Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: Metoprolol succinate; Placebo
Intervention description: Extended release Metoprolol succinate; Matching placebo
Intervention MeSH terms: Metoprolol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 532.0
Sex: All
Minimum age: 40 Years
Maximum age: 84 Years
Healthy volunteers: No
Keywords: Chronic Obstructive Pulmonary Disease; COPD; Exacerbation; Lung function; Cardiac; Cardiovascular; Beta blockers; Metoprolol succinate; Smoking

Summary:

      This is a multicenter, prospective, randomized, double-blind, placebo-controlled trial that
      will enroll 1028 patients with at least moderately severe COPD over a three year period and
      follow them at regular intervals for one year. The primary endpoint is time to first acute
      exacerbation. Secondary endpoints include rates and severity of COPD exacerbations,
      cardiovascular events, all-cause mortality, lung function, dyspnea, quality of life and
      metoprolol-related side effects.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male and female subjects, ≥ 40 and less than 85 years of age

          2. Clinical diagnosis of at least moderate COPD as defined by the Global Initiative for
             Obstructive Lung Disease (GOLD) criteria (53):

               -  Post bronchodilator FEV1/FVC < 70% (Forced expiratory volume in 1 second/ forced
                  vital capacity),

               -  Post bronchodilator FEV1 < 80% predicted, with or without chronic symptoms (i.e.,
                  cough, sputum production).

          3. Cigarette consumption of 10 pack-years or more. Patients may or may not be active
             smokers.

          4. To enrich the population for patients who are more likely to have acute exacerbations
             (54), each subject must meet one or more of the following 4 conditions:

               -  Have a history of receiving a course of systemic corticosteroids and/or
                  antibiotics for respiratory problems in the past year,

               -  Visiting an Emergency Department for a COPD exacerbation within the past year, or

               -  Being hospitalized for a COPD exacerbation within the past year

               -  Be using or be prescribed supplemental oxygen for 12 or more hours per day

               -  Willingness to make return visits and availability by telephone for duration of
                  study.

        Exclusion Criteria:

          1. A diagnosis of asthma established by each study investigator on the basis of the
             recent American Thoracic Society/European Respiratory Society and National Institute
             for Health and Care Excellence guidelines.

          2. The presence of a diagnosis other than COPD that results in the patient being either
             medically unstable, or having a predicted life expectancy < 2 years.

          3. Women who are at risk of becoming pregnant during the study (pre-menopausal) and who
             refuse to use acceptable birth control (hormone-based oral or barrier contraceptive)
             for the duration of the study.

          4. Current tachy or brady arrhythmias requiring treatment

          5. Presence of a pacemaker and/or internal cardioverter/defibrillator

          6. Patients with a history of second or third degree (complete) heart block, or sick
             sinus syndrome

          7. Baseline EKG revealing left bundle branch block, bifascicular block, ventricular
             tachyarrhythmia, atrial fibrillation, atrial flutter, supraventricular tachycardia
             (other than sinus tachycardia and multifocal atrial tachycardia), or heart block (2nd
             degree or complete)

          8. Resting heart rate less than 65 beats per minute, or sustained resting tachycardia
             defined as heart rate greater than 120 beats per minute.

          9. Resting systolic blood pressure of less than 100mm Hg.

         10. Subjects with absolute (Class 1) indications for beta-blocker treatment as defined by
             the combined American College of Cardiology Foundation/American Heart Association Task
             Force on Practice Guidelines, and the American College of Physicians, American
             Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association,
             Society for Cardiovascular Angiography and Interventions, and Society of Thoracic
             Surgeons Guidelines which include myocardial infarction, acute coronary syndrome,
             percutaneous coronary intervention or coronary artery bypass surgery within the prior
             3 years and patients with known congestive heart failure defined as left ventricular
             ejection fraction <40%.(29, 30)

         11. Critical ischemia related to peripheral arterial disease.

         12. Other diseases that are known to be triggered by beta-blockers or beta-blocker
             withdrawal including myasthenia gravis, periodic hypokalemic paralysis,
             pheochromocytoma, and thyrotoxicosis

         13. Patients on other cardiac medications known to cause atrioventricular (AV) node
             conduction delays such as amiodarone, digoxin, and calcium channel blockers including
             verapamil and diltiazem as well as patients taking clonidine.

         14. Hospitalization for uncontrolled diabetes mellitus or hypoglycemia within the last 12
             months.

         15. Patients with cirrhosis

         16. A clinical diagnosis of bronchiectasis defined as production of > one-half cup of
             purulent sputum/day.

         17. Patients otherwise meeting the inclusion criteria will not be enrolled until they are
             a minimum of four weeks from their most recent acute exacerbation (i.e., they will not
             have received a course of systemic corticosteroids, an increased dose of chronically
             administered systemic corticosteroids, and/or antibiotics for an acute exacerbation
             for a minimum of four weeks).