Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Hypothesis The primary hypothesis is that metoprolol succinate will reduce the risk of COPD
exacerbations as compared to placebo. The secondary hypothesis is that metoprolol succinate
will not adversely impact lung function, exercise tolerance, dyspnea or quality of life as
compared to placebo.

Study Flow Patients will be screened and then randomized over a 2 week period and will then
undergo a dose titration period for the following six weeks. Thereafter patients will be
followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a
4 week washout period.

Specific Aims:

Primary: To determine the effect of once daily metoprolol succinate compared with placebo on
the time to first exacerbation in moderate to severe COPD patients who are prone to
exacerbations and who do not have absolute indications for beta-blocker therapy.

Secondary: To estimate the effect of metoprolol succinate compared with placebo on:

1. The rate and severity of COPD exacerbations over 12 months

2. Incidence and severity of metoprolol-related side effects including those that require
cessation of drug

3. Lung function as assessed by spirometry, dyspnea as assessed by the Modified Medical
Research Council Scale (MMRC) and San Diego Shortness of Breath Questionnaire, exercise
tolerance as measured by six minute walk test (6MWD), and quality of life as assessed by
the Short Form 36, St. Georges Respiratory Questionnaire (SGRQ) and COPD Assessment Test
(CAT) and Personal HEART Score.

4. Hospitalizations

5. The rate of major adverse cardiovascular events (MACE) (defined by cardiovascular death,
hospitalization for myocardial infarction, heart failure, or stroke), percutaneous
coronary intervention or coronary artery bypass grafting

6. All-cause mortality

Secondary subgroup analyses for 1) cardiovascular risk based on Personal HEART Score and 2)
age greater versus less than 65.

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).