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

Beta-Blockers for the Prevention of Acute Exacerbations of COPD

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02587351

Enrollment

532

Registered

2015-10-27

Start date

2016-05-01

Completion date

2019-12-01

Last updated

2021-01-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

Chronic Obstructive Pulmonary Disease, COPD, Exacerbation, Lung function, Cardiac, Cardiovascular, Beta blockers, Metoprolol succinate, Smoking

Brief 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.

Detailed description

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.

Interventions

DRUGMetoprolol succinate

Extended release Metoprolol succinate

OTHERPlacebo

Matching placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

40 Years to 84 Years

Healthy volunteers

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).

Design outcomes

Primary

Measure	Time frame	Description
Time to First Occurrence of an Acute COPS Exacerbation	1 year	Acute exacerbations are defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness requiring treatment with antibiotics and/or systemic steroids for at least three days.

Secondary

Measure	Time frame	Description
Number of Emergency Department Visits Resulting From Acute Exacerbations of COPD	1 year	Number of Emergency Department visits resulting from acute exacerbations of COPD - rate
Number of Hospital Admissions Resulting From Acute Exacerbations of COPD	1 year	Number of hospital admissions resulting from acute exacerbations of COPD - rate
Hospital Days Resulting From Acute Exacerbations of COPD	14 months	Number of hospital days resulting from acute exacerbations of COPD reported as negative binomial estimates of mean hospital days per patient year.
Major Adverse Cardiovascular Events	12 months	Major adverse cardiovascular events (MACE), percutaneous coronary intervention or coronary artery bypass grafting. MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke
All-cause Mortality	1 year	All-cause mortality count
Incidence of Presumed Metoprolol-related Side-effects	1 year	New or worsened (Neural: depression, headache, syncope, seizures, somnolence, memory loss, loss of sexual desire or erectile dysfunction, and fatigue; Hypersensitivity: rash, pruritus, tongue or facial swelling; Gastrointestinal: diarrhea, vomiting, nausea or constipation; Cardiovascular: bradycardia and hypotension as discussed below; Respiratory: bronchospasm and changes in lung function as discussed below).
Modified Medical Research Council Dyspnea Scale (MMRC)	1 year	Modified Medical Research Council Dyspnea Scale (MMRC) change from baseline to visit day 336. The MMRC scale is a five-point scale originally published in 1959 that considers certain activities, such as walking or climbing stairs, which provoke breathlessness. Scale from 0 to 4 with lower scores indicating less breathlessness.
Forced Expiratory Volume in 1 Second (FEV1)	1 year	Change in FEV1 % Predicted from baseline to visit day 336 as assessed by spirometry
Exercise Capacity as Assessed by the 6 Minute Walk Distance (6MWD)	Baseline, 1 year	6MWD change from baseline to visit day 336. The 6MWD has been used as a simple tool to assess overall exercise tolerance in patients with chronic cardiopulmonary disease including COPD.
Markers of Systemic Inflammation	Baseline, 1 year	Fibrinogen: assessed at screening/randomization and at conclusion of the study to determine if beta-blockade impacts levels of systemic inflammation that portend overall cardiac risk.
St. George's Respiratory Questionnaire (SGRQ)	Baseline, 1 year	SGRQ change from baseline to visit day 336. The SGRQ total score change from baseline. SGRQ is a respiratory specific health status questionnaire with scores ranging from 0 to 100. The lower score indicates a better health status.
Number of Acute Exacerbations of COPD	1 year	Number of acute exacerbations of COPD - rate per person-year
San Diego Shortness of Breath Questionnaire (SOBQ)	1 year	San Diego Shortness of Breath Questionnaire (SOBQ) change from baseline. A 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. Each item has a 6-point scale (0 = not at all to 5 = maximal or unable to do because of breathlessness).
Acute Exacerbations of COPD and MACE	12 months	MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke
Short Form Health Survey (SF-36) Physical Function Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. 8 multi-item scales with higher score indicating better health state. The Physical Functioning scale is 10 items assessing the extent to which health limits physical activities such as self-care, walking, climbing stairs, bending lifting, and moderate and vigorous activities transformed to a score with a range of 0-100.
Short Form Health Survey (SF-36) Role Functioning - Physical Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The Role Functioning - Physical Scale contains 4 items assessing the extent to which physical health interferes with work or other daily activities, including accomplished less than wanted, limitations in the kind of activities. Items are transformed to a score with a range of 0-100.
Short Form Health Survey (SF-36) Role Functioning - Emotional Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The Role Functioning - Emotional Scale includes 3 items assessing extent to which emotional problems interfere with work or other daily activities. Items are transformed to a score with a range of 0-100.
Short Form Health Survey (SF-36) Energy/Fatigue Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The Energy/Fatigue Scale includes 4 items. Items are transformed to a score with a range of 0-100.
Short Form Health Survey (SF-36) Emotional Well-being Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The Emotional Well-being Scale includes 5 items assessing emotional wellbeing. Items are transformed to a score with a range of 0-100.
Short Form Health Survey (SF-36) Social Functioning Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The Social Functioning Scale includes 2 items assessing extent to which physical health or emotional problems interfere with normal social activities. Items are transformed to a score with a range of 0-100.
Short Form Health Survey (SF-36) Bodily Pain Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The Bodily Pain Scale includes 2 items assessing the intensity of pain and effect of pain on normal work, both inside and outside the house. Items are transformed to a score with a range of 0-100.
Short Form Health Survey (SF-36) General Health Scale	1 year	Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The General Health Scale includes 4 items assessing personal evaluations of health. Items are transformed to a score with a range of 0-100.
COPD Assessment Test (CAT)	Baseline, 1 year	COPD Assessment Test (CAT) change from baseline. The CAT is a simple, eight item, health status instrument for patients with COPD that provides a score of 0-40. Lower scores denote better health status.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Metoprolol Succinate Metoprolol succinate extended release tablets (50 mg) starting dose followed by a dose titration procedure which will result in a final dose of 25mg (1/2 of one tablet daily), 50 mg, or 100 mg (two tablets daily). Metoprolol succinate: Extended release Metoprolol succinate	268
Placebo Matched placebo Placebo: Matching placebo	264
Total	532

Baseline characteristics

Characteristic	Metoprolol Succinate	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	146 Participants	139 Participants	285 Participants
Age, Categorical Between 18 and 65 years	122 Participants	125 Participants	247 Participants
Age, Continuous	65.2 years STANDARD_DEVIATION 7.6	64.8 years STANDARD_DEVIATION 7.9	65.0 years STANDARD_DEVIATION 7.8
Diastolic Blood pressure - mm Hg	77.2 mm Hg STANDARD_DEVIATION 9.2	76.8 mm Hg STANDARD_DEVIATION 9.1	77.0 mm Hg STANDARD_DEVIATION 9.1
FEV1 after bronchodilation - % of predicted value	41.3 % of predicted value STANDARD_DEVIATION 16.3	40.8 % of predicted value STANDARD_DEVIATION 16.2	41.1 % of predicted value STANDARD_DEVIATION 16.3
FEV1:FVC ratio - %	44.2 ratio % STANDARD_DEVIATION 11.7	45.2 ratio % STANDARD_DEVIATION 21.6	44.7 ratio % STANDARD_DEVIATION 17.3
Race/Ethnicity, Customized Black	83 Participants	60 Participants	143 Participants
Race/Ethnicity, Customized Other	7 Participants	10 Participants	17 Participants
Race/Ethnicity, Customized White	178 Participants	194 Participants	372 Participants
Region of Enrollment United States	268 Participants	264 Participants	532 Participants
Sex: Female, Male Female	124 Participants	123 Participants	247 Participants
Sex: Female, Male Male	144 Participants	141 Participants	285 Participants
Smoking history No. of pack-yr	50.7 pack-years STANDARD_DEVIATION 28.7	49.5 pack-years STANDARD_DEVIATION 29.6	50.1 pack-years STANDARD_DEVIATION 29.1
Systolic Blood pressure - mm Hg	128.4 mm Hg STANDARD_DEVIATION 16.5	130.6 mm Hg STANDARD_DEVIATION 15.9	129.5 mm Hg STANDARD_DEVIATION 16.2

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	11 / 268	5 / 264
other Total, other adverse events	162 / 268	157 / 264
serious Total, serious adverse events	86 / 268	59 / 264

Outcome results

Primary

Time to First Occurrence of an Acute COPS Exacerbation

Acute exacerbations are defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness requiring treatment with antibiotics and/or systemic steroids for at least three days.

Time frame: 1 year

Arm	Measure	Value (MEAN)
Metoprolol Succinate	Time to First Occurrence of an Acute COPS Exacerbation	202 days
Placebo	Time to First Occurrence of an Acute COPS Exacerbation	222 days

Secondary

Acute Exacerbations of COPD and MACE

MACE defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke

Time frame: 12 months

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Metoprolol Succinate	Acute Exacerbations of COPD and MACE	Heart Failure	2 Participants
Metoprolol Succinate	Acute Exacerbations of COPD and MACE	Sudden cardiac death	0 Participants
Metoprolol Succinate	Acute Exacerbations of COPD and MACE	Stroke	1 Participants
Metoprolol Succinate	Acute Exacerbations of COPD and MACE	COPD Exacerbation (Serious)	55 Participants
Metoprolol Succinate	Acute Exacerbations of COPD and MACE	Myocardial Infarction	2 Participants
Placebo	Acute Exacerbations of COPD and MACE	COPD Exacerbation (Serious)	32 Participants
Placebo	Acute Exacerbations of COPD and MACE	Myocardial Infarction	1 Participants
Placebo	Acute Exacerbations of COPD and MACE	Heart Failure	3 Participants
Placebo	Acute Exacerbations of COPD and MACE	Stroke	1 Participants
Placebo	Acute Exacerbations of COPD and MACE	Sudden cardiac death	1 Participants

Secondary

All-cause Mortality

All-cause mortality count

Time frame: 1 year

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Metoprolol Succinate	All-cause Mortality	11 Participants
Placebo	All-cause Mortality	5 Participants

Secondary

COPD Assessment Test (CAT)

COPD Assessment Test (CAT) change from baseline. The CAT is a simple, eight item, health status instrument for patients with COPD that provides a score of 0-40. Lower scores denote better health status.

Time frame: Baseline, 1 year

Population: Participants with data at baseline and visit day 336

Arm	Measure	Value (MEAN)
Metoprolol Succinate	COPD Assessment Test (CAT)	0.88 score on a scale
Placebo	COPD Assessment Test (CAT)	-0.59 score on a scale

Secondary

Exercise Capacity as Assessed by the 6 Minute Walk Distance (6MWD)

6MWD change from baseline to visit day 336. The 6MWD has been used as a simple tool to assess overall exercise tolerance in patients with chronic cardiopulmonary disease including COPD.

Time frame: Baseline, 1 year

Population: Participants with data at baseline and visit day 336

Arm	Measure	Value (MEAN)
Metoprolol Succinate	Exercise Capacity as Assessed by the 6 Minute Walk Distance (6MWD)	-17.64 meters
Placebo	Exercise Capacity as Assessed by the 6 Minute Walk Distance (6MWD)	-11.87 meters

Secondary

Forced Expiratory Volume in 1 Second (FEV1)

Change in FEV1 % Predicted from baseline to visit day 336 as assessed by spirometry

Time frame: 1 year

Population: Participants with data at baseline and visit day 336

Arm	Measure	Value (MEAN)
Metoprolol Succinate	Forced Expiratory Volume in 1 Second (FEV1)	-2.24 percentage of predicted
Placebo	Forced Expiratory Volume in 1 Second (FEV1)	-1.46 percentage of predicted

Secondary

Hospital Days Resulting From Acute Exacerbations of COPD

Number of hospital days resulting from acute exacerbations of COPD reported as negative binomial estimates of mean hospital days per patient year.

Time frame: 14 months

Arm	Measure	Value (MEAN)
Metoprolol Succinate	Hospital Days Resulting From Acute Exacerbations of COPD	3.09 hospital days
Placebo	Hospital Days Resulting From Acute Exacerbations of COPD	0.96 hospital days

Secondary

Incidence of Presumed Metoprolol-related Side-effects

New or worsened (Neural: depression, headache, syncope, seizures, somnolence, memory loss, loss of sexual desire or erectile dysfunction, and fatigue; Hypersensitivity: rash, pruritus, tongue or facial swelling; Gastrointestinal: diarrhea, vomiting, nausea or constipation; Cardiovascular: bradycardia and hypotension as discussed below; Respiratory: bronchospasm and changes in lung function as discussed below).

Time frame: 1 year

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Depression	28 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Headache	71 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Fainting	4 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Daytime Sleepiness	58 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Memory Loss	20 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Loss of sexual desire or erectile dysfunction	10 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Lack of energy	91 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Rash	17 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Itching	11 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Tongue or facial swelling	7 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Vomiting	11 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Nausea	45 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Constipation	30 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Wheezing	88 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Shortness of breath	115 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Chest tightness	81 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Heart skipping or irregular beats	16 Participants
Metoprolol Succinate	Incidence of Presumed Metoprolol-related Side-effects	Dizziness/light headedness	74 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Wheezing	79 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Depression	39 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Tongue or facial swelling	5 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Headache	78 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Dizziness/light headedness	64 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Fainting	8 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Vomiting	18 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Daytime Sleepiness	70 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Shortness of breath	112 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Memory Loss	21 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Nausea	42 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Loss of sexual desire or erectile dysfunction	6 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Heart skipping or irregular beats	15 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Lack of energy	77 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Constipation	32 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Rash	21 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Chest tightness	80 Participants
Placebo	Incidence of Presumed Metoprolol-related Side-effects	Itching	18 Participants

Secondary

Major Adverse Cardiovascular Events

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

Time frame: 12 months

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Metoprolol Succinate	Major Adverse Cardiovascular Events	Myocardial Infarction	2 Participants
Metoprolol Succinate	Major Adverse Cardiovascular Events	Heart Failure	2 Participants
Metoprolol Succinate	Major Adverse Cardiovascular Events	Stroke	1 Participants
Metoprolol Succinate	Major Adverse Cardiovascular Events	Sudden Cardiac Death	0 Participants
Placebo	Major Adverse Cardiovascular Events	Sudden Cardiac Death	1 Participants
Placebo	Major Adverse Cardiovascular Events	Myocardial Infarction	1 Participants
Placebo	Major Adverse Cardiovascular Events	Stroke	1 Participants
Placebo	Major Adverse Cardiovascular Events	Heart Failure	3 Participants

Secondary

Markers of Systemic Inflammation

Fibrinogen: assessed at screening/randomization and at conclusion of the study to determine if beta-blockade impacts levels of systemic inflammation that portend overall cardiac risk.

Time frame: Baseline, 1 year

Arm	Measure	Group	Value (MEAN)	Dispersion
Metoprolol Succinate	Markers of Systemic Inflammation	Fibrinogen baseline	384.8 mg/dL	Standard Deviation 94.6
Metoprolol Succinate	Markers of Systemic Inflammation	Fibrinogen Visit 336	392.5 mg/dL	Standard Deviation 90.5
Placebo	Markers of Systemic Inflammation	Fibrinogen baseline	378.2 mg/dL	Standard Deviation 91.9
Placebo	Markers of Systemic Inflammation	Fibrinogen Visit 336	386.0 mg/dL	Standard Deviation 110

Secondary

Modified Medical Research Council Dyspnea Scale (MMRC)

Modified Medical Research Council Dyspnea Scale (MMRC) change from baseline to visit day 336. The MMRC scale is a five-point scale originally published in 1959 that considers certain activities, such as walking or climbing stairs, which provoke breathlessness. Scale from 0 to 4 with lower scores indicating less breathlessness.

Time frame: 1 year

Population: Participants with data at baseline and visit day 336

Arm	Measure	Value (MEDIAN)
Metoprolol Succinate	Modified Medical Research Council Dyspnea Scale (MMRC)	2.0 score on a scale
Placebo	Modified Medical Research Council Dyspnea Scale (MMRC)	2.0 score on a scale

Secondary

Number of Acute Exacerbations of COPD

Number of acute exacerbations of COPD - rate per person-year

Time frame: 1 year

Arm	Measure	Value (MEAN)
Metoprolol Succinate	Number of Acute Exacerbations of COPD	1.40 no. of events/person-yr
Placebo	Number of Acute Exacerbations of COPD	1.33 no. of events/person-yr

Secondary

Number of Emergency Department Visits Resulting From Acute Exacerbations of COPD

Number of Emergency Department visits resulting from acute exacerbations of COPD - rate

Time frame: 1 year

Arm	Measure	Value (MEAN)
Metoprolol Succinate	Number of Emergency Department Visits Resulting From Acute Exacerbations of COPD	0.17 events per person-year
Placebo	Number of Emergency Department Visits Resulting From Acute Exacerbations of COPD	0.18 events per person-year

Secondary

Number of Hospital Admissions Resulting From Acute Exacerbations of COPD

Number of hospital admissions resulting from acute exacerbations of COPD - rate

Time frame: 1 year

Arm	Measure	Value (MEAN)
Metoprolol Succinate	Number of Hospital Admissions Resulting From Acute Exacerbations of COPD	0.66 events per person-year
Placebo	Number of Hospital Admissions Resulting From Acute Exacerbations of COPD	0.42 events per person-year

Secondary

San Diego Shortness of Breath Questionnaire (SOBQ)

San Diego Shortness of Breath Questionnaire (SOBQ) change from baseline. A 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. Each item has a 6-point scale (0 = not at all to 5 = maximal or unable to do because of breathlessness).

Time frame: 1 year

Population: Participants with data at baseline and visit day 336

Arm	Measure	Value (MEAN)
Metoprolol Succinate	San Diego Shortness of Breath Questionnaire (SOBQ)	0.52 score on a scale
Placebo	San Diego Shortness of Breath Questionnaire (SOBQ)	-0.25 score on a scale

Secondary

Short Form Health Survey (SF-36) Bodily Pain Scale

Short Form Health Survey (SF-36) is a generic tool to assess overall health status and allows comparison between different diseases. Includes 8 multi-item scales with higher score indicating better health state. The Bodily Pain Scale includes 2 items assessing the intensity of pain and effect of pain on normal work, both inside and outside the house. Items are transformed to a score with a range of 0-100.

Time frame: 1 year