Cardiovascular Function in COPD Patients
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: Tiotropium; Olodaterol; Fluticasone propionate; Salmeterol
Intervention description: Fixed Dose Combination; Fixed Dose Combination; Fixed Dose Combination; Fixed Dose Combination
Intervention MeSH terms: Fluticasone; Xhance; Tiotropium Bromide; Salmeterol Xinafoate; Olodaterol
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 76.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.