Inhaled Bronchodilators to support the use of Beta-Blockers in Chronic Obstructive Pulmonary Disease (COPD).

INTERVENTION: RESPONSE: Doubling the dose has been explained in following the text from the protocol page 6, Telephone Call: "One week after starting each treatment, participants will be contacted by telephone to enquire about possible adverse effects to the study medication including dizziness/light‐headedness, falls, worsening of respiratory symptoms. If necessary a clinic visit will be arranged to assess these symptoms. If no symptoms or only minor symptoms have been reported, the participants is willing and it is judged safe to increase the beta‐blocker dose, participants will be instructed to double the dose of beta‐blocker (taking 2 tablets each morning). If there are concerns about increasing the dose, but the participant is willing to continue in the study, the same dose can be continued (i.e. 2.5mg bisoprolol, 12.5mg carvedilol or matching placebo)." Eligible participants will undergo baseline measurements before an open‐label test dose of ß–blocker (carvedilol 12.5mg). Participants who tolerate the test dose will be randomised to one of 6 treatment regimens, a. Placebo inhaler and placebo tablet b. Placebo inhaler and carvedilol 12.5mg/25mg c. Placebo inhaler and bisoprolol 2.5mg/5mg d. Umeclidinium/vilanterol 62.5/25mcg inhaler and placebo tablet e. Umeclidinium/vilanterol 62.5/25mcg inhaler and carvedilol 12.5mg/25mg f. Umeclidinium/vilanterol 62.5/25mcg inhaler and bisoprolol 2.5mg/5mg Treatment (inhaler and tablet) will be administered once per day in the morning. Each treatment arm lasts for 14 days, however 7 days after starting each treatment, participants will be contacted by telephone to enquire about possible adverse effects to the study medication including dizziness/light‐headedness, falls, worsening of respiratory symp CONDITION: Cardiovascular ‐ Coronary heart disease COPD;Cardiac Disease; ; COPD ; Cardiac Disease Respiratory ‐ Chronic obstructive pulmonary disease PRIMARY OUTCOME: Difference in FEV1 between patients taking carvedilol and placebo with and without inhaled umeclidinium/vilanterol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines.; ; i.e. FEV1 of arms A minus B vs. D minus E; [Difference in FEV1 defined as 2 hours post participants taking carvedilol or placebo with and without inhaled umeclidinium / vilanterol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).] SECONDARY OUTCOME: Difference in 6MWT distance between patients taking bisoprolol and placebo with and without umeclidinium/vilanterol. ; ; i.e. 6MWT distance of arms A‐C vs. D‐F ; [Difference in 6MWT distance between patients taking bisoprolol and placebo with and without umeclidinium/vilanterol. at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.] Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with placebo inhaler. ; ; i.e. 6MWT distance of arms B vs. C[Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with placebo inhaler.at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.] Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with umeclidinium/vilanterol. ; ; i.e. 6MWT distance of arm E vs. F ; ; i.e. 6MWT distance of arms D vs. F ; ; i.e. 6MWT distance of arms A‐B vs. D‐E ; ; i.e. 6MWT distance of arms D vs. E ; ; ; ; i.e. FEV1 of arms A minus C vs. D minus F ; ; i.e. FEV1 of arms B vs. C ; ; i.e. FEV1 of arm E vs. F ; ; i.e. FEV1 of arms D vs. F ; [Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with umeclidinium/vilanterol at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.] Difference in 6MWT distance between patients taking bisoprolol vs. placebo while treated with umeclidinium/vilanterol. ; [Difference in 6MWT distance between patients taking bisoprolol vs. placebo while treated with umeclidinium/vilanterol at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.] Difference in 6MWT distance between patients taking carvedilol and placebo with and without umeclidinium/vilanterol. ; [Difference in 6MWT distance between patients taking carvedilol and placebo with and without umeclidinium/vilanterol. at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.] Difference in 6MWT distance between patients taking carvedilol vs. placebo while treated with umeclidinium/vilanterol ; [Difference in 6MWT distance between patients taking carvedilol vs. placebo while treated with umeclidinium/vilanterol at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.] Difference in Area Under Curve FEV1 before taking the study medication and at 1, 2, and 3 hours after administration of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol.[Difference in Area Under Curve FEV1 before taking the study medication and at 1, 2, and 3 hours after administration at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment). ; The medication/placebo combinations of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol are as described in Primary outcome 1 and Secondary outcomes 1‐5.] Difference in change in heart rate and blood pressure following carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol.[Heart rate and blood pressure will be measured between the 2nd and 3rd hour after taking the medication. ; The medication/placebo combinations of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol are as described in Primary outcome 1 and Secondary outcomes 1‐5.] Difference in FEV1 between patients taking bisoprolol and placebo with and without inhaled umeclidinium/vilanterol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines. ; [Difference in FEV1 defined as 2 hours post participants taking bisoprolol or placebo with and without inhaled umeclidinium/vilanterol. at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).] Difference in FEV1 between patients taking bisoprolol vs carvedilol while treated with placebo inhalers. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines. ; [Difference in FEV1 defined as 2 hours post participants taking bisoprolol vs carvedilol while treated with placebo inhalers at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment). ] Difference in FEV1 between patients taking bisoprolol vs carvedilol while treated with umeclidinium/vilanterol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines. ; ; i.e. FEV1 of arms D vs. E ; ; a. Withdrawals ; b. AEs & SAEs with each intervention INCLUSION CRITERIA: • Physician diagnosis of COPD • Post‐bronchodilator FEV1/FVC <0.70 ; [Difference in FEV1 defined as 2 hours post participants taking bisoprolol vs carvedilol while treated with umeclidinium/vilanterol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment). ] Difference in FEV1 between patients taking umeclidinium/vilanterol on placebo beta‐blocker and umeclidinium/vilanterol on bisoprolol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines. ; [Difference in FEV1 defined as 2 hours post participants taking umeclidinium/vilanterol on placebo beta‐blocker and umeclidinium/vilanterol on bisoprolol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment). ] Difference in FEV1 between patients taking umeclidinium/vilanterol on placebo beta‐blocker and umeclidinium/vilanterol on carvedilol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines. ; [Difference in FEV1 defined as 2 hours post participants taking umeclidinium/vilanterol on placebo beta‐blocker and umeclidinium/vilanterol on carvedilol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).] Differences in any serious adverse events (SAEs) and Adverse Events (AEs) that occurred during each intervention including: ; [Differences in any SAEs and AEs as assessed at telephone calls One week after starting each treatment and at visits 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment).] Differences in COPD Assessment Test (CAT) score (for respiratory symptoms in the last week) while on a combination of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol.[Differences in COPD Assessment Test (CAT) score (for respiratory symptoms in the last week) as assessed by the CAT questionnaire which will be completed at visits 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment), to reflect the symptoms of last 1 week. Any adverse effects will be recorded.] • Post‐bronchodilator FEV1 between 30% and 80% of predicted • Minimum 10 pack‐year smoking history • Age 40 years and over • BP and spirometry criteria must be met after test dose of carvedilol • Written informed consent