What is the efficacy of a cardio-selective beta-blocker (bisoprolol) taken in addition to usual care in participants with chronic obstructive pulmonary disease (COPD) over 24 months to reduce combined all-cause mortality, cardiac and respiratory hospital admissions and Major Adverse Cardiovascular Event (MACE) compared to placebo?

Study Setting: National Hospital Sri Lanka, Colombo 08 National Hospital for Respiratory Diseases, Welisara Kandy National Hopital, Kandy This is a Phase III, randomized, double blind, placebo controlled, multi-center, multi-country study to assess the efficacy of proactive treatment of cardiac risk in people with COPD. Participants will be screened for eligibility criteria and then randomized in a 1:1 ratio to one of the two treatment arms, in addition to receiving usual care for their COPD over the study duration of 24 months. Participants will receive either 1.25-5 mg Bisoprolol once daily or 1.25-5 mg Matched placebo (constitute of ProSolv powder) once daily. Randomisation will occur using a secure web-based randomisation system developed and maintained by the study sponsor, using the IBM Clinical Development electronic data capture software. Treatment allocation will be determined by computer-generated random numbers and will be fully automated via a password-protected encrypted website interface. The randomisation list will be concealed and generated centrally using a random combination of 4 by 6 permuted blocks within each stratum. Participants will be stratified for smoking (current or not) and clinical history of cardiac disease requiring current treatment. Up titration of study medication will be undertaken as recommended in the study protocol. From baseline to Visit 2 (4 Weeks), participants will be taking a daily dose of half a tablet of study medication (1.25mg bisoprolol or placebo) once daily. At the 4-week safety visit participants will be up-titrated to one whole tablet (2.5mg bisoprolol or placebo) once daily, provided they have not experienced any of the adverse events (AEs) given in the study protocol. At Visit 3 (12 Weeks) if the participant is not experiencing any AEs as outlined in the study protocol, the dose of study medication will be increased to two whole tablets (5mg bisoprolol or placebo) once daily. If any AEs have occurred, the lower will be maintained until review at the next visit. If any AEs persist throughout the study, the dosage will be reduced as per the study protocol. All dose changes are subject to investigator’s discretion. If between visits, participants experience symptoms suggesting blocker side-effects (light-headedness or falls, other manifestations of hypotension, extreme fatigability, or apparent bronchoconstriction without a clear trigger), their study medication dose will be down-titrated by the investigator. The intervention treatment will continue for 24 months.

1. Have provided written informed consent
2. Have COPD defined by the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria
3. Aged 40-85 years (both male and female)
4. Forced Expiratory Volume in one second (FEV1) ?30% and ?70% predicted post-bronchodilator
5. FEV1/Forced Vital Capacity (FVC) <0.7 post-bronchodilator
6. Have had a COPD exacerbation in the previous 12 months requiring oral corticosteroid, antibiotics, or both
7. If taking maintenance oral corticosteroids (OCS), dosage is stable and ?10mg daily for 4 weeks prior to randomisation
8. Resting systolic blood pressure (SBP) ?100mmHg
9. SBP and spirometry criteria must be met after the test dose of bisoprolol of 1.25mg.

1. Concurrent therapy with any other –? blocker
2. Resting heart rate (HR) <60bpm
3. Unstable left HF (i.e. symptomatic and/or necessary change in management in the last 12 weeks, or in investigator’s opinion)
4. Clinically significant pulmonary hypertension, which in the investigator’s opinion would be a contra-indication for ? -blocker therapy
5. Severe end-stage peripheral vascular disease
6. 2nd or 3rd degree heart block
7. Currently using or have been prescribed long-term oxygen therapy (LTOT) or resting saturated oxygen level <90% when stable
8. Expected survival is less than 12 months, or in the investigator’s opinion, the person has such unstable disease (of any type) that maintaining 12 months’ participation would be unlikely
9. Clinical instability since a major adverse cardiac event (MACE) in the previous 12 weeks
10. Lower respiratory tract infection or AECOPD within the last 4 weeks
11. COPD not clinically stable as determined by the investigator
12. In the investigator’s opinion, have asthma-COPD overlap or co-existent asthma are present; or an improvement in FEV1 ? 400mL post-bronchodilator is observed on two occasions
13. Females of child-bearing age and capability who are pregnant or breastfeeding or those in this group not using adequate birth control
14. Coexistent illness which precludes participation in the study (e.g. poorly controlled diabetes, active malignancy)
15. Severe end-stage liver disease defined by INR>1.3 and albumin<30g/L or portal hypertension/ascites
16. High chance in the opinion of the investigator that the potential participant will not adhere to study requirements.