio R2.5 | FVC Individual Measurements at Each Time-point | Timepoint 3:00 hr response | 0.454 Litre | Standard Error 0.048 |
| Tio R5 | FVC Individual Measurements at Each Time-point | Timepoint 2:00 hr response | 0.423 Litre | Standard Error 0.048 |
| Tio R5 | FVC Individual Measurements at Each Time-point | Timepoint 0:30 hr response | 0.409 Litre | Standard Error 0.049 |
| Tio R5 | FVC Individual Measurements at Each Time-point | Timepoint -0:10 hr response | 0.400 Litre | Standard Error 0.047 |
| Tio R5 | FVC Individual Measurements at Each Time-point | Timepoint 1:00 hr response | 0.448 Litre | Standard Error 0.049 |
| Tio R5 | FVC Individual Measurements at Each Time-point | Timepoint 3:00 hr response | 0.456 Litre | Standard Error 0.048 |
Secondary
FVC Trough Response
The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing FVC data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Trough Response | 0.357 Litre | Standard Error 0.047 |
| Tio R1.25 | FVC Trough Response | 0.375 Litre | Standard Error 0.047 |
| Tio R2.5 | FVC Trough Response | 0.381 Litre | Standard Error 0.047 |
| Tio R5 | FVC Trough Response | 0.400 Litre | Standard Error 0.047 |
Secondary
Mean Evening PEF Response
Mean evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing evening PEF data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Evening PEF Response | -0.552 Litre/min | Standard Error 6.098 |
| Tio R1.25 | Mean Evening PEF Response | 5.985 Litre/min | Standard Error 6.089 |
| Tio R2.5 | Mean Evening PEF Response | 18.971 Litre/min | Standard Error 6.043 |
| Tio R5 | Mean Evening PEF Response | 16.565 Litre/min | Standard Error 5.97 |
Secondary
Mean Morning Peak Expiratory Flow (PEF) Response
Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing morning PEF data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Morning Peak Expiratory Flow (PEF) Response | 7.267 Litre/min | Standard Error 6.152 |
| Tio R1.25 | Mean Morning Peak Expiratory Flow (PEF) Response | 18.613 Litre/min | Standard Error 6.118 |
| Tio R2.5 | Mean Morning Peak Expiratory Flow (PEF) Response | 23.185 Litre/min | Standard Error 6.146 |
| Tio R5 | Mean Morning Peak Expiratory Flow (PEF) Response | 20.491 Litre/min | Standard Error 6.031 |
Secondary
Trough FEV1 Response
The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
Time frame: Baseline and 4 weeks
Population: FAS with non-missing FEV1 data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | 0.292 Litre | Standard Error 0.045 |
| Tio R1.25 | Trough FEV1 Response | 0.384 Litre | Standard Error 0.045 |
| Tio R2.5 | Trough FEV1 Response | 0.353 Litre | Standard Error 0.045 |
| Tio R5 | Trough FEV1 Response | 0.442 Litre | Standard Error 0.045 |