Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The overall objective is to assess the effect of once daily tiotropium + olodaterol fixed dose combination compared to 5 µg tiotropium (both delivered with the Respimat® inhaler) on moderate to severe COPD exacerbation in patients with severe to very severe COPD.
Interventions
DRUGolodaterol
fixed dose combination
DRUGtiotropium
fixed dose combination
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients, 40 years of age or older. * Diagnosis of COPD with a documented post-bronchodilator Forced expiratory volume in one second (FEV1)\< 60% of predicted normal and a post-bronchodilator FEV1/ forced vital capacity (FVC) \<70% at Visit 1 * Documented history of at least one moderate to severe COPD exacerbation in the previous 12 months requiring treatment with systemic corticosteroids and/or antibiotics and/or related hospitalization. * Symptomatically stable as defined by: no evidence of COPD exacerbation requiring use of either antibiotics and/or steroids 4 weeks prior to visit 1 and no evidence of change in their usual COPD medication 4 weeks prior to visit 1. * Current or ex-smokers with a smoking history of more than 10 pack years.
Exclusion criteria
* Significant disease other than COPD. * Clinically relevant abnormal baseline haematology, blood chemistry or creatinine \> x2 ULN will be excluded regardless of clinical condition. ( A repeat laboratory evaluation can be conducted if deemed necessary by the investigator.) * Current documented diagnosis of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma * A diagnosis of thyrotoxicosis * A history of myocardial infarction within 6 months of screening visit. * Life-threatening cardiac arrhythmia. * Known active tuberculosis. * Any malignancy unless free of disease for at least 5 years (patients with treated basal cell carcinoma or squamous cell skin cancers are allowed). * A history of cystic fibrosis. * Clinically relevant bronchiectasis. * Patients with severe emphysema requiring endobronchial interventions within 6 months prior to screening * A history of significant alcohol or drug abuse in the opinion of the investigator. * Patients who have undergone thoracotomy with pulmonary resection * Patients being treated with oral or patch ß-adrenergics. * Patients being treated with oral corticosteroid medication at unstable doses * Patients being treated with antibiotics for any reasons within 4 weeks of screening visit * Patients being treated with PDE4 inhibitors within 3 months of screening visit * Patients who have taken an investigational drug within one month or six half-lives * Pregnant or nursing women. * Women of childbearing potential not using a highly effective method of birth control.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualised Rate of Moderate to Severe COPD Exacerbations During the Actual Treatment Period. | From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days | Annualised rate of moderate to severe COPD exacerbations during the actual treatment period was calculated per treatment per patient-year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. Least Squares Means are actually exponentiated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With at Least One Moderate to Severe COPD Exacerbation During the Actual Treatment Period. | From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days | Key secondary endpoint: Number of patients with at least one moderate to severe COPD exacerbation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation is presented. |
| Annualised Rate of Exacerbations Leading to Hospitalisation During the Actual Treatment Period. | From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days | Annualised rate of exacerbations leading to hospitalisation during the actual treatment period was calculated per treatment per patient-year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. |
| Number of Patients With at Least One COPD Exacerbation Leading to Hospitalisation During the Actual Treatment Period. | From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days | Number of patients with at least one COPD exacerbation leading to hospitalisation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation leading to hospitalisation is presented. |
| Number of Patients With All-cause Mortality Occurring During the Actual Treatment Period. | From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days | Number of patients with all-cause mortality occurring during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with all-cause mortality is presented. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, Finland, France, Germany, Greece, Guatemala, Hong Kong, Hungary, India, Ireland, Italy, Japan, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Romania, Russia, Serbia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
A randomised, double-blind, active-controlled parallel group study to evaluate the effect of 52 weeks of once daily treatment of orally inhaled tiotropium + olodaterol fixed dose combination compared with tiotropium on Chronic Obstructive Pulmonary Disease (COPD) exacerbation in patients with severe to very severe COPD.
Pre-assignment details
Following informed consent, the patient was entered into a maximum 7-day screening period to confirm the patient's eligibility. At Visit 2, after a successful review of the inclusion and exclusion criteria, the patient was randomly allocated in equal ratio to receive once daily trial treatment and then entered the 360 days treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| Tiotropium 5 Microgram (μg) Patient received 5 μg Tiotropium inhalation solution - RESPIMAT inhaler once daily orally for 360 days | 3,941 |
| Tiotropium (5 μg) + Olodaterol (5 μg) Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution - RESPIMAT inhaler once daily orally for 360 days | 3,939 |
| Total | 7,880 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 348 | 259 |
| Overall Study | Lack of Efficacy | 59 | 37 |
| Overall Study | Lost to Follow-up | 9 | 12 |
| Overall Study | Not Treated | 1 | 1 |
| Overall Study | Other than specified | 15 | 13 |
| Overall Study | Patients with data irregularities | 10 | 11 |
| Overall Study | Protocol Violation | 35 | 36 |
| Overall Study | Withdrawal by Subject | 184 | 131 |
Baseline characteristics
| Characteristic | Tiotropium (5 μg) + Olodaterol (5 μg) | Total | Tiotropium 5 Microgram (μg) |
|---|---|---|---|
| Age, Continuous | 66.5 Years STANDARD_DEVIATION 8.4 | 66.4 Years STANDARD_DEVIATION 8.5 | 66.3 Years STANDARD_DEVIATION 8.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 77 Participants | 141 Participants | 64 Participants |
| Race (NIH/OMB) Asian | 557 Participants | 1164 Participants | 607 Participants |
| Race (NIH/OMB) Black or African American | 58 Participants | 110 Participants | 52 Participants |
| Race (NIH/OMB) More than one race | 22 Participants | 42 Participants | 20 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 88 Participants | 168 Participants | 80 Participants |
| Race (NIH/OMB) White | 3134 Participants | 6247 Participants | 3113 Participants |
| Sex: Female, Male Female | 1154 Participants | 2254 Participants | 1100 Participants |
| Sex: Female, Male Male | 2785 Participants | 5626 Participants | 2841 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 98 / 3,941 | 92 / 3,939 |
| other Total, other adverse events | 1,786 / 3,941 | 1,770 / 3,939 |
| serious Total, serious adverse events | 862 / 3,941 | 810 / 3,939 |
Outcome results
Primary
Annualised Rate of Moderate to Severe COPD Exacerbations During the Actual Treatment Period.
Annualised rate of moderate to severe COPD exacerbations during the actual treatment period was calculated per treatment per patient-year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. Least Squares Means are actually exponentiated.
Time frame: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Population: Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tiotropium 5 Microgram (μg) | Annualised Rate of Moderate to Severe COPD Exacerbations During the Actual Treatment Period. | 0.97 Rate per patient-year |
| Tiotropium (5 μg) + Olodaterol (5 μg) | Annualised Rate of Moderate to Severe COPD Exacerbations During the Actual Treatment Period. | 0.90 Rate per patient-year |
Comparison: Annualised rate of moderate to severe COPD exacerbation was analysed using a negative binomial model including the fixed, categorical effect of treatment as well as the logarithm of the treatment exposure as an offset.p-value: 0.049899% CI: [0.85, 1.02]Negative binomial model
Comparison: Model was based on SPARK/FLAME- Covariates: Smoking status, baseline inhaled corticosteroid, Global Initiative on Chronic Obstructive Lung Disease stage, region, COPD Assessment Test score (replacing baseline symptom score), exacerbations treated with antibiotics/steroids history in previous year (replacing 1-year history of exacerbations)p-value: 0.00195% CI: [0.84, 0.96]Negative binomial model
Comparison: Model was based on HERMES- Covariates: age, sex, smoking status, baseline Long-acting Beta-agonist/inhaled corticosteroid, region and percent predicted post-bronchodilator Forced Expiratory Volume in One Secondp-value: 0.00895% CI: [0.85, 0.98]Negative binomial model
Comparison: Model was based on TRINITY/TRILOGY- Covariates: Treatment, region, severity of airflow limitation, and smoking status as effects, and exacerbations treated with antibiotics/steroids in previous year.p-value: 0.001195% CI: [0.84, 0.96]Negative binomial model
Secondary
Annualised Rate of Exacerbations Leading to Hospitalisation During the Actual Treatment Period.
Annualised rate of exacerbations leading to hospitalisation during the actual treatment period was calculated per treatment per patient-year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication.
Time frame: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Population: Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tiotropium 5 Microgram (μg) | Annualised Rate of Exacerbations Leading to Hospitalisation During the Actual Treatment Period. | 0.20 Rate per patient-year |
| Tiotropium (5 μg) + Olodaterol (5 μg) | Annualised Rate of Exacerbations Leading to Hospitalisation During the Actual Treatment Period. | 0.18 Rate per patient-year |
Comparison: Annualised rate of exacerbations leading to hospitalization was analysed using a negative binomial model including the fixed, categorical effect of treatment as well as the logarithm of the treatment exposure as an offset.p-value: 0.126595% CI: [0.76, 1.03]Negative binomial model
Secondary
Number of Patients With All-cause Mortality Occurring During the Actual Treatment Period.
Number of patients with all-cause mortality occurring during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with all-cause mortality is presented.
Time frame: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Population: Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 5 Microgram (μg) | Number of Patients With All-cause Mortality Occurring During the Actual Treatment Period. | 32 Number of patients |
| Tiotropium (5 μg) + Olodaterol (5 μg) | Number of Patients With All-cause Mortality Occurring During the Actual Treatment Period. | 36 Number of patients |
Comparison: A Cox's proportional hazard model was used to estimate the hazard ratio and the corresponding Confidence Interval. A log-rank test was used to obtain the p-valuep-value: 0.735795% CI: [0.67, 1.75]Log Rank
Secondary
Number of Patients With at Least One COPD Exacerbation Leading to Hospitalisation During the Actual Treatment Period.
Number of patients with at least one COPD exacerbation leading to hospitalisation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation leading to hospitalisation is presented.
Time frame: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Population: Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 5 Microgram (μg) | Number of Patients With at Least One COPD Exacerbation Leading to Hospitalisation During the Actual Treatment Period. | 469 Number of patients |
| Tiotropium (5 μg) + Olodaterol (5 μg) | Number of Patients With at Least One COPD Exacerbation Leading to Hospitalisation During the Actual Treatment Period. | 450 Number of patients |
Comparison: A Cox's proportional hazard model was used to estimate the hazard ratio and the corresponding Confidence Interval. A log-rank test was used to obtain the p-valuep-value: 0.277395% CI: [0.82, 1.06]Log Rank
Secondary
Number of Patients With at Least One Moderate to Severe COPD Exacerbation During the Actual Treatment Period.
Key secondary endpoint: Number of patients with at least one moderate to severe COPD exacerbation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation is presented.
Time frame: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Population: Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tiotropium 5 Microgram (μg) | Number of Patients With at Least One Moderate to Severe COPD Exacerbation During the Actual Treatment Period. | 1777 Number of patients |
| Tiotropium (5 μg) + Olodaterol (5 μg) | Number of Patients With at Least One Moderate to Severe COPD Exacerbation During the Actual Treatment Period. | 1746 Number of patients |
Comparison: A Cox's proportional hazard model was used to estimate the hazard ratio and the corresponding Confidence Interval. A log-rank test was used to obtain the p-valuep-value: 0.118899% CI: [0.87, 1.03]Log Rank