An investigation into how adding an inhaled steroid to COPD treatment may potentially protect against heart disease.

INTERVENTION: COPD CardioProtect is an exploratory, single‐centre, laboratory‐blind, randomised controlled cross‐over trial of inhaled trial IMP on platelet reactivity and function in patients with COPD. The trial will compare the trial IMP is Budesonide 160 micrograms, Glycopyrronium bromide 9 micrograms and Formoterol fumarate dihydrate 5 micrograms in the Aerosphere device to be taken 2 inhalations twice daily [BUD/GLY/FORM also known as Trixeo Aerosphere] with the comparator medication of inhaled Glycopyrronium bromide 9 micrograms and Formoterol fumarate dihydrate 5 micrograms in the Aerosphere device to be taken 2 inhalations twice daily [GLY/FORM also known as Bevespi Aerosphere]. All participants will be issued with a SABA reliever [Salamol CFC‐Free pMDI: Salbutamol sulfate 100 microgams] alongside their allocated study treatment to be taken 1‐2 inhalations as required for relief of symptoms related to bronchospasm in COPD, up to a maximum of 8 inhalations in 24‐hours. All participants will receive both trial IMP and comparator medications during the trial. The order of treatments will be randomly allocated using an online tool embedded within the study database in a 1:1 ratio as follows: A) GLY/FORM (run‐in) for 4 weeks; BUD/GLY/FORM (Phase 1) for 4 weeks; GLY/FORM (wash‐out) for 4 weeks; GLY/FORM (Phase 2) for 4 weeks B) GLY/FORM (run‐in) for 4 weeks, GLY/FORM (Phase 1) for 4 weeks, GLY/FORM (wash‐out) for 4 weeks, BUD/GLY/FORM (Phase 2) for 4 weeks The trial will recruit 40 participants with COPD from a single centre with each participant remaining in the trial for 16 weeks. There are no follow up visits. CONDITION: Chronic Obstructive Airways Disease [COPD] ; Respiratory PRIMARY OUTCOME: Change in platelet activation measured by P‐selectin expression (unstimulated and following stimulation with escalating concentrations of ADP and collagen) using FACs analysis following treatment with inhaled BUD/GLY/FORM compared with inhaled GLY/FORM measured at 16 weeks. SECONDARY OUTCOME: Measured at 16 weeks:; 1. Platelet‐Monocyte Aggregate formation and platelet fibrinogen binding (unstimulated and following stimulation with escalating concentrations of ADP and collagen) following treatment with inhaled BUD/GLY/FORM compared with inhaled GLY/FORM.; All other platelet markers/assays (below) will be evaluated before and after treatment with inhaled BUD/GLY/FORM compared with inhaled GLY/FORM. ; 2. Platelet‐leucocyte interactions will be analysed using FACs: Whole blood will be stained with antibodies for CD45 for all white blood cells or CD14 (Monocytes) and CD16 (Neutrophils). CD41 will be used to identify platelets within these different populations to identify Platelet leucocyte aggregates. This will be completed in duplicate.; 3. Additional markers of Platelet activity will be assessed using the following assays:; 3.1. FACs: Platelet integrin IIb3 activation to escalating doses of different agonists (collagen and ADP) will be completed, in duplicate.; 3.2. Platelet aggregation: Platelet responses to escalating doses of different agonists (collagen and ADP) will be completed. ; 3.3. Platelet spreading: This technique demonstrates how well platelets adhere and activate on various matri Xproteins (fibrinogen, and collagen). These proteins are either within the thrombus (fibrinogen) or within the extracellular matri X(collagen). ; 3.4. Seahorse Analyser (Metabolism): This process identifies how platelets use energy via glycolysis and oxidative phosphorylation in both basal conditions and after stimulation with platelet agonists such as Thrombin and collagen.; 4. Additional clinical outcome measures will include:; 4.1. Spirometry (FEV‐1, FVC, FEV‐1/FVC ratio); 4.2. CAT score; 4.3. Cardiac biomarkers – high sensitivity troponin T, nt‐proBNP; INCLUSION CRITERIA: 1. Males and females aged =40 years old 2. Primary respiratory diagnosis of COPD 3. FEV‐1 <80% predicted and FEV‐1/FVC <0.7 at screening 4. Current or former smoker with at least 10 pack year smoking history 5. Able to demonstrate adequate inhaler technique with a pMDI inhaler and willing to take study medications as instructed 6. =2 moderate and/or =1 severe exacerbation of COPD (AECOPD) within the 12 months prior to recruitment* 7. Willing to undertake study procedures and assessments 8. Provided written informed consent * A moderate exacerbation is classified as an AECOPD treated with oral antibiotics and/or corticosteroids without ED attendance and/or hospitalisation. A severe AECOPD is one that requires ED attendance and/or hospitalisation