Asthma
Conditions
Brief summary
The aim of this trial is to evaluate the safety and efficacy of 2.5 and 5 µg tiotropium over a 52-week treatment period as compared to placebo. Tiotropium inhalation solution delivered by the Respimat inhaler will be examined on top of maintenance treatment with inhaled corticosteroid controller medication in patients with moderate to severe persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on asthma control, and number of adverse events.
Interventions
DRUGTiotropium Respimat
Tiotropium high dose once daily delivered with Respimat inhaler
DRUGPlacebo Respimat
Tiotropium placebo once daily delivered with Respimat inhaler
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 including the patients under age (under 20 years old) must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and Good Clinical Practice (GCP) prior to participation in the trial \[i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test (PFT) at Visit 1\]. Regarding patients under age, a guardian or a legally authorised representative must also sign and date an Informed Consent Form. 2. Male or female outpatients aged at least 18 years but not more than 75 years at Visit 0. 3. All patients must have at least a 12-week history of asthma at the time of enrolment (Visit 0) into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5. 4. The initial diagnosis of asthma must have been made before the patient's age of 40. 5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15-30 minutes after 400 µg salbutamol) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200 mL . 6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (ICS) \[alone or in a fixed combination with a Long-acting beta-adrenergic (LABA)\] for at least 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of at least 1.5. 8. All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1. 9. Patients must be never-smokers or ex-smokers who stopped smoking at least one year (52 weeks) prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years. 10. Patients must be able to use the Respimat inhaler correctly, which is judged at the discretion of the investigator.. 11. Patients must be able to perform all trial related procedures including technically acceptable PFTs and use of electronic diary (eDiary)/peak flow meter, which is judged at the discretion of the investigator.
Exclusion criteria
1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial. 2. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion no 1. 3. Patients with a recent history (i.e. 6 months or less) of myocardial infarction prior to Visit 0. 4. Patients who have been hospitalised for cardiac failure during the past year prior to Visit 0. 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 prior to Visit 0. 6. Patients with lung diseases other than asthma (e.g. COPD). 7. Patients with known active tuberculosis. 8. Patients with malignancy and/or patients who have undergone resection, radiation therapy or chemotherapy for malignancy within the last 5 years prior to Visit 0. Patients with treated basal cell carcinoma are allowed. 9. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1. 10. Patients with significant alcohol or drug abuse, which is judged at the discretion of the investigator, within the past 2 years prior to Visit 0. 11. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA), or any other components of the study medication delivery systems. 12. Pregnant or nursing women. 13. Women of childbearing potential not using a highly effective method of birth control. 14. Patients who have taken an investigational drug within 4 weeks prior to Visit 1. 15. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period. Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed. 16. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva) within four weeks prior to Visit 1 and/or during the screening period. 17. Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period. 18. Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1 and/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 and/or during the screening period. 20. Patients who have been treated with other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period. 21. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period. 22. Patients who are currently participating in another trial. 23. Patients with narrow-angle glaucoma and/or micturition disorder due to prostatic hyperplasia. 24. Patients with below 80% of the eDiary completion compliance on Visit 2 (diary compliance of at least 80% is required).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Drug-related Adverse Events | after the first dose of trial medication and within 30 days after the last dose of trial medication, up to 409 | The primary endpoint is the number of patients with drug-related adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough FVC Response | baseline and week 52 | Trough FVC response was defined as change from baseline at week 52 |
| Trough PEF Response | baseline and week 52 | Trough PEF response was defined as change from baseline at week 52 |
| Weekly Mean PEFam Response | baseline and week 52 | Weekly mean PEFam response was defined as change from baseline at week 52 |
| Weekly Mean PEFpm Response | baseline and week 52 | Weekly mean PEFpm response was defined as change from baseline at week 52 |
| Trough FEV1 Response | baseline and week 52 | Trough FEV1 response was defined as change from baseline at week 52 |
| Weekly Mean Number of Puffs of Rescue Medication During the Whole Day (Response) | baseline and week 52 | Response of weekly mean number of puffs of rescue medication during the whole day at week 52. Response was defined as change from baseline. |
| Weekly Mean Score of Asthma Symptoms in the Morning (Response) | baseline and week 52 | Response of weekly mean score of asthma symptoms in the morning at week 52. Response was defined as change from baseline. 5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment. |
| Weekly Mean Score of Asthma Symptoms During the Day (Response) | baseline and week 52 | Response of weekly mean score of asthma symptoms during the day at week 52. Response was defined as change from baseline. 5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment. |
| Weekly Mean PEF Variability Response | baseline and week 52 | Weekly mean PEF variability response was defined as change from baseline at week 52. 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. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Respimat Placebo Respimat: Tiotropium placebo once daily delivered with Respimat inhaler | 57 |
| Tiotropium Respimat (2.5 µg) Tiotropium Respimat: Tiotropium 2.5 µg once daily delivered with Respimat inhaler | 114 |
| Tiotropium Respimat (5 μg) Tiotropium Respimat: Tiotropium 5 μg once daily delivered with Respimat inhaler | 114 |
| Total | 285 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 2 |
| Overall Study | Other reason not defined above | 3 | 5 | 4 |
| Overall Study | Protocol Violation | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Respimat | Tiotropium Respimat (2.5 µg) | Tiotropium Respimat (5 μg) | Total |
|---|---|---|---|---|
| Age, Continuous | 47.8 years STANDARD_DEVIATION 13 | 44.7 years STANDARD_DEVIATION 12.1 | 42.6 years STANDARD_DEVIATION 12.8 | 44.5 years STANDARD_DEVIATION 12.7 |
| Sex: Female, Male Female | 38 Participants | 72 Participants | 66 Participants | 176 Participants |
| Sex: Female, Male Male | 19 Participants | 42 Participants | 48 Participants | 109 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 | 50 / 57 | 97 / 114 | 101 / 114 |
| serious Total, serious adverse events | 9 / 57 | 4 / 114 | 4 / 114 |
Outcome results
Primary
Number of Patients With Drug-related Adverse Events
The primary endpoint is the number of patients with drug-related adverse events
Time frame: after the first dose of trial medication and within 30 days after the last dose of trial medication, up to 409
Population: Treated set: all randomised patients who received at least 1 dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Respimat | Number of Patients With Drug-related Adverse Events | 3 participants |
| Tiotropium Respimat (2.5 µg) | Number of Patients With Drug-related Adverse Events | 6 participants |
| Tiotropium Respimat (5 μg) | Number of Patients With Drug-related Adverse Events | 10 participants |
Secondary
Trough FEV1 Response
Trough FEV1 response was defined as change from baseline at week 52
Time frame: baseline and week 52
Population: Full analysis set: all patients of the treated set for which baseline and at least 1 post-baseline efficacy measurement were available
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Trough FEV1 Response | 0.075 Liter | Standard Error 0.039 |
| Tiotropium Respimat (2.5 µg) | Trough FEV1 Response | 0.087 Liter | Standard Error 0.027 |
| Tiotropium Respimat (5 μg) | Trough FEV1 Response | 0.187 Liter | Standard Error 0.027 |
Comparison: Difference calculated as Tiotropium 2.5 µg minus placebop-value: 0.797195% CI: [-0.082, 0.106]Mixed Models Analysis
Comparison: Difference calculated as Tiotropium 5 μg minus placebop-value: 0.020395% CI: [0.018, 0.207]Mixed Models Analysis
Secondary
Trough FVC Response
Trough FVC response was defined as change from baseline at week 52
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Trough FVC Response | 0.122 Liter | Standard Error 0.044 |
| Tiotropium Respimat (2.5 µg) | Trough FVC Response | 0.085 Liter | Standard Error 0.03 |
| Tiotropium Respimat (5 μg) | Trough FVC Response | 0.204 Liter | Standard Error 0.031 |
Comparison: Difference calculated as Tiotropium 2.5 µg minus placebop-value: 0.494495% CI: [-0.141, 0.068]Mixed Models Analysis
Comparison: Difference calculated as Tiotropium 5 μg minus placebop-value: 0.12795% CI: [-0.023, 0.188]Mixed Models Analysis
Secondary
Trough PEF Response
Trough PEF response was defined as change from baseline at week 52
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Trough PEF Response | 35.078 L/min | Standard Error 10.119 |
| Tiotropium Respimat (2.5 µg) | Trough PEF Response | 35.576 L/min | Standard Error 6.917 |
| Tiotropium Respimat (5 μg) | Trough PEF Response | 69.254 L/min | Standard Error 7.004 |
Comparison: Difference calculated as Tiotropium 2.5 µg minus placebop-value: 0.967795% CI: [-23.634, 24.63]Mixed Models Analysis
Comparison: Difference calculated as Tiotropium Respimat 5 μg minus placebop-value: 0.005895% CI: [9.919, 58.432]Mixed Models Analysis
Secondary
Weekly Mean Number of Puffs of Rescue Medication During the Whole Day (Response)
Response of weekly mean number of puffs of rescue medication during the whole day at week 52. Response was defined as change from baseline.
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Weekly Mean Number of Puffs of Rescue Medication During the Whole Day (Response) | -0.25 Puffs | Standard Deviation 0.77 |
| Tiotropium Respimat (2.5 µg) | Weekly Mean Number of Puffs of Rescue Medication During the Whole Day (Response) | -0.29 Puffs | Standard Deviation 1.01 |
| Tiotropium Respimat (5 μg) | Weekly Mean Number of Puffs of Rescue Medication During the Whole Day (Response) | -0.22 Puffs | Standard Deviation 0.96 |
Secondary
Weekly Mean PEFam Response
Weekly mean PEFam response was defined as change from baseline at week 52
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Weekly Mean PEFam Response | 2.288 L/min | Standard Error 7.554 |
| Tiotropium Respimat (2.5 µg) | Weekly Mean PEFam Response | 10.934 L/min | Standard Error 5.231 |
| Tiotropium Respimat (5 μg) | Weekly Mean PEFam Response | 8.504 L/min | Standard Error 5.267 |
Comparison: Difference calculated as Tiotropium 2.5 µg minus placebop-value: 0.346895% CI: [-9.388, 26.68]Mixed Models Analysis
Comparison: Difference calculated as Tiotropium 5 μg minus placebop-value: 0.501395% CI: [-11.927, 24.359]Mixed Models Analysis
Secondary
Weekly Mean PEFpm Response
Weekly mean PEFpm response was defined as change from baseline at week 52
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Weekly Mean PEFpm Response | -10.357 L/min | Standard Error 7.566 |
| Tiotropium Respimat (2.5 µg) | Weekly Mean PEFpm Response | 1.101 L/min | Standard Error 5.239 |
| Tiotropium Respimat (5 μg) | Weekly Mean PEFpm Response | 6.041 L/min | Standard Error 5.284 |
Comparison: Difference calculated as Tiotropium 2.5 µg minus placebop-value: 0.213295% CI: [-6.601, 29.517]Mixed Models Analysis
Comparison: Difference calculated as Tiotropium 5 μg minus placebop-value: 0.076695% CI: [-1.759, 34.555]Mixed Models Analysis
Secondary
Weekly Mean PEF Variability Response
Weekly mean PEF variability response was defined as change from baseline at week 52. 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.
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Weekly Mean PEF Variability Response | -0.367 percentage | Standard Error 0.851 |
| Tiotropium Respimat (2.5 µg) | Weekly Mean PEF Variability Response | -0.968 percentage | Standard Error 0.595 |
| Tiotropium Respimat (5 μg) | Weekly Mean PEF Variability Response | 0.197 percentage | Standard Error 0.595 |
Comparison: Difference calculated as Tiotropium 2.5 µg minus placebop-value: 0.562995% CI: [-2.637, 1.436]Mixed Models Analysis
Comparison: Difference calculated as Tiotropium 5 μg minus placebop-value: 0.587195% CI: [-1.473, 2.601]Mixed Models Analysis
Secondary
Weekly Mean Score of Asthma Symptoms During the Day (Response)
Response of weekly mean score of asthma symptoms during the day at week 52. Response was defined as change from baseline. 5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment.
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Weekly Mean Score of Asthma Symptoms During the Day (Response) | -0.24 Scores on a scale | Standard Deviation 0.35 |
| Tiotropium Respimat (2.5 µg) | Weekly Mean Score of Asthma Symptoms During the Day (Response) | -0.15 Scores on a scale | Standard Deviation 0.48 |
| Tiotropium Respimat (5 μg) | Weekly Mean Score of Asthma Symptoms During the Day (Response) | -0.17 Scores on a scale | Standard Deviation 0.48 |
Secondary
Weekly Mean Score of Asthma Symptoms in the Morning (Response)
Response of weekly mean score of asthma symptoms in the morning at week 52. Response was defined as change from baseline. 5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment.
Time frame: baseline and week 52
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Respimat | Weekly Mean Score of Asthma Symptoms in the Morning (Response) | -0.22 Scores on a scale | Standard Deviation 0.43 |
| Tiotropium Respimat (2.5 µg) | Weekly Mean Score of Asthma Symptoms in the Morning (Response) | -0.14 Scores on a scale | Standard Deviation 0.49 |
| Tiotropium Respimat (5 μg) | Weekly Mean Score of Asthma Symptoms in the Morning (Response) | -0.21 Scores on a scale | Standard Deviation 0.43 |