Asthma
Conditions
Brief summary
The trial is a randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 5 µg tiotropium over a 48-week treatment period as compared to placebo. Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined as add-on controller therapy on top of usual care in patients with severe persistent asthma. The primary objective of each trial is to evaluate the long term efficacy of tiotropium over placebo on top of usual care in patients with severe persistent asthma as determined by pulmonary function testing, effects on asthma exacerbations, effects on quality of life, on asthma control and health care resource utilisation. The secondary objective of each trial is to compare the long term safety of tiotropium with placebo in this patient population.
Interventions
Intervention = Randomisation: patient to receive double-blind treatment with either 5mcg/day tiotropium inhalation solution or placebo inhalation solution
DRUGplacebo
Intervention = Randomisation: patient to receive double-blind treatment with either 5mcg/day tiotropium inhalation solution or placebo inhalation solution
Sponsors
Pfizer
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. All patients must sign and date an Informed Consent Form consistent with 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 5-year history of asthma at the time of enrolment into the trial and the diagnosis of asthma must have been made before the patient´s age of 40. 4. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent 5. All patients must have a history of one or more asthma exacerbation in the past year. 6. Patients must have evidence of treated, severe, persistent asthma in postbronchodilator pulmonary function tests. 7. Patients should 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 8. Patients must be able to use the Respimat® inhaler correctly 9. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the electronic diary/peak flow meter.
Exclusion criteria
1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient´s ability to participate in the trial. 2. Patients with clinically relevant abnormal screening haematology or blood chemistry. 3. Patients with a recent history (i.e. six months or less) of myocardial infarction, hospitalisation for cardiac failure during the past year, any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year, known active tuberculosis, malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years (treated basal cell carcinoma allowed), lung diseases other than asthma (e.g. COPD), significant alcohol or drug abuse within the past two years, patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1. 4. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1). 5. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day. 6. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. 7. Pregnant or nursing women or women of childbearing potential not using a highly effective method of birth control. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years. 8. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1. 9. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®), beta-blocker medication, oral beta-adrenergics, other non-approved and according to international guidelines not recommended ´experimental´ drugs for routine asthma therapy (e.g. TNF-alpha blockers, methotrexate, cyclosporin) within four weeks prior to the Screening Visit (Visit 1) or during the screening period. 10. Patients with any asthma exacerbation or respiratory tract infection in the four weeks prior to the trial. 11. Patients who have previously been randomised in this trial or in the respective twin trial (205.416 versus 205.417) or are currently participating in another trial. 12. Patients with a known narrow-angle glaucoma. Note: As with other anticholinergic drugs, tiotropium should be used with caution in patients with prostatic hyperplasia or bladder neck obstruction. As with all predominantly renally excreted drugs, patients with moderate to severe renal impairment (known creatinine clearance of \<= 50 mL/min) treated with tiotropium should be monitored closely.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks. | Baseline and 24 weeks | Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Trough FEV1 Response Determined After a Treatment Period of 24 Weeks. | Baseline and 24 weeks | The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 24 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984). | 48 weeks | Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FVC (AUC0-3h) Response at the End of the 24-week Treatment Period. | Baseline and 24 weeks | The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit. |
| Peak FEV1 0-3h Response at the End of the 48-week Treatment Period. | Baseline and 48 weeks | Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Trough FEV1 Response at the End of the 48-week Treatment Period. | Baseline and 48 weeks | The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 48 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| AUC0-3h FEV1 Response at the End of the 48-week Treatment Period. | Baseline and 48 weeks | The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit. |
| Peak FVC 0-3h Response at the End of the 48-week Treatment Period. | Baseline and 48 weeks | Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Trough FVC Response at the End of the 48-week Treatment Period. | Baseline and 48 weeks | The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 48 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| FVC AUC0-3h Response at the End of the 48-week Treatment Period. | Baseline and 48 weeks | The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit. |
| Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit . | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit. | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit. | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit. | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit. | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The PEF variability is the absolute difference between morning and evening PEF value divided by their mean, expressed as a percent. Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Time to First Severe Asthma Exacerbation During the 48-week Treatment. | 48 weeks | Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. |
| Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period. | Baseline and 24 weeks | Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 48 weeks | Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. |
| Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period. | 48 weeks | Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation. |
| Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period. | 48 weeks | Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. |
| Time to First Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period. | 48 weeks | Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation. |
| Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 48 weeks | — |
| Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period. | 48 weeks | — |
| Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period. | 24 weeks | The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| AQLQ(S) Total Score at the End of the 48-week Treatment Period. | 48 weeks | The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period. | 24 weeks | For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| ACQ Score at the End of the 48-week Treatment Period. | 48 weeks | For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit . | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The response is defined as the change of the weekly mean from the baseline weekly mean. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit . | Baseline and last 7 days before week 24 visit | Weekly means obtained during the last 7 days before week 24 visit were compared. The response is defined as the change of the weekly mean from the baseline weekly mean. The use of PRN salbutamol (albuterol rescue medication) is determined by the number of puffs of rescue therapy used per day. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 48 weeks | Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation. |
| Trough FVC Response at the End of the 24-week Treatment Period. | Baseline and 24 weeks | The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 24 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit. |
| FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period. | Baseline and 24 weeks | The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit. |
Countries
Australia, Canada, Denmark, Germany, Italy, Japan, Netherlands, New Zealand, Russia, Serbia, South Africa, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients treated with matching placebo | 234 |
| Tio R5 Patients treated with tiotropium inhalation solution 5 microgram qd | 219 |
| Total | 453 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Other | 5 | 9 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Withdrawal by Subject | 12 | 7 |
Baseline characteristics
| Characteristic | Placebo | Tio R5 | Total |
|---|---|---|---|
| Age, Continuous | 53.6 Years STANDARD_DEVIATION 11.7 | 51.4 Years STANDARD_DEVIATION 12.5 | 52.5 Years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 135 Participants | 127 Participants | 262 Participants |
| Sex: Female, Male Male | 99 Participants | 92 Participants | 191 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 171 / 234 | 134 / 219 |
| serious Total, serious adverse events | 25 / 234 | 19 / 219 |
Outcome results
Primary
Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks.
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 24 weeks
Population: All patients from Full Analysis Set (FAS) FAS is defined as all patients in the treated set who have baseline data and at least one on-treatment efficacy value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks. | 0.248 Liter | Standard Error 0.024 |
| Tio R5 | Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks. | 0.401 Liter | Standard Error 0.025 |
p-value: <0.000195% CI: [0.091, 0.217]Mixed Models Analysis
Primary
Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984).
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time frame: 48 weeks
Population: All patients from FAS of the pooled twin studies 205.416 and 205.417. As \<50percent (149 of 454 patients in the placebo group and 122 of 453 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984). | NA Days |
| Tio R5 | Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984). | NA Days |
p-value: 0.0343Regression, Cox
Primary
Trough FEV1 Response Determined After a Treatment Period of 24 Weeks.
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 24 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 24 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response Determined After a Treatment Period of 24 Weeks. | 0.044 Liter | Standard Error 0.022 |
| Tio R5 | Trough FEV1 Response Determined After a Treatment Period of 24 Weeks. | 0.155 Liter | Standard Error 0.023 |
p-value: 0.000295% CI: [0.053, 0.169]Mixed Models Analysis
Secondary
ACQ Score at the End of the 48-week Treatment Period.
For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | ACQ Score at the End of the 48-week Treatment Period. | 2.159 Scores on a scale | Standard Error 0.051 |
| Tio R5 | ACQ Score at the End of the 48-week Treatment Period. | 2.027 Scores on a scale | Standard Error 0.053 |
p-value: 0.053395% CI: [-0.267, 0.002]Mixed Models Analysis
Secondary
AQLQ(S) Total Score at the End of the 48-week Treatment Period.
The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AQLQ(S) Total Score at the End of the 48-week Treatment Period. | 4.945 Scores on a scale | Standard Error 0.06 |
| Tio R5 | AQLQ(S) Total Score at the End of the 48-week Treatment Period. | 5.085 Scores on a scale | Standard Error 0.062 |
p-value: 0.080395% CI: [-0.017, 0.296]Mixed Models Analysis
Secondary
Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period.
For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: 24 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period. | 2.210 Score on a scale | Standard Error 0.05 |
| Tio R5 | Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period. | 2.011 Score on a scale | Standard Error 0.052 |
p-value: 0.00395% CI: [-0.33, -0.068]Mixed Models Analysis
Secondary
Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit .
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The response is defined as the change of the weekly mean from the baseline weekly mean. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and last 7 days before week 24 visit
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit . | 0.065 Days | Standard Error 0.023 |
| Tio R5 | Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit . | 0.077 Days | Standard Error 0.024 |
p-value: 0.663295% CI: [-0.043, 0.067]Mixed Models Analysis
Secondary
AUC0-3h FEV1 Response at the End of the 48-week Treatment Period.
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit.
Time frame: Baseline and 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC0-3h FEV1 Response at the End of the 48-week Treatment Period. | 0.172 Liter | Standard Error 0.023 |
| Tio R5 | AUC0-3h FEV1 Response at the End of the 48-week Treatment Period. | 0.310 Liter | Standard Error 0.024 |
p-value: <0.000195% CI: [0.078, 0.199]Mixed Models Analysis
Secondary
FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period.
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit.
Time frame: Baseline and 24 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period. | 0.164 Liter | Standard Error 0.022 |
| Tio R5 | FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period. | 0.307 Liter | Standard Error 0.023 |
p-value: <0.000195% CI: [0.084, 0.202]Mixed Models Analysis
Secondary
FVC (AUC0-3h) Response at the End of the 24-week Treatment Period.
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit.
Time frame: Baseline and 24 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC (AUC0-3h) Response at the End of the 24-week Treatment Period. | 0.187 Liter | Standard Error 0.03 |
| Tio R5 | FVC (AUC0-3h) Response at the End of the 24-week Treatment Period. | 0.295 Liter | Standard Error 0.031 |
p-value: 0.006395% CI: [0.031, 0.187]Mixed Models Analysis
Secondary
FVC AUC0-3h Response at the End of the 48-week Treatment Period.
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit baseline\*visit.
Time frame: Baseline and 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC AUC0-3h Response at the End of the 48-week Treatment Period. | 0.190 Liter | Standard Error 0.031 |
| Tio R5 | FVC AUC0-3h Response at the End of the 48-week Treatment Period. | 0.299 Liter | Standard Error 0.032 |
p-value: 0.007495% CI: [0.029, 0.189]Mixed Models Analysis
Secondary
Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit.
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The PEF variability is the absolute difference between morning and evening PEF value divided by their mean, expressed as a percent. Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and last 7 days before week 24 visit
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit. | -1.808 Percent | Standard Error 0.617 |
| Tio R5 | Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit. | -0.611 Percent | Standard Error 0.641 |
p-value: 0.107395% CI: [-0.261, 2.655]Mixed Models Analysis
Secondary
Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit.
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and last 7 days before week 24 visit
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit. | -7.295 L/min | Standard Error 4.188 |
| Tio R5 | Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit. | 25.158 L/min | Standard Error 4.397 |
p-value: <0.000195% CI: [22.532, 42.374]Mixed Models Analysis
Secondary
Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit.
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and last 7 days before week 24 visit
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit. | 0.006 Liter | Standard Error 0.025 |
| Tio R5 | Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit. | 0.096 Liter | Standard Error 0.026 |
p-value: 0.002795% CI: [0.031, 0.149]Mixed Models Analysis
Secondary
Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit.
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and last 7 days before week 24 visit
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit. | -0.015 Liter | Standard Error 0.027 |
| Tio R5 | Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit. | 0.122 Liter | Standard Error 0.028 |
p-value: <0.000195% CI: [0.074, 0.2]Mixed Models Analysis
Secondary
Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit .
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and last 7 days before week 24 visit
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit . | -3.258 L/min | Standard Error 3.954 |
| Tio R5 | Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit . | 17.396 L/min | Standard Error 4.136 |
p-value: <0.000195% CI: [11.199, 30.108]Mixed Models Analysis
Secondary
Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit .
Weekly means obtained during the last 7 days before week 24 visit were compared. The response is defined as the change of the weekly mean from the baseline weekly mean. The use of PRN salbutamol (albuterol rescue medication) is determined by the number of puffs of rescue therapy used per day. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and last 7 days before week 24 visit
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit . | -0.881 Puffs | Standard Error 0.158 |
| Tio R5 | Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit . | -1.144 Puffs | Standard Error 0.163 |
p-value: 0.166495% CI: [-0.635, 0.11]Mixed Models Analysis
Secondary
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 5 asthma exacerbations | 9 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 1 asthma exacerbation | 53 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 6 asthma exacerbations | 9 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 3 asthma exacerbations | 13 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 7-10 asthma exacerbations | 10 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 0 asthma exacerbations | 82 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 11-20 asthma exacerbations | 13 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 4 asthma exacerbations | 14 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 21+ asthma exacerbations | 2 Participants |
| Placebo | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 2 asthma exacerbations | 27 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 21+ asthma exacerbations | 2 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 1 asthma exacerbation | 44 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 2 asthma exacerbations | 22 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 3 asthma exacerbations | 8 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 4 asthma exacerbations | 10 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 5 asthma exacerbations | 3 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 6 asthma exacerbations | 2 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 7-10 asthma exacerbations | 8 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 11-20 asthma exacerbations | 11 Participants |
| Tio R5 | Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 0 asthma exacerbations | 106 Participants |
p-value: 0.100795% CI: [0.61, 1.04]Poisson Regression
Secondary
Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 0 hospitalisations | 222 Participants |
| Placebo | Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 1 hospitalisations | 9 Participants |
| Placebo | Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 2+ hospitalisations | 1 Participants |
| Tio R5 | Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 0 hospitalisations | 208 Participants |
| Tio R5 | Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 1 hospitalisations | 6 Participants |
| Tio R5 | Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 2+ hospitalisations | 2 Participants |
p-value: 0.850395% CI: [0.59, 1.54]Poisson Regression
Secondary
Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period.
Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period. | 150 Participants |
| Tio R5 | Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period. | 110 Participants |
p-value: 0.00495% CI: [0.38, 0.84]Fisher Exact
Secondary
Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period. | 10 Participants |
| Tio R5 | Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period. | 8 Participants |
p-value: 0.812995% CI: [0.29, 2.46]Fisher Exact
Secondary
Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period.
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period. | 81 Participants |
| Tio R5 | Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period. | 69 Participants |
p-value: 0.548195% CI: [0.58, 1.32]Fisher Exact
Secondary
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time frame: 48 weeks
Population: All patients from FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 11-20 severe asthma exacerbations | 1 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 0 severe asthma exacerbations | 151 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 1 severe asthma exacerbation | 51 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 2 severe asthmaexacerbations | 19 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 3 severe asthma exacerbations | 5 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 4 severe asthma exacerbations | 3 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 5 severe asthma exacerbations | 2 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 6 severe asthma exacerbations | 0 Participants |
| Placebo | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 7-10 severe asthma exacerbations | 0 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 6 severe asthma exacerbations | 1 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 4 severe asthma exacerbations | 3 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 0 severe asthma exacerbations | 147 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 11-20 severe asthma exacerbations | 0 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 1 severe asthma exacerbation | 38 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 5 severe asthma exacerbations | 1 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 2 severe asthmaexacerbations | 17 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 7-10 severe asthma exacerbations | 1 Participants |
| Tio R5 | Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. | 3 severe asthma exacerbations | 8 Participants |
p-value: 0.790695% CI: [0.71, 1.3]Poisson Regression
Secondary
Peak FEV1 0-3h Response at the End of the 48-week Treatment Period.
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 0-3h Response at the End of the 48-week Treatment Period. | 0.245 Liter | Standard Error 0.025 |
| Tio R5 | Peak FEV1 0-3h Response at the End of the 48-week Treatment Period. | 0.397 Liter | Standard Error 0.026 |
p-value: <0.000195% CI: [0.087, 0.217]Mixed Models Analysis
Secondary
Peak FVC 0-3h Response at the End of the 48-week Treatment Period.
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FVC 0-3h Response at the End of the 48-week Treatment Period. | 0.305 Liter | Standard Error 0.033 |
| Tio R5 | Peak FVC 0-3h Response at the End of the 48-week Treatment Period. | 0.420 Liter | Standard Error 0.034 |
p-value: 0.008895% CI: [0.029, 0.2]Mixed Models Analysis
Secondary
Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period.
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 24 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period. | 0.323 Liter | Standard Error 0.032 |
| Tio R5 | Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period. | 0.416 Liter | Standard Error 0.033 |
p-value: 0.027595% CI: [0.01, 0.177]Mixed Models Analysis
Secondary
Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period.
The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: 24 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period. | 4.869 Scores on a scale | Standard Error 0.058 |
| Tio R5 | Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period. | 5.047 Scores on a scale | Standard Error 0.061 |
p-value: 0.022595% CI: [0.025, 0.331]Mixed Models Analysis
Secondary
Time to First Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time frame: 48 weeks
Population: All patients from FAS. As \< 50 percent (10 of 232 patients in the placebo group and 8 of 216 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.
p-value: 0.718895% CI: [0.33, 2.14]Regression, Cox
Secondary
Time to First Severe Asthma Exacerbation During the 48-week Treatment.
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time frame: 48 weeks
Population: All patients from FAS. As \< 50 percent (81 of 232 patients in the placebo group and 69 of 216 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.
p-value: 0.478895% CI: [0.65, 1.23]Regression, Cox
Secondary
Trough FEV1 Response at the End of the 48-week Treatment Period.
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 48 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response at the End of the 48-week Treatment Period. | 0.063 Liter | Standard Error 0.023 |
| Tio R5 | Trough FEV1 Response at the End of the 48-week Treatment Period. | 0.155 Liter | Standard Error 0.023 |
p-value: 0.002695% CI: [0.032, 0.151]Mixed Models Analysis
Secondary
Trough FVC Response at the End of the 24-week Treatment Period.
The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 24 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 24 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response at the End of the 24-week Treatment Period. | 0.044 Liter | Standard Error 0.03 |
| Tio R5 | Trough FVC Response at the End of the 24-week Treatment Period. | 0.150 Liter | Standard Error 0.032 |
p-value: 0.009995% CI: [0.025, 0.186]Mixed Models Analysis
Secondary
Trough FVC Response at the End of the 48-week Treatment Period.
The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 48 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment\*visit and baseline\*visit.
Time frame: Baseline and 48 weeks
Population: All patients from FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response at the End of the 48-week Treatment Period. | 0.072 Liter | Standard Error 0.031 |
| Tio R5 | Trough FVC Response at the End of the 48-week Treatment Period. | 0.142 Liter | Standard Error 0.032 |
p-value: 0.093395% CI: [-0.012, 0.153]Mixed Models Analysis
Post Hoc
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984)
The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at 24-weeks and 48-weeks (on combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). This outcome definition is taken from the primary outcome definition for the twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) of the same development program.
Time frame: 24 weeks, 48 weeks
Population: FAS of combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984) | 24 weeks | 46.9 percentage of participants |
| Placebo | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984) | 48 weeks | 45.2 percentage of participants |
| Tio R5 | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984) | 24 weeks | 53.9 percentage of participants |
| Tio R5 | The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984) | 48 weeks | 58.1 percentage of participants |
Comparison: Comparison at 24 weeksp-value: 0.042795% CI: [1.01, 1.73]Fisher Exact
Comparison: Comparison at 48 weeksp-value: 0.000195% CI: [1.28, 2.21]Fisher Exact