Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
To demonstrate the efficacy of inhaled tiotropium + olodaterol via Respimat® on lung function in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD) with optimal and sub-optimal Peak Inspiratory Flow Rate (PIFR). Disease severity (moderate to severe) is based on the Global Initiative for Chronic Lung Disease (GOLD) guidelines (GOLD 2 - 3)
Interventions
Oral Inhalation
DRUGPlacebo
Oral Inhalation
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
* Signed and dated written informed consent in accordance with International Council on Harmonisation Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial. * Male or female patients, 40 years of age or older. * All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) \>30% and \<80% of predicted normal (European Coal and Steel Community (ECSC), \[R94-1408\]); and a postbronchodilator FEV1/ Functional Residual Capacity (FVC) \<70%, at the screening visit. * Patients must be current or ex-smokers with a smoking history of more than 10 pack years * Patients should meet the peak inspiratory flow rate criteria (optimal or sub-optimal) at the time of randomization depending on which strata is available for inclusion in the study. * Women of childbearing potential must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. * Patients are expected to be able to perform, according to investigator's judgment, all trial related procedures including: * Technically acceptable pulmonary function tests (spirometry) * Use of In-Check DIAL G16 device to measure peak inspiratory flow rate. * Inhale medication in a competent manner (in the opinion of the investigator) from the Respimat® device * Perform technically acceptable body plethysmography measurements. This is applicable only to patients who will consent to the optional trial procedure at the selected sites.
Exclusion criteria
* Patients with a significant disease other than chronic obstructive pulmonary disease; a significant disease defined as a disease which, in the opinion of the investigator, and referring to the warnings to be observed as quoted in the locally applicable SmPC or prescribing information, could (i) put the patient at risk because of participation in the trial, (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial. * Patients who have had a chronic obstructive pulmonary disease exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to screening visit or during the screening period. * Patients who experienced two or more moderate chronic obstructive pulmonary disease exacerbations (exacerbation that required treatment with antibiotics and/or oral corticosteroids), or one or more exacerbation leading to hospitalization within a year prior to visit 1. * Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. * Patients taking inhaled corticosteroids (including combinations, e.g. inhaled corticosteroids / Long-Acting β2-agonist) in the 6 months prior to screening visit. * Patients being treated with oral corticosteroid medication due to reasons other than chronic obstructive pulmonary disease exacerbation within 6 weeks prior to the screening visit. * Patients who have completed a pulmonary rehabilitation program in the 6 weeks prior to screening visit or patients who are currently in a pulmonary rehabilitation program. * Further criteria apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment. | At baseline and at week 4: 10 minutes (min) prior and 5 min, 15 min, 30 min and 1 hour (h), 2h and 3h after drug administration, respectively. | FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters. Mean is adjusted mean. A hierarchical testing procedure was used to test the primary endpoint. Each of the tests were considered confirmatory only if all previous tests were successful. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment | At baseline and at week 4. | Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment. |
Countries
Germany, United States
Participant flow
Recruitment details
A randomised, double-blind, placebo-controlled trial to demonstrate the efficacy of 5µg/5µg inhaled tiotropium + olodaterol (Tio+Olo) via Respimat® on lung function in patients with moderate to severe chronic obstructive pulmonary disease (COPD) with optimal and sub-optimal peak inspiratory flow rate (PIFR).
Pre-assignment details
Only patients that met all inclusion and none of the exclusion criteria were included in this trial. Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. Each patient signed and dated an Informed Consent Form (ICF) according to the local regulatory and legal requirements.
Participants by arm
| Arm | Count |
|---|---|
| Tio+Olo (5μg/5μg) - Sub-optimal PIFR A fixed dose combination of 5 microgram (μg)/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (\<60 Liter(L)/minute (min)) over a 4-week treatment period. | 55 |
| Matching Placebo - Sub-optimal PIFR 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (\<60 L/min) over a 4-week treatment period. | 55 |
| Tio+Olo (5μg/5μg ) - Optimal PIFR A fixed dose combination of 5μg/5μg (two times 2.5µg/2.5µg) tiotropium + olodaterol (Tio+Olo) inhalation solution was administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with sub-optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period. | 51 |
| Matching Placebo - Optimal PIFR 2 inhalation solutions of matching placebo were administered orally once daily via Respimat inhaler in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and with optimal peak inspiratory flow rate (PIFR) (≥60 L/min) over a 4-week treatment period. | 52 |
| Total | 213 |
Baseline characteristics
| Characteristic | Tio+Olo (5μg/5μg) - Sub-optimal PIFR | Total | Matching Placebo - Optimal PIFR | Tio+Olo (5μg/5μg ) - Optimal PIFR | Matching Placebo - Sub-optimal PIFR |
|---|---|---|---|---|---|
| Age, Continuous | 64 Years STANDARD_DEVIATION 9.79 | 64.96 Years STANDARD_DEVIATION 8.25 | 65.88 Years STANDARD_DEVIATION 7.43 | 62.80 Years STANDARD_DEVIATION 7.48 | 67.05 Years STANDARD_DEVIATION 7.54 |
| Forced Expiratory Volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h) | 1.224 Liter (L) STANDARD_DEVIATION 0.06 | 1.324 Liter (L) STANDARD_DEVIATION 0.467 | 1.523 Liter (L) STANDARD_DEVIATION 0.074 | 1.388 Liter (L) STANDARD_DEVIATION 0.07 | 1.277 Liter (L) STANDARD_DEVIATION 0.079 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 51 Participants | 203 Participants | 51 Participants | 50 Participants | 51 Participants |
| Sex: Female, Male Female | 28 Participants | 109 Participants | 20 Participants | 24 Participants | 37 Participants |
| Sex: Female, Male Male | 27 Participants | 104 Participants | 32 Participants | 27 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 106 | 0 / 107 |
| other Total, other adverse events | 0 / 106 | 0 / 107 |
| serious Total, serious adverse events | 2 / 106 | 1 / 107 |
Outcome results
Primary
Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment.
FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters. Mean is adjusted mean. A hierarchical testing procedure was used to test the primary endpoint. Each of the tests were considered confirmatory only if all previous tests were successful.
Time frame: At baseline and at week 4: 10 minutes (min) prior and 5 min, 15 min, 30 min and 1 hour (h), 2h and 3h after drug administration, respectively.
Population: Full Analysis Set (FAS): This patient set was nested within the TS and included all patients who had a baseline and at least 1 post-baseline measurement for at least 1 efficacy endpoint. Only patients with non-missing endpoint results were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tio+Olo (5μg/5μg) - Sub-optimal PIFR | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment. | 0.250 Liter (L) | Standard Error 0.033 |
| Matching Placebo - Sub-optimal PIFR | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment. | -0.086 Liter (L) | Standard Error 0.031 |
| Tio+Olo (5μg/5μg ) - Optimal PIFR | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment. | 0.333 Liter (L) | Standard Error 0.032 |
| Matching Placebo - Optimal PIFR | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment. | 0.012 Liter (L) | Standard Error 0.031 |
Comparison: H0: There is no difference in the mean FEV1 AUC0-3 change from baseline between Tio+Olo and matching placebo.p-value: <0.000195% CI: [0.246, 0.425]ANCOVA
Comparison: H0: There is no difference in the mean FEV1 AUC0-3h change from baseline between Tio+Olo and matching placebo.p-value: <0.000195% CI: [0.233, 0.409]ANCOVA
Secondary
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment
Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment.
Time frame: At baseline and at week 4.
Population: FAS: This patient set was nested within the TS and included all patients who had a baseline and at least 1 post-baseline measurement for at least 1 efficacy endpoint. Only patients with non-missing endpoint results were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tio+Olo (5μg/5μg) - Sub-optimal PIFR | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment | 0.095 Liter | Standard Error 0.031 |
| Matching Placebo - Sub-optimal PIFR | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment | -0.106 Liter | Standard Error 0.03 |
| Tio+Olo (5μg/5μg ) - Optimal PIFR | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment | 0.177 Liter | Standard Error 0.03 |
| Matching Placebo - Optimal PIFR | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment | -0.040 Liter | Standard Error 0.029 |
Comparison: H0: There is no difference in the mean trough FEV1 change from baseline between Tio+Olo and matching placebo.p-value: <0.000195% CI: [0.117, 0.286]Mixed Models Analysis
Comparison: H0: There is no difference in the mean trough FEV1 change from baseline between Tio+Olo and matching placebo.p-value: <0.000195% CI: [0.135, 0.299]Mixed Models Analysis