Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The objectives of the study are to explore the effect of treatment with tiotropium + olodaterol fixed dose combination (FDC) compared to fluticasone propionate + salmeterol FDC on: * reversal of left ventricular diastolic dysfunction assessed with cardiac magnetic resonance (CMR) imaging, * measures of arterial stiffness assessed by CMR and pulse wave analysis (PWA), * reduction of hyperinflation assessed with body plethysmography and * post dose spirometry.
Interventions
DRUGTiotropium
Fixed Dose Combination
DRUGOlodaterol
Fixed Dose Combination
DRUGFluticasone propionate
Fixed Dose Combination
DRUGSalmeterol
Fixed Dose Combination
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* All patients must sign an informed consent consistent with International Council on Harmonisation - Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions. * All patients must have a diagnosis of chronic obstructive pulmonary disease for which they are treated with one or more long-acting inhaled bronchodilators prior to enrolment and must meet the following spirometric criteria: Patients must have stable airway obstruction with a post-bronchodilator Forced Expiratory Volume in 1st second (FEV1) \< 70% of predicted normal calculated with European Coal and Steel Community (ECSC) formulas, and a post-bronchodilator FEV1/Forced Vital Capacity (FVC)\< 70% at Visit 1 * Patients with hyperinflation at rest defined as Functional Residual capacity (FRC) \> 120 % predicted, with post-bronchodilator reversibility greater than and equal to 7,5 % predicted at Visit 1. * Male or female patients between 40 and 75 years of age (inclusive) on day of signing informed consent. * Patients with a smoking history of more than 10 pack years. * Patients with Modified Medical Research Council (mMRC) Dyspnoea score \> 1 at Visit 1. * Patients must be able to perform technically acceptable pulmonary function tests (spirometry and body plethysmography), Cardiac Magnetic Resonance (CMR), brachial blood pressure measurements with Pulse Wave Analysis (PWA) and other tests during the study period as required in the protocol. * Patients must be able to inhale medication in a competent manner from the Respimat and Accuhaler inhalers and from a metered dose inhaler (MDI).
Exclusion criteria
* Patients with a significant disease other than Chronic Obstructive Pulmonary Disease (COPD). * Patients with a clinically relevant abnormal baseline haematology, blood chemistry, or creatinine. * Patients with a diagnosis of asthma. * Patients with a COPD exacerbation in the 6 weeks prior to screening (Visit 1) and patients who experience COPD exacerbation or respiratory tract infection during the washout phase prior to randomisation. * A history of myocardial infarction, cerebrovascular event or coronary artery intervention other than Coronary Artery Bypass Graft (CABG) within 1 year of screening. * Abnormal and clinically significant 12-lead Electrocardiogram (ECG). * Hospitalized for heart failure within the past year. Current severe heart failure (New York Heart Association (NYHA) class IV. Ejection fraction \<= 40% from Cardiac Magnetic Resonance (CMR) baseline assessment. * Patients with systolic blood pressure \> 140mmHg and/or diastolic blood pressure \> 90mmHg at Visit 1. * A diagnosis of thyrotoxicosis. * Known active tuberculosis, cardiac sarcoidosis. * Any malignancy unless free of disease for at least five years. * A history of cystic fibrosis. * Clinically evident bronchiectasis. * Patients with severe emphysema requiring endobronchial interventions within 6 months prior to screening. * A history of significant alcohol or drug abuse. * Patients who have undergone thoracotomy with pulmonary resection. * Patients being treated with any oral ß-adrenergics. * Patients being treated with oral corticosteroid medication within 6 weeks prior to Visit 1. * Patients being prescribed long-term home oxygen treatment. * Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit or patients who are currently in a pulmonary rehabilitation program. * Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit. * Patients with known hypersensitivity to ß-adrenergics drugs, anticholinergic drugs, fluticasone propionate or to any of the excipients, Benzalkonium chloride (BAC), Disodium edentate (EDTA) or Lactose monohydrate (which contains milk proteins) or any other component of the Respimat® or Accuhaler® delivery systems. * Women who are pregnant, nursing, or who plan to become pregnant while in the trial. * Women of childbearing potential not using highly effective methods of birth control. * Patients who have previously been enrolled in this study or are currently enrolled in another study. * Patient who are unable to comply with pulmonary medication restrictions prior to randomisation * Patients with pacemakers and metal implants (i.e. vascular clips and stents, metal silver in patient's eye) and patients with claustrophobia, due to contraindications for CMR.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment | Baseline and 6 weeks | LVEDVI is normalised left ventricular end diastolic volume, divided by body surface area. Baseline was defined as the value obtained during the assessment performed in a week prior to Visit 2 (Day 1). The change from baseline was calculated as the value obtained in a week prior to Visits 3 and 4 (end of each treatment periods) minus the baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pulmonary Artery Pulsatility After 6 Weeks of Treatment | Baseline and 6 weeks | Change from baseline in pulmonary artery pulsatility (PAP) is presented. Pulmonary artery pulsatility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries. |
| Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment | Baseline and 6 weeks | Change from baseline in central systolic pressure is presented. |
| Change From Baseline in Pulse Pressure After 6 Weeks of Treatment | Baseline and 6 weeks | Change from baseline in pulse pressure is presented. |
| Change From Baseline in Aortic Distensibility After 6 Weeks of Treatment | Baseline and 6 weeks | Change from baseline in aortic distensibility is presented. Aortic distensibility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries. |
| Change From Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment | Baseline and 6 weeks | Change from Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % predicted is presented. Functional residual capacity, percent predicted is a lung volume at the end of normal expiration assessed/measured by body plethysmography and compared to predicted capacity for such subject, if nonsmoker and without a disease which could compromise their ventilator function, to give a percentage predicted. |
| Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment | Baseline and 6 weeks | Change from baseline in 1.5 hour post dose Forced Expiratory Volume in 1st second (FEV1) is presented. |
| Change From Baseline in 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment | Baseline and 6 weeks | Change from baseline in 1.5 hour post dose Forced Vital Capacity (FVC) is presented. |
| Change From Baseline in Aortic Augmentation Index After 6 Weeks of Treatment | Baseline and 6 weeks | Change from baseline in aortic augmentation index is presented. Augmentation index was derived from brachial pulse wave separation analysis as augmentation pressure (pressure difference between the reflection wave to the ejection wave) divided by central pulse pressure (at the central aortic site) multiplied by 100. |
Countries
Germany
Participant flow
Recruitment details
Randomised, double-blind, active-controlled, two-period cross-over study in patients with chronic obstructive pulmonary disease (COPD) to investigate effect of 6-week treatment of tiotropium + olodaterol fixed dose combination (FDC) with fluticasone propionate + salmeterol FDC orally inhaled by the Respimat® and Accuhaler® inhaler respectively.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensured that all patients met all inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| Total Patients Patients orally inhaled total 2 inhalations daily (one inhalation in the morning and evening) via Accuhaler® inhaler of 1000 microgram (μg) fluticasone propionate + 100 μg salmeterol dry powder for inhalation (F+S 1000/100) (500 μg / 50 μg per actuation) or orally inhaled 2 inhalations once daily (in the morning) via Respimat® inhaler of 5 μg tiotropium + 5 μg olodaterol inhalation solution (T+O 5/5) (2.5 μg /2.5 μg per actuation). Patients were randomly assigned to a treatment sequence in two 6-week periods. There was no washout between treatments. | 76 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 0 | 1 |
| Period 1 | Lost to Follow-up | 1 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 4 |
| Period 2 | Adverse Event | 0 | 1 |
| Period 2 | Other than listed | 1 | 1 |
Baseline characteristics
| Characteristic | Total Patients |
|---|---|
| Age, Continuous | 61.86 Years STANDARD_DEVIATION 7.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 75 Participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 74 |
| other Total, other adverse events | 7 / 70 | 13 / 74 |
| serious Total, serious adverse events | 0 / 70 | 2 / 74 |
Outcome results
Primary
Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment
LVEDVI is normalised left ventricular end diastolic volume, divided by body surface area. Baseline was defined as the value obtained during the assessment performed in a week prior to Visit 2 (Day 1). The change from baseline was calculated as the value obtained in a week prior to Visits 3 and 4 (end of each treatment periods) minus the baseline value.
Time frame: Baseline and 6 weeks
Population: FullAnalysisSet (FAS)ExcludingExacerbation (FAS-EE) nested within FAS and data from patients who had an exacerbation during treatments were excluded from this set. FAS nested within treated set and included patients who had baseline measurement and at least one post-baseline measurement for primary or secondary endpoints. (Including available data)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment | 2.855 Millilitre/ meter^2 (mL/m^2) | Standard Error 1.137 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment | 2.317 Millilitre/ meter^2 (mL/m^2) | Standard Error 1.136 |
Comparison: Mixed model repeated measures (MMRM) model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation. H0: Mean change from baseline in LVEDVI for (Tiotropium + Olodaterol) = Mean change from baseline in LVEDVI for (Fluticasone propionate + Salmeterol)p-value: 0.633195% CI: [-2.779, 1.705]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment
Change from baseline in 1.5 hour post dose Forced Expiratory Volume in 1st second (FEV1) is presented.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in FEV1.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment | 0.158 Litre (L) | Standard Error 0.037 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment | 0.339 Litre (L) | Standard Error 0.037 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: <0.000195% CI: [0.121, 0.24]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment
Change from baseline in 1.5 hour post dose Forced Vital Capacity (FVC) is presented.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in FVC.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment | 0.159 Litre (L) | Standard Error 0.054 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment | 0.445 Litre (L) | Standard Error 0.054 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: <0.000195% CI: [0.171, 0.4]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in Aortic Augmentation Index After 6 Weeks of Treatment
Change from baseline in aortic augmentation index is presented. Augmentation index was derived from brachial pulse wave separation analysis as augmentation pressure (pressure difference between the reflection wave to the ejection wave) divided by central pulse pressure (at the central aortic site) multiplied by 100.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in aortic augmentation index.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in Aortic Augmentation Index After 6 Weeks of Treatment | 1.723 Percentage of index (%) | Standard Error 1.175 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in Aortic Augmentation Index After 6 Weeks of Treatment | 1.404 Percentage of index (%) | Standard Error 1.175 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: 0.83395% CI: [-3.341, 2.702]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in Aortic Distensibility After 6 Weeks of Treatment
Change from baseline in aortic distensibility is presented. Aortic distensibility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in aortic distensibility.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in Aortic Distensibility After 6 Weeks of Treatment | -0.006 Percentage/millimeter of mercury(%/mmHg) | Standard Error 0.036 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in Aortic Distensibility After 6 Weeks of Treatment | -0.005 Percentage/millimeter of mercury(%/mmHg) | Standard Error 0.036 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: 0.981795% CI: [-0.072, 0.074]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment
Change from baseline in central systolic pressure is presented.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in central systolic pressure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment | 0.202 mmHg | Standard Error 1.559 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment | 2.271 mmHg | Standard Error 1.559 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: 0.268795% CI: [-1.64, 5.779]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment
Change from Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % predicted is presented. Functional residual capacity, percent predicted is a lung volume at the end of normal expiration assessed/measured by body plethysmography and compared to predicted capacity for such subject, if nonsmoker and without a disease which could compromise their ventilator function, to give a percentage predicted.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in FRCpleth.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment | -10.211 Percentage of FRCpleth (%) | Standard Error 2.066 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment | -18.168 Percentage of FRCpleth (%) | Standard Error 2.065 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: 0.001995% CI: [-12.865, -3.05]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in Pulmonary Artery Pulsatility After 6 Weeks of Treatment
Change from baseline in pulmonary artery pulsatility (PAP) is presented. Pulmonary artery pulsatility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in pulmonary artery pulsatility.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in Pulmonary Artery Pulsatility After 6 Weeks of Treatment | -0.175 Percentage of PAP (%) | Standard Error 1.837 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in Pulmonary Artery Pulsatility After 6 Weeks of Treatment | 1.105 Percentage of PAP (%) | Standard Error 1.836 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: 0.523895% CI: [-2.719, 5.279]Mixed model repeated measures (MMRM)
Secondary
Change From Baseline in Pulse Pressure After 6 Weeks of Treatment
Change from baseline in pulse pressure is presented.
Time frame: Baseline and 6 weeks
Population: FAS-EE set including participants with available data for change from baseline in pulse pressure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | Change From Baseline in Pulse Pressure After 6 Weeks of Treatment | 0.170 mmHg | Standard Error 1.014 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | Change From Baseline in Pulse Pressure After 6 Weeks of Treatment | 0.579 mmHg | Standard Error 1.014 |
Comparison: MMRM model included treatment and period as fixed effects, patient as a random effect and baseline as covariate. Unstructured covariance structure was used for within patient variation.p-value: 0.760495% CI: [-2.264, 3.082]Mixed model repeated measures (MMRM)