Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
Direct comparison studies of the tiotropium HandiHaler® 18 µg and Respimat® 5 µg formulations have been limited to 4-week crossover studies. Therefore, prospective data from a trial of adequate size and duration is required to establish that compared to tiotropium HandiHaler®, tiotropium Respimat® will have (a) similar effects on safety and (b) similar or superior effects on exacerbations.
Interventions
HandiHaler
DRUGtiotropium 1.25 mcg (2 actuations/day)
soft mist inhaler 2 actuations=2 puffs/day
DRUGtiotropium 2.5 mcg (2 actuations/day)
soft mist inhaler (2 actuations=2 puffs/day)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. All patients must sign an informed consent consistent with International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions. 2. Male or female patients 40 years of age or older. 3. Patients must be current or ex-smokers with a smoking history of ≥10 pack-years. (Patients who have never smoked cigarettes must be excluded) 4. All patients must have a diagnosis of COPD (P06-12085), and must meet the following criteria: Relatively stable airway obstruction with a post-bronchodilator FEV1 ≤ 70% of predicted normal and post-bronchodilator FEV1 / FVC ≤70%. Pulmonary function tests (PFTs) were conducted after the inhalation of 400 μg salbutamol / albuterol (preferred), however testing with either 200 μg salbutamol/albuterol or a combination of salbutamol / albuterol with ipratropium bromide (2 to 4 actuations) was acceptable. Other short-acting beta agonists, such as terbutaline, may have been used for the testing. The medication used for the testing was documented. Further, historical data from measurements within the past 6 months either at the site or at a referral site may have been used (see Section 6.2.1 of the CTP, located in Appendix 16.1.1). Subjects were not to have been randomized to the study without the availability of spirometry data at the actual study site. Eligibility for PFT sub-study: For subjects participating in the spirometry sub-study, historical data may not have been used for inclusion. These subjects must have qualified in the clinic at Visit 1 after performing a baseline measurement. These subjects performed a pre-dose PFT which was followed by the administration of 400 μg salbutamol / albuterol only (no other short-acting beta agonist was allowed), followed by a post-dose PFT for qualification. 5. Able to inhale from the HandiHaler® and the Respimat® devices.
Exclusion criteria
1. Significant diseases other than COPD. A significant disease is defined as a disease or condition which, in the opinion of the investigator, may put the patient at risk because of participation in the study or may influence the patients ability to participate in the study. 2. Patients with a recent history (i.e., six months or less) of myocardial infarction. 3. Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the last year. 4. Hospitalisation for cardiac failure (New York Heart Association (NYHA) Class III or IV) during the past year. 5. Known active tuberculosis. 6. Patients with a history of asthma, cystic fibrosis, clinically evident bronchiectasis, interstitial lung disease, or pulmonary thromboembolic disease. 7. History of thoracotomy with pulmonary resection. Subjects with a history of thoracotomy for other reasons were to have been evaluated per exclusion criterion 1. 8. Subject was planning to undergo lung transplant or lung volume reduction surgery (LVRS). 9. Malignancy for which the subject had undergone resection, radiation, chemotherapy or biological treatments within the last 5 years. Subjects with treated basal cell carcinoma were allowed. 10. Known respiratory infection or exacerbation of COPD in the 4 weeks prior to randomization. 11. Known hypersensitivity to anticholinergic drugs, lactose, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA), or any other components of the HandiHaler® or Respimat® inhalation solution delivery system. 12. Known moderate to severe renal impairment (as judged by the investigator). 13. Known narrow angle glaucoma. 14. Known significant symptomatic prostatic hyperplasia or bladder-neck obstruction. Subjects whose symptoms were controlled on treatment may have been included. 15. Use of systemic corticosteroid medication at unstable doses (i.e., less than 6 weeks on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone per day. 16. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception for at least 3 months prior to and for the duration of the trial. 17. Significant alcohol or drug abuse within the past 12 months. 18. Subjects requiring the use of supplemental oxygen therapy for \> 12 hours per day. 19. Subjects who had completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit or subjects who were currently in a pulmonary rehabilitation program that was not maintained throughout the duration of the study. 20. Subjects who had taken an investigational drug within 30 days prior to the Screening Visit. 21. Previous participation (receipt of randomized treatment) in this study. 22. Subjects who were currently participating in an interventional study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to All-Cause Mortality | Up to 3 years | Number of patients with all-cause mortality |
| Time to First COPD Exacerbation | Up to 3 years | Defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). Onset of exacerbation was defined by the onset of first recorded symptom. The end of exacerbation was decided by the investigator based on clinical judgement. Exacerbations were classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Hospitalization Associated With COPD Exacerbation | Up to 3 years | The results presented below are for the patients with hospitalizations due to COPD exacerbations. |
| Number of Hospitalizations Associated With COPD Exacerbation | Up to 3 years | Total number of hospitalizations associated with COPD exacerbation. |
| Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients) | Up to 3 years | Trough forced expiratory volume in one second (FEV1) over 120 weeks (in a substudy of 1370 patients) |
| Time to Onset of First Major Adverse Cardiovascular Event (MACE) | Up to 3 years | Time to onset of first major adverse cardiovascular event (MACE). MACE was defined as: Fatal event in the system organ classes of cardiac and vascular disorders, Preferred terms: sudden death, cardiac death, sudden cardiac death, Outcome events of myocardial infarction (serious and non-serious), Outcome events of stroke (serious and non-serious) and Outcome events of TIA (serious and non-serious). The results presented below are for the number of patients with MACE. |
| Time to Death From Major Adverse Cardiovascular Event (MACE) | Up to 3 years | The results presented below are number of patients with death from MACE. |
| Time to First Moderate to Severe COPD Exacerbation | Up to 3 years | COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). Exacerbations classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization. Results presented below are number of patients with moderate to severe exacerbations. |
| Number of COPD Exacerbations | Up to 3 years | The number of COPD exacerbations. COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Denmark, Finland, France, Georgia, Germany, Greece, Guatemala, Hungary, India, Ireland, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Panama, Peru, Philippines, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Tunisia, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
This table summarizes study treatment disposition and reasons for discontinuation of study medication. Deaths that caused discontinuation from trial medications are included in AEs. Lost to follow-up indicates status at time of discontinuation of trial medication. Vital status was ascertained for 99.7% of patients.
Participants by arm
| Arm | Count |
|---|---|
| Tiotropium 2.5 mcg and Placebo Patients receive one of the active tiotropium arms daily
tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day | 5,724 |
| Tiotropium 5 mcg and Placebo Patients receive one of the active tiotropium arms daily
tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day) | 5,705 |
| Tiotropium 18 mcg and Placebo Patients receive one of the active tiotropium arms daily
tiotropium 18 mcg: HandiHaler | 5,687 |
| Total | 17,116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 602 | 606 | 635 |
| Overall Study | Lack of Efficacy | 65 | 60 | 59 |
| Overall Study | Lost to Follow-up | 52 | 63 | 55 |
| Overall Study | Not treated | 11 | 18 | 19 |
| Overall Study | Other reason not specified | 210 | 176 | 178 |
| Overall Study | Protocol Violation | 64 | 66 | 41 |
| Overall Study | Sites with data irregularities/fraud | 6 | 6 | 7 |
| Overall Study | Withdrawal by Subject | 331 | 335 | 319 |
Baseline characteristics
| Characteristic | Tiotropium 2.5 mcg and Placebo | Tiotropium 5 mcg and Placebo | Tiotropium 18 mcg and Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 65.1 years STANDARD_DEVIATION 9.1 | 64.9 years STANDARD_DEVIATION 9.1 | 65.0 years STANDARD_DEVIATION 9 | 65.0 years STANDARD_DEVIATION 9.1 |
| Sex: Female, Male Female | 1656 Participants | 1571 Participants | 1652 Participants | 4879 Participants |
| Sex: Female, Male Male | 4068 Participants | 4134 Participants | 4035 Participants | 12237 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 | 1,932 / 5,724 | 1,876 / 5,705 | 1,928 / 5,687 |
| serious Total, serious adverse events | 1,932 / 5,724 | 1,876 / 5,705 | 1,928 / 5,687 |
Outcome results
Primary
Time to All-Cause Mortality
Number of patients with all-cause mortality
Time frame: Up to 3 years
Population: Death analysis set (DAS) including vital status follow-up: This analysis set included all randomized subjects excluding only subjects who were documented as not treated.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Time to All-Cause Mortality | 440 Number of deaths | 7.7 |
| Tiotropium 5 mcg and Placebo | Time to All-Cause Mortality | 423 Number of deaths | 7.4 |
| Tiotropium 18 mcg and Placebo | Time to All-Cause Mortality | 439 Number of deaths | 7.7 |
Comparison: H0: Hazard Ratio for Respimat/HandiHaler \>= 1.25 Ha: Hazard Ratio for Respimat/HandiHaler \< 1.2595% CI: [0.837, 1.094]Regression, Cox
Comparison: H0: Hazard Ratio for Respimat/HandiHaler \>= 1.25 Ha: Hazard Ratio for Respimat/HandiHaler \< 1.2595% CI: [0.872, 1.136]Regression, Cox
Primary
Time to First COPD Exacerbation
Defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). Onset of exacerbation was defined by the onset of first recorded symptom. The end of exacerbation was decided by the investigator based on clinical judgement. Exacerbations were classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization.
Time frame: Up to 3 years
Population: Treated set (TS, on-treatment only)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Time to First COPD Exacerbation | 707 days to event |
| Tiotropium 5 mcg and Placebo | Time to First COPD Exacerbation | 756 days to event |
| Tiotropium 18 mcg and Placebo | Time to First COPD Exacerbation | 719 days to event |
Comparison: H0: Hazard Ratio for Respimat/HandiHaler = 1 Ha: Hazard Ratio for Respimat/HandiHaler ≠ 1~at alpha = 0.05p-value: 0.419495% CI: [0.928, 1.032]Regression, Cox
Comparison: H0: Hazard Ratio for Respimat/HandiHaler = 1 Ha: Hazard Ratio for Respimat/HandiHaler ≠ 1~at alpha = 0.05p-value: 0.559395% CI: [0.964, 1.07]Regression, Cox
Comparison: H0: Hazard Ratio for Respimat/HandiHaler = 1 Ha: Hazard Ratio for Respimat/HandiHaler ≠ 1~at alpha = 0.05p-value: 0.163995% CI: [0.985, 1.094]Regression, Cox
Secondary
Number of COPD Exacerbations
The number of COPD exacerbations. COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines).
Time frame: Up to 3 years
Population: Treated Set - on treatment only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Number of COPD Exacerbations | 6565 number of COPD exacerbations |
| Tiotropium 5 mcg and Placebo | Number of COPD Exacerbations | 6425 number of COPD exacerbations |
| Tiotropium 18 mcg and Placebo | Number of COPD Exacerbations | 6504 number of COPD exacerbations |
p-value: 0.83395% CI: [0.95, 1.06]Negative binomial regression
p-value: 0.804795% CI: [0.94, 1.05]Negative binomial regression
p-value: 0.646895% CI: [0.96, 1.07]Negative binomial regression
Secondary
Number of Hospitalizations Associated With COPD Exacerbation
Total number of hospitalizations associated with COPD exacerbation.
Time frame: Up to 3 years
Population: treated set - on treatment only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Number of Hospitalizations Associated With COPD Exacerbation | 1316 number of hospitalizations |
| Tiotropium 5 mcg and Placebo | Number of Hospitalizations Associated With COPD Exacerbation | 1284 number of hospitalizations |
| Tiotropium 18 mcg and Placebo | Number of Hospitalizations Associated With COPD Exacerbation | 1216 number of hospitalizations |
p-value: 0.125595% CI: [0.98, 1.22]Negative binomial regression
p-value: 0.344195% CI: [0.94, 1.18]Negative binomial regression
p-value: 0.557395% CI: [0.92, 1.16]Negative binomial regression
Secondary
Time to Death From Major Adverse Cardiovascular Event (MACE)
The results presented below are number of patients with death from MACE.
Time frame: Up to 3 years
Population: TS including vital status follow-up, DAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Time to Death From Major Adverse Cardiovascular Event (MACE) | 119 Number of deaths from MACE |
| Tiotropium 5 mcg and Placebo | Time to Death From Major Adverse Cardiovascular Event (MACE) | 113 Number of deaths from MACE |
| Tiotropium 18 mcg and Placebo | Time to Death From Major Adverse Cardiovascular Event (MACE) | 101 Number of deaths from MACE |
Comparison: Time to death from MACE was analyzed using the full study duration including vital status follow-up.p-value: 0.243995% CI: [0.898, 1.526]Regression, Cox
Comparison: Time to death from MACE was analyzed using the full study duration including vital status follow-up.p-value: 0.441395% CI: [0.85, 1.453]Regression, Cox
Comparison: Time to death from MACE was analyzed using the full study duration including vital status follow-up.p-value: 0.69195% CI: [0.814, 1.363]Regression, Cox
Secondary
Time to First Hospitalization Associated With COPD Exacerbation
The results presented below are for the patients with hospitalizations due to COPD exacerbations.
Time frame: Up to 3 years
Population: treated set - on-treatment only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Time to First Hospitalization Associated With COPD Exacerbation | 869 Number of patients with event |
| Tiotropium 5 mcg and Placebo | Time to First Hospitalization Associated With COPD Exacerbation | 826 Number of patients with event |
| Tiotropium 18 mcg and Placebo | Time to First Hospitalization Associated With COPD Exacerbation | 811 Number of patients with event |
p-value: 0.176295% CI: [0.971, 1.176]Regression, Cox
p-value: 0.638495% CI: [0.929, 1.128]Regression, Cox
p-value: 0.378495% CI: [0.949, 1.148]Regression, Cox
Secondary
Time to First Moderate to Severe COPD Exacerbation
COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). Exacerbations classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization. Results presented below are number of patients with moderate to severe exacerbations.
Time frame: Up to 3 years
Population: treated set - on treatment only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Time to First Moderate to Severe COPD Exacerbation | 2769 number of patients with event |
| Tiotropium 5 mcg and Placebo | Time to First Moderate to Severe COPD Exacerbation | 2694 number of patients with event |
| Tiotropium 18 mcg and Placebo | Time to First Moderate to Severe COPD Exacerbation | 2732 number of patients with event |
p-value: 0.682395% CI: [0.959, 1.066]Regression, Cox
p-value: 0.537795% CI: [0.932, 1.037]Regression, Cox
p-value: 0.304895% CI: [0.975, 1.084]Regression, Cox
Secondary
Time to Onset of First Major Adverse Cardiovascular Event (MACE)
Time to onset of first major adverse cardiovascular event (MACE). MACE was defined as: Fatal event in the system organ classes of cardiac and vascular disorders, Preferred terms: sudden death, cardiac death, sudden cardiac death, Outcome events of myocardial infarction (serious and non-serious), Outcome events of stroke (serious and non-serious) and Outcome events of TIA (serious and non-serious). The results presented below are for the number of patients with MACE.
Time frame: Up to 3 years
Population: Treated set - on treatment only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Time to Onset of First Major Adverse Cardiovascular Event (MACE) | 224 number of patients with MACE |
| Tiotropium 5 mcg and Placebo | Time to Onset of First Major Adverse Cardiovascular Event (MACE) | 222 number of patients with MACE |
| Tiotropium 18 mcg and Placebo | Time to Onset of First Major Adverse Cardiovascular Event (MACE) | 202 number of patients with MACE |
Comparison: Causes of death from MACE were determined by adjudication.p-value: 0.304395% CI: [0.913, 1.336]Regression, Cox
Comparison: Causes of death from MACE were determined by adjudication.p-value: 0.326395% CI: [0.909, 1.331]Regression, Cox
Comparison: Causes of death from MACE were determined by adjudication.p-value: 0.964495% CI: [0.834, 1.209]Regression, Cox
Secondary
Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients)
Trough forced expiratory volume in one second (FEV1) over 120 weeks (in a substudy of 1370 patients)
Time frame: Up to 3 years
Population: SSS - PFT - Sub-study set (pulmonary function testing). This analysis set included all subjects in the TS who signed informed consent to participate in the spirometry sub-study and had at least baseline and one on-treatment trough FEV1.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tiotropium 2.5 mcg and Placebo | Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients) | 1.258 Liter | Standard Error 0.012 |
| Tiotropium 5 mcg and Placebo | Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients) | 1.285 Liter | Standard Error 0.012 |
| Tiotropium 18 mcg and Placebo | Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients) | 1.295 Liter | Standard Error 0.012 |
Comparison: FEV1 was analyzed through Week 120 using REML-based repeated measures.~H0: Adjusted mean difference for Respimat/HandiHaler ≥ 50ml Ha: Adjusted mean difference for Respimat/HandiHaler \< 50 ml95% CI: [-0.038, 0.018]Mixed Model Repeated Measures
Comparison: FEV1 was analyzed through Week 120 using REML-based repeated measures.~H0: Adjusted mean difference for Respimat/HandiHaler ≥ 50ml Ha: Adjusted mean difference for Respimat/HandiHaler \< 50 ml95% CI: [-0.065, -0.009]Mixed Model Repeated Measures